# Nutraceuticals in the management of autonomic function and related disorders: A comprehensive review

Paulo César Trindade Costa, Micaelle Oliveira de Luna Freire, Daniella de Oliveira Coutinho, Murielle Godet, Marciane Magnani, Vagner Roberto Antunes, Evandro Leite de Souza, Hubert Vidal, José Luiz de Brito Alves

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Paulo César Trindade Costa, Micaelle Oliveira de Luna Freire, Daniella de Oliveira Coutinho, Murielle Godet, Marciane Magnani, et al.. Nutraceuticals in the management of autonomic function and related disorders: A comprehensive review. Pharmacological Research, 2024, 208, pp.107368. 10.1016/j.phrs.2024.107368. hal-04720035

HAL Id: hal-04720035

https://hal.inrae.fr/hal-04720035v1

Submitted on 3 Dec 2025

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_2.png" /></figure>
<figure><img src="image_3.png" /></figure>

# Nutraceuticals in the management of autonomic function and related disorders: A comprehensive review

<figure><img src="image_4.png" /></figure>

Check for
updates

Paulo César Trindade Costa<sup>a,b</sup>, Micaelle Oliveira de Luna Freire<sup>a</sup>,
Daniella de Oliveira Coutinho<sup>a</sup>, Murielle Godet<sup>b</sup>, Mariane Magnani<sup>c</sup>,
Vagner Roberto Antunes<sup>d</sup>, Evandro Leite de Souza<sup>a</sup>, Hubert Vidal<sup>b</sup>, José Luiz de Brito Alves<sup>a,*</sup>

## ARTICLE INFO

### Keywords:

Nutraceuticals

Autonomic function, brain-gut axis

Cardiac autonomic control

## ABSTRACT

Nutraceuticals have been described as phytocomplexes when derived from foods of plant origin or a pool of secondary metabolites when derived from foods of animal origin, which are concentrated and administered in an appropriate form and can promote beneficial health effects in the prevention/treatment of diseases. Considering that pharmaceutical medications can cause side effects, there is a growing interest in using nutraceuticals as an adjuvant therapeutic tool for several disorders involving autonomic dysfunction, such as obesity, atherosclerosis and other cardiometabolic diseases. This review summarizes and discusses the evidence from the literature on the effects of various nutraceuticals on autonomic control, addressing the gut microbiota modulation, production of secondary metabolites from bioactive compounds, and improvement of physical and chemical properties of cell membranes. Additionally, the safety of nutraceuticals and prospects are discussed. Probiotics, resveratrol, quercetin, curcumin, nitrate, inositol, L-carnosine, and n-3 polyunsaturated fatty acids (n-3 PUFAs) are among the nutraceuticals most studied to improve autonomic dysfunction in experimental animal models and clinical trials. Further human studies are needed to elucidate the effects of nutraceuticals formulated on multitarget compounds and their underlying mechanisms of action, which could benefit conditions involving autonomic dysfunction.

## 1. Introduction

Nutraceuticals are defined as phytocomplexes when derived from plant-origin foods or a pool of secondary metabolites when derived from animal-origin foods, which are concentrated and administered in an appropriate form, with beneficial effects in the prevention or treatment of diseases [1]. The side effects and drug tolerance associated with pharmaceutical medications have heightened interest in nutraceuticals as an adjunctive therapeutic tool for various diseases, among them, autonomic nervous system (ANS) dysfunction can be counteracted by several nutraceuticals, avoiding its detrimental consequences [2-4].

The ANS is one of the major systems that account for regulating body homeostasis [5]. ANS is divided into the sympathetic nervous system (SNS), parasympathetic nervous system (PNS), and enteric nervous system [5-7]. The enteric nervous system has a close relationship with

the detection of metabolites produced by the gut microbiota, which send afferent signals to the central nervous system (CNS). In addition, gut-derived endotoxins and pro-inflammatory cytokines in the blood circulation can reach the brain or be detected by brain cells, leading to neuroinflammation and consequently autonomic dysfunction. In addition, the reduction of beneficial secondary metabolites with anti-inflammatory properties, such as short-chain fatty acids (SCFAs) and nitric oxide (NO) in the blood circulation or brain, may contribute to autonomic dysfunction [8-10]. Furthermore, the impairment of vascular function due to autonomic dysfunction is characterized as an aggravating factor in these situations due to alterations in factors related to endothelial function. [11].

In this sense, nutraceuticals have a good potential of treatment because they can exert a range of beneficial effects on the gut microbiota and gut barrier integrity, besides stimulating the production of

<footnote><sup>a</sup> Department of Nutrition, Federal University of Paraíba, João Pessoa, PB, Brazil</footnote>

<footnote><sup>b</sup> Laboratoire CarMeN, INSERM U.1060, INRAe U. 1397, Université Claude Bernard Lyon1, Pierre Bénite, France</footnote>

<footnote><sup>c</sup> Department of Food Engineering, Federal University of Paraíba, João Pessoa, PB, Brazil</footnote>

<footnote><sup>d</sup> Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil</footnote>

<footnote>* Correspondence to: Federal University of Paraíba, Department of Nutrition, Campus I - Jd, Cidade Universitária, João Pessoa, PB 58051-900, Brazil.
E-mail address: jose.luiz@academico.ufpb.br (J.L. de Brito Alves).</footnote>
secondary metabolites for the blood circulation and the brain and improving electrophysiological signals through modification of cell membrane structure and function [3,12,13]. However, the effects of nutraceuticals on health-related parameters could vary according to the origin/nature of these products and the pharmaceutical formula used to deliver them [14-16].

Considering the importance and beneficial effects of different nutraceuticals in the prevention and treatment of autonomic dysfunction [17-19], this review summarizes and discusses the evidence in the literature about the effects of different nutraceuticals on autonomic control, addressing the gut microbiota modulation, production of secondary metabolites from bioactive compounds, and improvement of physical and chemical properties of cell membranes. Additionally, the safety of nutraceuticals and prospects are discussed.

## 2. Nutraceuticals: definition and main compounds

There is a growing interest in the development of nutraceuticals since these products contain natural-origin compounds with preventive and therapeutic effects on diseases [14-16]. In 1989, Stephen DeFelice defined the term "nutraceutical" as "foods or parts of foods that provide medical or health benefits, including the prevention and treatment of disease" [20]. The concept of nutraceuticals has evolved continuously over the years, with significant variations between countries, and there is currently no definitive consensus on a precise definition [1,20].

Nutraceuticals are concentrated and administered in an appropriate pharmaceutical formulation that can promote beneficial health effects in the prevention or treatment of diseases [1]. Foods bioactive compounds and probiotics can be considered nutraceuticals when formulated in a suitable pharmaceutical form and not in a food matrix [21,22].

Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" [23]. Although several bacterial strains have been studied regarding their claimed probiotic effects, *Lactobacillus* and *Bifidobacterium* genera stand out as the most widely used in clinical practice [24,25]. Pre-clinical and clinical studies have documented the evidence related to several strains with probiotic properties and their health benefits on the host health. The bidirectional interactions between the gut microbiota and central nervous system could provide communication along the gut-brain axis [4, 26-28] linked to modulatory effects on gut microbiota [29,30], improved metabolic and inflammatory parameters [31,32], reduced oxidative stress [33], and lowered sympathetic hyperactivity and blood pressure (BP), which are indicative of improved autonomic function [17, 30,34].

Phenolic compounds are a group of phytochemicals with various reported beneficial effects on health [35,36]. Quercetin and resveratrol have received the most attention among dietary phenolic compounds due to their strong antioxidant and anti-inflammatory effects [37,38], and ability to modulate autonomic function [39], improving endothelial function, lowering BP, and changing lipid profile, leading to reduced cardiovascular risk [40-44]. Most dietary phenolic compounds cannot be absorbed in the small intestine, reaching the colon to be fermented by gut microbiota with the production of derived metabolites better absorbed and more bioactive than their parental molecules [45,46]. Additionally, other compounds acting through similar mechanisms have been investigated regarding their effects on human health, such as nitrate [47], curcumin [48], L-carnosine [49], inositol [50], vitamins, and amino acids [51,52].

n-3 PUFAs, such as alpha-linolenic acid (ALA) and its derivatives, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), derived from food sources, such as vegetable oils, blue ocean fish, and fish oil, have been investigated as potential nutraceuticals [53]. Studies have shown that n-3 PUFAs ingestion can decrease the production of inflammatory, vasodilatory, and antiaggregatory signaling molecules, reducing inflammation, inhibiting thrombosis, and promoting atherosclerotic plaque stabilization [54-56]. High doses of n-3 PUFAs were

shown effective in improving lipid profile, decreasing plasma TG, and increasing HDL-c concentrations [57,58]. In addition, EPA and DHA exert beneficial effects on ANS with improvement in the heart rate (HR) variability due to increased vagal tone [59-61].

Prebiotics are defined as "a substrate that is selectively utilized by host microorganisms to confer a health benefit" [62]. In general, established prebiotics, such as fructans, fructooligosaccharides (FOS), inulin, galactans, and galactooligosaccharides, are not digested in the small intestine and exert beneficial effects by promoting the growth of beneficial bacteria in the intestine [62,63]. In contrast to traditional approaches focusing on a single compound, a nutraceutical could provide a wider range of health benefits to the host. This approach is based on the idea that different compounds can interact in the body in complex and complementary ways, leading to an enhanced biological effect. Besides the benefits arising from the diversity of compounds in nutraceuticals, the nutraceuticals market has grown in recent years, reflecting the increasing consumer demand for alternative health solutions and the recognition of these product's efficacy.

## 3. Autonomic nervous system and blood pressure control

There is a close relationship between the ANS and the vascular system, with evidence of mutual regulatory interactions between the two systems [11]. Vascular function and the ANS may be affected by the same factors, such as asymmetric dimethylarginine (ADMA), NO, ROS, endothelin, and the renin-angiotensin system [11]. ADMA is responsible for inhibiting the production of NO, an important vasodilator at the vascular level and a neurotransmitter involved in the autonomic regulation of vascular function [11]. ROS can also decrease the bioavailability of NO, and oxidative stress at the central level is responsible for increasing sympathetic activation and consequently BP [64]. Increased ROS may also occur due to elevated angiotensin II, which upregulates NADPH oxidase through activation of type 1 receptors [65]. Furthermore, reduced NO availability appears to allow increased endothelin, which causes vasoconstriction and exerts central effects on the regulation of vasomotor tone [66]. Therefore, important central autonomic control structures and the main mechanisms of blood pressure control are discussed below.

### 3.1. Anatomy of the autonomic nervous system

The anatomical division of the ANS is organized by a topographic distribution into zones of the spinal cord. SNS neurons are essentially located at the thoracolumbar level, whereas PNS neurons are primarily located in the craniosacral medullary topography [5,7]. The neurotransmitters involved in the SNS and PNS are primarily acetylcholine, noradrenaline, and epinephrine. In general, the preganglionic fibers of SNS and PNS use acetylcholine as a neurotransmitter, as do the post-ganglionic fibers of the PNS [7,67]. On the other hand, the neurotransmitter of the postganglionic fibers of the SNS is noradrenaline. Without the action of a postganglionic neuron, adrenaline can be produced in the adrenal medulla and enter the bloodstream [7,67].

The main CNS nuclei responsible for activation of the ANS are the nucleus of the solitary tract (NTS), the rostral ventrolateral medulla (RVLM), and the caudal ventrolateral medulla (CVLM) in the brainstem, and the paraventricular nucleus of the hypothalamus (PVN) (Fig. 1) [68-72]. PVN is an important brain region regulating sympathetic vasomotor tone through projections to the intermediolateral column and RVLM, which is a major source of sympathetic stimulation to the vascular system. The effect of sympathetic tone depends on the greater or lesser activity of RVLM neurons, which increases or decreases the discharge frequency of preganglionic neurons located in the intermediolateral column of the spinal cord. The NTS can suppress RVLM activity through the CVLM, a column of neurons that extends into the RVLM to inhibit it and alter sympathetic tone [68-72].
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Neural control mechanisms of blood pressure. The neural control of BP is mediated by CNS nuclei responsible for autonomic control. A reduction or increase in BP promotes the activation of baroreceptors and chemoreceptors (located in the aortic arch and carotid sinus), which send afferent messages to the CNS. The NTS is one of the regions responsible for receiving these afferent signals and sending projections to nuclei involved in the activation or inhibition of the sympathetic nervous system. To increase sympathetic drive, the NTS can send projections to the PVN, a region of the hypothalamus known to regulate vasomotor tone, via excitatory projections to the RVLM. Conversely, to suppress sympathetic tone, the NTS can activate the CVLM, which in turn extends inhibitory projections to the RVLM, resulting in reduced sympathetic activity. These autonomic control mechanisms affect the determinants of BP by increasing or decreasing cardiac output and vasoconstrictor and vasodilator mediators. **Abbreviations:** NO: nitric oxide; ADMA: asymmetric dimethylarginine; ROS: reactive species of oxygen; RAAS: renin–angiotensin–aldosterone system; CVLM: caudal ventrolateral medulla; NTS: nucleus of the solitary tract; RVLM: rostral ventrolateral medulla; PVN: paraventricular nucleus.</figcaption></figure>

## 3.2. Blood pressure control

The functional organization of SNS and PNS has been considered antagonistic, but it is now known that in addition to performing opposing functions, these systems can work synergistically, complementarily, or independently to control autonomous effector targets [5,6,73]. The main mechanism for short-term control of BP, also called neural control of circulation (Fig. 1), is provided by feedback reflexes originating from baroreceptors, which are mechanoreceptors located primarily in the aortic arch and carotid sinus that respond to deformation or stretch induced by pressure in the vessel wall [74,75]. Baroreceptors detect fluctuation in the BP at every heart beating and decrease or increase in BP triggers action potentials from these receptors that reaches the CNS nuclei responsible for regulating the ANS, which in turn promotes responses to HR control, cardiac contractility, and vascular tone [76–78].

Another mechanism related to BP control is the chemoreflex, mainly through the action of peripheral chemoreceptors [79,80]. These receptors are located mainly in the aortic arch and carotid body and can detect changes mainly in the partial pressures of oxygen, but also in the carbon dioxide and arterial blood pH [81,82]. The peripheral chemoreflex contributes to cardiorespiratory control, by increasing ventilation and activating the SNS and PNS [82,83]. Increased activation of the peripheral chemoreflex is associated with pathophysiological conditions such as sympathetic hyperactivity, neurogenic hypertension, heart failure, and metabolic dysfunction [79,80,84,85].

Preclinical and clinical studies have shown that dysfunction in these

CNS areas influences baroreflex and chemoreflex dysfunction and sympathetic hyperactivity, resulting in elevated BP [9,10,69,86,87]. Activation of PVN neurons by microinjection of excitatory amino acid receptor agonists lead to increase in sympathetic outflow and mean arterial pressure (MAP) in animal models of hypertension. Conversely, the inhibition of PVN neurons leads to reduction in BP, highlighting the involvement of PVN with systemic arterial hypertension (SAH) [69,88].

In addition, gut dysbiosis, systemic inflammation, and gut microbiota-derived secondary metabolites can alter endothelial and autonomic function [89]. In the next topic we will discuss the role of gut microbiota in altering autonomic function via the vagus nerve and systemic inflammation.

## 4. The impact of dysbiosis on autonomic nervous system function and central nervous system inflammation

The gut microbiota consists of a highly diverse set of microorganisms, including fungi, viruses, protozoa, and helminths, but it is predominantly composed of bacteria [90]. These microorganisms live in symbiosis in the gastrointestinal tract and can influence the health condition of the host [90,91]. One of the ways of interaction between gut microbiota and the host is through the immune system, promoting the protection of the gut barrier, modulation of regulatory T cells (Treg), and microglia, which are immune cells present in CNS and play a significant role in inflammatory responses [92,93]. The gut epithelium, combined with the immune system action, protects the gut from pathogens and other harmful stimuli. However, perturbations in the
composition, diversity, and function of the gut microbiota predispose
the host to pro-inflammatory conditions [94–96].

In recent years, the crossover mechanism between gut dysbiosis and neuroinflammation has been attributed to the bidirectional communication between the gut and CNS, named the gut-brain axis [89]. Functions of this axis include ANS activation, immune system regulation, and production of neurotransmitters and gut hormones [97]. However, evidence suggests that dysfunctions in the gut-brain axis may affect the ANS and cardiac and vascular functions in different ways [8,98,99].

4.1. Vagal response

Direct bidirectional communication through the vagus nerve is one
of the reported gut-brain connecting pathways. Among the known
mechanisms, gut microbiota-derived neurotransmitters, including se-
rotonin, dopamine, gamma-aminobutyric acid (GABA), and noradren-
aline, modulate vagus nerve activity [100], while the colonic afferents of
the vagus nerve act controlling the brain nuclei responsible for ANS
activity [101]. Furthermore, the role of the vagus nerve in inflammation
has been associated with the cholinergic immune pathway, which will
be discussed below.

Gut exposure to harmful agents, such as elevated lipopolysaccharides (LPS), promotes the activation of innate immune cells by triggering a vagus nerve-related inflammatory reflex [102,103]. The increase in

pro-inflammatory cytokines, such as IL-1β, activates the sensory afferent fibers of the vagus nerve by binding to the glomus cells of the vagal paraganglia, which express IL-1 receptors [104–106].

These vagal afferent fibers originate from different layers of the in-
testine and ascend to the NTS and then to the area postrema [107,108].
The NTS, the area postrema, and the dorsal motor nucleus of the vagus
(DMVN), together compose the dorsal vagal brainstem complex [107].
The information sent from the NTS to the DMVN activates the function
of vagal efferent pathways, which promotes a reduction in the release of
inflammatory cytokines from tissue macrophages through the secretion
of acetylcholine (ACh) by the distal end of the vagus nerve. This
mechanism became known as the cholinergic anti-inflammatory
pathway [102,109].

The NTS is also responsible for sending vagal projections to other
regions of the CNS that make up the central autonomic network, such as
the locus coeruleus, parabrachial nucleus, central nucleus of the
amygdala, periventricular nucleus of the thalamus, arcuate nucleus of
the hypothalamus, PVN and RVLM [103,107,110]. Projections from the
NTS to corticotropin-releasing factor neurons in the PVN induce pitui-
tary release of adrenocorticotropic hormone, which stimulates adrenal
secretion of glucocorticoids, known as the anti-inflammatory pathway of
the hypothalamic-pituitary-adrenal (HPA) axis [102,107]. Under
stressful situations, such as an increase in systemic pro-inflammatory
cytokines, the HPA axis is activated to promote the inhibition of

<figure><img src="image_6.png" /><figcaption>**Fig. 2. Vagal immune reflex stimulated by gut microbiota.** In dysbiosis, increased levels of LPS in the gut are translated into increased levels of proinflammatory cytokines through the interaction of this endotoxin with TLR4 receptors expressed on immune cells and consequent activation of the NF-κB complex. Afferent pathways of the vagus nerve detect the increase in proinflammatory cytokines and normally send efferent signals to the celiac ganglion by releasing ACh. This in turn sends signals to the spleen to release NE in lymphocytes, which release ACh to macrophages, inhibiting the production of proinflammatory cytokines and preventing the increase of systemic inflammation. In addition, signals are sent from the celiac ganglion to immune cells in the intestine, where ACh uses the same mechanism to attenuate local inflammation. **Abbreviations:** LPS: Lipopolysaccharides; TNF-α: tumor necrosis factor-α; IL-1β: Interleukin 1β; TLR4: Toll-like receptor 4; NF-κB: nuclear factor kappa B; ACh: Acetylcholine; NE: noradrenaline; HPA: hypothalamic-pituitary-adrenal; a7nAChr: alpha-7 nicotinic receptor; TNF-αr: tumor necrosis factor-α receptor; IL-1βr: Interleukin 1β receptor.</figcaption></figure>
peripheral inflammation, through the secretion of cortisol, which binds to NF-κB receptors on immune cells, preventing the secretion of pro-inflammatory cytokines [103,107,109,111].

Therefore, a reduction in the vagus nerve immune response, which is found in several pathologies characterized by dysbiosis, impairs the reduction of both local and systemic inflammation, contributing to neuroinflammation (Fig. 2). In addition, other mechanisms related to the dysfunction of the gut microbiota and the gut barrier are associated with neuroinflammation, such as the translocation of endotoxins and proinflammatory cytokines into the bloodstream.

## 4.2. Humoral responses

To understand the humoral mechanisms, it is important to highlight that gut dysbiosis can promote a reduction in the mucus layer production, abundance of SCFAs-producing bacteria, and expression of junctional proteins in the gut epithelium [112–114]. These changes damage the gut barrier, facilitating the passage of harmful agents to the host, including LPS and proinflammatory cytokines.

Regarding pathogen-associated molecular patterns (PAMPs), LPS is one of the most important harmful agents, derived from the wall of gram-negative bacteria [96,115]. An increase in LPS in the bloodstream may trigger neuroinflammation in the NTS-PVN-RVLM axis in two ways.

LPS can overcome the BBB and can bind to the TLR4 receptor and activate an intracellular signaling cascade mediated by activation of myeloid differentiation factor 88 (MyD88) protein pathway, and nuclear factor kappa B (NFκB). This can lead to increased synthesis of pro-inflammatory cytokines, such as IL-1β, and TNF-α (tumor necrosis factor-α) into the CNS, causing microglial activation [96,115–118] (Fig. 3).

The compromised gut barrier not only favors the translocation of LPS into the bloodstream, but also of proinflammatory cytokines produced in the gut. Other PAMPs and damage-associated molecular pattern molecules (DAMPs), such as stress and ultra-processed foods, increase the levels of proinflammatory cytokines in the gut, which can cross the gut barrier and enter the circulation, contributing to an increase in systemic inflammation. In this case, neuroinflammation can occur through a region of the CNS called the subfornical organ (SFO), which is a circumventricular organ that lacks a BBB. [119]. SFO neurons can detect an increase in peripheral pro-inflammatory cytokines, project to the PVN, and promote microglial activation [101] (Fig. 3).

Experimental studies demonstrate the participation of the mechanisms discussed above in the reduction of cardiac and vascular function through sympathetic hyperactivity and hypertension. For example, a LPS infusion for 14 days causes microglial activation and oxidative stress in the RVLM of hypertensive rats [120], while inhibition of microglia in

<figure><img src="image_7.png" /><figcaption>**Fig. 3.** **Humoral mechanisms involving gut dysbiosis and neuroinflammation.** Gut dysbiosis promotes changes in the composition and diversity of the gut microbiota, reduces the mucus layer, and increases gut permeability. This impairment of the intestinal barrier makes the intestine susceptible to the entry of LPS into the bloodstream, causing peripheral inflammation and promoting central immune responses through distinct underlying mechanisms. Damage to the BBB allows LPS to enter the central nervous system (CNS) and cause microglial activation. This occurs because microglia have TLR-4 receptors that, upon binding to LPS, activate the NF-κB signaling pathway, promoting increased inflammation in regions of the CNS associated with autonomic control. Another mechanism is that the SFO, a region of CNS that does not have the protection of BBB can detect an increase in peripheral pro-inflammatory cytokines, project to the PVN, and promote microglial activation, linking systemic inflammation and neuroinflammation. Together, these mechanisms cause neuroinflammation, especially in the autonomic nuclei, such as the NTS-PVN-RVLM. **Abbreviations:** PAMPs: Pathogen-associated molecular pattern; DAMPs: Damage-associated molecular pattern molecules; LPS: Lipopolysaccharides; NF-κB: nuclear factor kappa B; SFO: subfornical organ. TNF-α tumor necrosis factor-α; IL-1β: Interleukin 1β.</figcaption></figure>
the PVN of hypertensive rats decreases BP levels associated with bene-
ficial changes in gut microbiota composition [121]. A microinjection of
TNF-α or IL-1β into SFO promoted an increase in sympathetic outflow
and BP in rats, indicating the role of this pathway in the autonomic
regions of the CNS responsible for ANS control [119]. Mechanistically,
there is evidence that sympathetic efferent impulses from cardiac and
vascular control regions such as the RVLM, NTS, and PVN can be
modulated by several factors, including glutamate, angiotensin II, and
proinflammatory cytokines. In the case of proinflammatory cytokines,
especially IL-1 β and TNF-α, they can stimulate neuronal activity by
altering cellular Ca²⁺ and K⁺ levels, resulting in depolarization and
neuronal discharge [122,123].

After discussing the link between dysbiosis and autonomic dysfunction mediated by neuroinflammation, it is important to highlight that there is increasing evidence that these three factors are associated with several clinical conditions (e.g., stress, obstructive sleep apnea) and some disorders (e.g., psoriatic arthritis, kidney disease, mental disorders, arterial hypertension, and obesity) [50,124–127] (Fig. 4). The use of compounds capable of modulating gut microbiota and other parameters represents a promising strategy to ameliorate clinical disorders related to dysbiosis, neuroinflammation, and autonomic dysfunction [114,124], as will be discussed in the next topic.

5. Impacts of nutraceuticals on conditions linked to autonomic dysfunction in preclinical studies

Preclinical studies have shown that compounds/components, such as
probiotics, n-3 PUFAs, and isolated bioactives, such as inositol, quer-
cetin, resveratrol, and nitrate, have beneficial effects on autonomic
function (Table 1). The effects of three strains of *Limosilactobacillus fer-*
*mentum* (139, 263, and 296) on the gut microbiota and cardiometabolic
parameters in rat offspring, from dams exposed to HFD during preg-
nancy and lactation, were investigated [34]. The administration of
*L. fermentum* strains (1×10⁹ colony-forming units per milliliter
(CFU)/mL) for eight weeks to female and male offspring decreased the
BP levels in male and sympathetic tone, and fecal *Lactobacillus* spp.
counts [34]. The administration of the same *L. fermentum* formulation
(1×10⁹ CFU/mL) for 4 weeks in rats fed a high-fat diet (HFD) decreased
the fecal abundance of *Proteobacteria* and *Epsilonbacteraeota*, increased
the abundance of *Firmicutes* phyla, and decreased BP [30].

Administration of *L. fermentum* 296 (1 × 10⁹ CFU/mL) to HFD-fed rats for 4 weeks attenuated sympathetic hyperactivity and reduced SBP [17].

The administration of *L. brevis* ProGA28 (40 mg/kg/day) for 2 weeks increased parasympathetic activity and improved sleep quality parameters including sleep latency, initial sleep loss, and quiet sleep intensity in rats with stress-related sleep disorders [125]. In this study, although the authors made interesting discoveries, they could have performed metabolic analyses, such as measuring physiological markers related to sleep, such as hormones and neurotransmitters. Administration of a probiotic formulation containing *Lactobacillus helveticus* R0052 and *B. longum* R0175 (1×10⁹ CFU) for two weeks improved HPA axis function by reducing plasma levels of corticosterone, epinephrine, and noradrenaline, and increasing brain-derived neurotrophic factor (BDNF) gene expression in rats subjected to water deprivation stress [128]. Administration of *B. longum* NCC3001 (100 µL of 1×10¹⁰ CFU/mL, for two weeks) to mice with colitis improved anxious behavior and decreased excitability of enteric neurons but did not affect BDNF mRNA expression and chronic inflammation [129].

The effects of interventions with n-3 PUFAs on the autonomic function of rats were investigated. Diabetic rats receiving 100 mg/kg/day of EPA for six weeks had reduced cardiac noradrenaline concentration [130]. In this case, interventions could have been conducted with additional groups, offering different doses of EPA and testing other compounds such as DHA. Hypertensive rats receiving 300 mg/kg/day of DHA for 12 weeks had reduced SBP, and noradrenalin concentration [131].

The administration of inositol (myo-inositol - 0.8 mg/g; d-chiro-
inositol - 0.02 mg/g) for four weeks in rats with induced obesity
improved HRV indices, electrical and structural cardiac activity, dia-
stolic function, and oxidative stress, and enhanced hepatic fat meta-
bolism and cardiac oxidative function [50]. Although the researchers
found interesting results, molecular assays should be further investi-
gated to elucidate the pathways by which inositol reduces autonomic
dysfunction. In addition, the treatment with d-chiro-inositol
(20 mg/kg/12 h) for 60 days in diabetic mice improved neuronal elec-
trical and noradrenergic responses and prevented neuronal damage
[132]. Administration of a formulation containing myoinositol
(7.99 mg/mL), D-chiro-inositol (0.19 mg/mL), fucoxanthin
(1.00 mg/mL), and hydroxytyrosol (1.67 mg/mL) for 18 days to preg-
nant hypertensive mice reduced SBP and increased vasorelaxation in

<figure><img src="image_8.png" /><figcaption>Fig. 4. Main diseases related to neuroinflammation, autonomic dysfunction, and sympathetic hyperactivity.</figcaption></figure>
<table><caption>**Table 1**
Preclinical evidence of the effects of nutraceuticals on diseases related to autonomic dysfunction.</caption><thead><tr><th>Reference</th><th>Target population</th><th>Composition of nutraceutical</th><th>Duration of treatment</th><th>Dose of administration</th><th>Comparison</th><th>Age</th><th>Outcomes</th></tr></thead><tbody><tr><td>de Oliveira et al. 2020</td><td>Rat offspring exposed to maternal HFD (n=42)</td><td>Lactobacillus fermentum</td><td>8 weeks</td><td>L. fermentum 139, L. fermentum 263, and L. fermentum 296 (10<sup>9</sup> CFU/mL of each strain)</td><td>Placebo with saline solution</td><td>30 days</td><td>Reduced LF oscillations of the SBP, attenuated the sympathetic pathway of the peripheral chemoreflex, and reduced the sympathetic tone</td></tr><tr><td>Ferreira et al. 2022</td><td>HFD-fed rats (n=18)</td><td>L. fermentum</td><td>4 weeks</td><td>L. fermentum 139, L. fermentum 263, and L. fermentum 296 (10<sup>9</sup> CFU/mL of each strain)</td><td>Placebo with saline solution</td><td>90 days</td><td>Reduced SBP and DBP; reduced LF and LF/HF ratio; improved spontaneously baroreflex sensitivity; decreased Proteobacteria and Epsilonbacteraeota phyla. Alleviated sympathetic hyperactivity; Reduced SBP</td></tr><tr><td>Cavalcante et al. 2019</td><td>HFD-fed rats (n=24)</td><td>L. fermentum</td><td>4 weeks</td><td>L. fermentum 296 (1 × 10<sup>9</sup> CFU/mL)</td><td>Placebo with saline solution</td><td>90 days</td><td>Increased parasympathetic activity and reduced anxiety level</td></tr><tr><td>Lai et al. 2022</td><td>Rats with stress-related sleep disturbance (n=16)</td><td>Lactobacillus brevis (ProGA28)</td><td>2 weeks</td><td>40 mg/kg</td><td>Placebo with water</td><td>10–14 weeks</td><td>Decrease in plasmatic levels of corticosterone, adrenaline, and noradrenaline; increased the expression of BDNF; prevented reduction of neurogenesis in the hippocampus; improved HPA axis function</td></tr><tr><td>Ait-Belgaoui et al. 2014</td><td>Mice with psychological stress (n=64)</td><td>Lactobacillus helveticus and B. longum</td><td>2 weeks</td><td>Lactobacillus helveticus R0052, and B. longum R0175 (10<sup>9</sup> CFU)</td><td>Placebo with saline solution</td><td>6–8 weeks</td><td>Did not affect BDNF mRNA expression and chronic inflammation; normalized anxious behavior; decreased excitability of enteric neurons</td></tr><tr><td>Bercik et al. 2011</td><td>Mice with infectious colitis (n=NR)</td><td>B. longum NCC3001</td><td>2 weeks</td><td>(100 µL of 1 × E10 CFU/mL)</td><td>Placebo</td><td>6–8 weeks</td><td>Reduced cardiac NA concentration</td></tr><tr><td>Nishimura et al. 2000</td><td>Rats with diabetes mellitus (n=20)</td><td>n-3 PUFAs</td><td>6 weeks</td><td>EPA (100 mg/kg/day)</td><td>Placebo with distilled water</td><td>6 weeks</td><td>Reduced SBP and noradrenalin concentration</td></tr><tr><td>Hashimoto et al. 1999</td><td>Hypertensive rats (n=28)</td><td>n-3 PUFAs</td><td>12 weeks</td><td>DHA (300 mg/kg/day)</td><td>Placebo</td><td>100–105 weeks</td><td>Improved LF, HF, and LF/HF; improved liver fat metabolism; improved oxidative activity; improved electrical activity and diastolic function</td></tr><tr><td>L'Abbate et al. 2020</td><td>Mice with obesity (n=48)</td><td>Inositols</td><td>4 weeks</td><td>myo-inositol (0.8 mg/g) and d-chiro-inositol (0.02 mg/g), ratio of 40:1</td><td>Placebo</td><td>9 weeks</td><td>Improved neuronal electrical responses and prevented neuronal damage</td></tr><tr><td>Farias et al. 2011</td><td>Mice with diabetes (n=30)</td><td>D-chiro-inositol</td><td>60 days</td><td>20 mg/kg/12 h</td><td>NaCl 0.9% in distilled water</td><td>6 weeks</td><td>Decreased in SBP; Improved ACh vasorelaxation</td></tr><tr><td>Menichini et al. 2020</td><td>Pregnant mice with hypertension (n=60)</td><td>Myoinositol, D-chiro-inositol, fucoxanthin, and hydroxytyrosol (MDFH)</td><td>18 days</td><td>Myoinositol, 7.99 mg/mL; D-chiro-inositol, 0.19 mg/mL; fucoxanthin, 1.00 mg/mL; and hydroxytyrosol, 1.67 mg/mL.</td><td>Placebo with water</td><td>6 weeks</td><td>Decreased in SBP; Improved ACh vasorelaxation</td></tr><tr><td>Guimarães et al. 2019</td><td>Rats with hypertension (n=82)</td><td>ANG II+ L-NAME + Inorganic nitrate</td><td>2 weeks</td><td>10 mmol/L</td><td>ANG II+ L-NAME + placebo</td><td>NR</td><td>Decreased mean arterial pressure; improved drug-induced baroreflex sensitivity; decreased renal sympathetic nerve activity; increased plasma and cerebrospinal fluid nitrate; decreased AT1A and AT1B</td></tr><tr><td>Dillenburg et al. 2013</td><td>Rats with hemodynamic changes (n=21)</td><td>Resveratrol</td><td>30 days</td><td>0.062 mg of resveratrol per 100 mL of solution. It was used 2 mL/day.</td><td>Placebo with L-NAME</td><td>12 weeks</td><td>No significant differences in BP and HR; Reduced LF and LF/HF and increased HF; Improved baroreflex sensitivity</td></tr><tr><td>Mozafari et al. 2015</td><td>Rats with simultaneous type 2 diabetes and renal hypertension (n=80)</td><td>Resveratrol</td><td>4 weeks</td><td>5, 10, or 20 mg/kg/day</td><td>Placebo</td><td>NR</td><td>Reduced Serum malondialdehyde, SBP, HR, maximal response and effective concentration 50 of phenylephrine, and inhibitory concentration 50 of acetylcholine; Increased serum SOD, glutathione reductase, and maximal response to acetylcholine</td></tr><tr><td>Monteiro et al. 2012</td><td>Rats SHR and WKY with hypertension (n=93)</td><td>Quercetin</td><td>7 days</td><td>2, 10 or 25 mg/kg/day</td><td>Placebo</td><td>12 weeks</td><td>Decreased MAP in SHR; Increased the sensitivity of parasympathetic component of the baroreflex in SHR; Decreased oxidative stress in SHR</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Reference</th><th>Target population</th><th>Composition of nutraceutical</th><th>Duration of treatment</th><th>Dose of administration</th><th>Comparison</th><th>Age</th><th>Outcomes</th></tr></thead><tbody><tr><td>Dou et al. 2018</td><td>Rats with arthritis (n=18)</td><td>Curcumin</td><td>2 weeks</td><td>100 mg/kg,</td><td>Placebo</td><td>6–8 weeks</td><td>Improved sympathetic and parasympathetic tones; increased ChAT activity and expression of ChAT and VACHT in the gut, brain, and synovium; Improved ACh biosynthesis and transport; Increased neuronal excitability of the vagus nerve</td></tr><tr><td>Li et al. 2021</td><td>Rats with hypertension (n=32)</td><td>Curcumin</td><td>12 weeks</td><td>100 or 300 mg/kg/day</td><td>Placebo</td><td>8–10 weeks</td><td>Reduced BP; Improved gut microbiota composition and intestinal integrity; Increased the butyrate level in plasma; Reduced neuroinflammation and oxidative stress, and activated GPR43 in the PVN</td></tr><tr><td>Pongchaidecha et al. 2009</td><td>Rats with obesity (n=60)</td><td>Curcumin</td><td>12 weeks</td><td>30 mg, 60 mg or 90 mg/kg/BW</td><td>Placebo</td><td>12 weeks</td><td>Decreased in plasma FFA, LF (nu), and LF/HF ratio</td></tr></tbody></table>

Table organized by composition of nutraceuticals.

NR: Not Reported; BP: blood pressure; HR; heart rate; HRV: heart rate variability; SBP: systolic blood pressure; PVAT: perivascular adipose tissue; UCP1: uncoupling protein 1; HIF-1α: Hypoxia-Inducible Factor 1alpha; IL-1β: interleukin-1β; MDA: Malondialdehyde; BW: body weight; AT1: Ang II [angiotensin II] type-1 receptor; CFU: colony forming units; BDNF: brain-derived neurotrophic factor; SCFAs: Short-chain fatty acids; HPA: Hypothalamic-pituitary-adrenal; LF: low-frequency; HF: high-frequency; SREBP-1c: Sterol regulatory element-binding protein 1; ChAT: choline acetyltransferase; VACHT: vesicular acetylcholine transporter; ACh: acetylcholine; PPARγ: Peroxisome proliferator-activated receptor gamma; SHR: Spontaneously Hypertensive; GPR43: short-chain fatty acid receptor 43; PVN: paraventricular nucleus; FFA: free fat acids

response to ACh (acetylcholine) [133].

Treatment with 10 m/mol/L inorganic nitrate for two weeks decreased MAP and increased baroreflex sensitivity in rats with angiotensin II- and L-NAME-induced hypertension, besides reducing renal and cardiovascular sympathetic activity and increasing nitrate levels in both plasma and cerebrospinal fluid [47]. This study was extremely important in demonstrating the role of inorganic NO in preventing autonomic dysfunction by attenuating the development of hypertension. However, studies are also needed to demonstrate the effects of NO in the treatment of pre-existing hypertension.

Some phenolic compounds, such as resveratrol and quercetin, have been investigated as strategies for adjuvant treatment in some clinical conditions linked to autonomic dysfunction, including hypertension and kidney disease [134,135]. The administration of resveratrol (0.062 mg per 100 mL of solution; 2 mL/day) for 30 days to rats with hemodynamic changes reduced the ratio of low frequency to high frequency (LF/HF), considered as an indicative of sympathetic to parasympathetic autonomic balance, increased HF (vagal component), and improved baroreflex sensitivity, with no effect on BP and HR [39]. The administration of resveratrol (5, 10, or 20 mg/kg/day) for four weeks to rats with simultaneous type 2 diabetes and renal hypertension reduced glycemia, BP, HR oxidative stress, and vascular reactivity [134]. The administration of quercetin (2, 10, or 25 mg/kg/day) to spontaneously hypertensive rats (SHR) for seven days decreased MAP and oxidative stress and increased the sensitivity of the parasympathetic component of baroreflex [135].

Curcumin is a compound with positive impacts on improving autonomic dysfunction [18,114,136]. The administration of curcumin (100 mg/kg/day) for 2 weeks to rats with arthritis improved sympathetic and parasympathetic tones, increased choline acetyltransferase (ChAT) activity, and expression of ChAT and vesicular acetylcholine transporter (VACHT) in the gut, brain, and synovium, in addition to improving ACh biosynthesis and transport and increasing neuronal excitability of vagus nerve [136]. Hypertensive rats treated with curcumin (100 or 300 mg/kg/day) for 12 weeks had reduced BP, neuroinflammation, and oxidative stress, and activated short-chain fatty acid receptor 43 (GPR43) in the PVN, besides improving gut microbiota composition and gut barrier integrity, and increasing butyrate levels in the plasma [114]. The administration of curcumin (30 mg, 60 mg, or

90 mg/kg/body weight (BW)) for 12 weeks to rats with obesity decreased plasma free fatty acid (FFA), LF (nu), and LF/HF ratio [18].

## 6. Impacts of nutraceuticals on conditions linked to autonomic dysfunction in clinical studies

Studies in humans have shown beneficial effects of various nutraceuticals, including probiotics, n-3 PUFAS, and other bioactive compounds on autonomic control (Table 2). The effects of an eight-week intervention with a nutraceutical containing different strains of probiotics (*Lactobacillus paracasei* LPC-37, *Lactobacillus rhamnosus* HN001, *Lactobacillus acidophilus* NCFM, and *B. lactis* HN019) on cardiometabolic parameters and autonomic function in women with hypertension in a randomized, triple-blind, placebo-controlled trial was investigated. The consumption of 10⁹ CFU of each strain improved blood glucose levels, TC, and HDL-c, reduced LF and LF/HF ratio, and increased HF [4]. In a randomized double-blinded placebo-controlled trial, individuals with autism spectral disorders receiving *Lactobacillus plantarum* (6 × 10¹⁰ CFU daily) for 16 weeks had decreased mean change of RMSSD and PNN50, both as an indicative of cardiac parasympathetic activity [137].

Other nutraceuticals, such as n-3 PUFAs, have been studied for their potential to ameliorate the autonomic nervous system in diseases associated with autonomic dysfunction.

A randomized, placebo-controlled trial in patients with heart failure showed that the intervention with n-3PUFAs (2 g/day for 4 months) elicited an improvement in the alpha index in response to stimulation of carotid baroreceptors, related to baroreflex control, besides to an improvement in general HRV and LF component [19]. In clinical trial with individuals undergoing kidney transplantation, participants were given three capsules per day of n-3 PUFAs (460 mg/g EPA and 380 mg/g DHA for 44 weeks) for 44 weeks, and the results showed a significant improvement in the frequency domain HRV indices, but did not affect time domain indices and resting HR [138]. A randomized, double-blinded, controlled trial examined the impact of 2 g of n-3 PUFAs on individuals undergoing chronic dialysis and reported improved vagal tone by increasing SDNN [127].

The use of 9 g of fish oil (1.6 g EPA, 1.1 g DHA) for eight weeks improved HR and muscle sympathetic activity in a double-blind, randomized, placebo-controlled trial with individuals with hypertension.
<table><caption>**Table 2**

Clinical evidences of effects of nutraceuticals on diseases related to autonomic dysfunction.</caption><thead><tr><th>Reference</th><th>Target Population</th><th>Composition of nutraceutical</th><th>Duration of treatment</th><th>Dose of administration</th><th>Comparison</th><th>Age (years)</th><th>Outcomes</th></tr></thead><tbody><tr><td>Romão da Silva et al. 2020</td><td>Hypertensive woman (n=40)</td><td>Lactobacillus paracasei LPC-37, Lactobacillus rhamnosus HN001, Lactobacillus acidophilus NCFM, and B. lactis HN019</td><td>8 weeks</td><td>10<sup>9</sup> CFU of each strain</td><td>Sachets with polydextrose</td><td>43.3 (34-50)</td><td>Improved LF, HF, and LF/HF ratio</td></tr><tr><td>Kong, Kang and Liu, 2023</td><td>Individuals with autism spectral disorder (n=35)</td><td>Lactobacillus plantarum PS128</td><td>16 weeks</td><td>6 × 10<sup>10</sup> CFU daily</td><td>Placebo</td><td>3.0-25.0</td><td>Decreased mean change in RMSSD and pNN5</td></tr><tr><td>Radaelli et al. 2006</td><td>Heart failure patients (n=25)</td><td>n-3 PUFAs</td><td>4 months</td><td>2 g/day with more of 85% of EPA and DHA</td><td>Placebo</td><td>59.4 ± 2.5</td><td>Improved the baroreceptor control of HR and HRV</td></tr><tr><td>Lilleberg et al. 2019</td><td>Renal transplant recipients (n=132)</td><td>n-3 PUFAs</td><td>44 weeks</td><td>3 capsules of 1 g per day, each containing 460 mg/g EPA and 380 mg/g DHA</td><td>3 g of olive oil</td><td>52.8 (13.5)</td><td>Improved LF and HF indices, but there are not difference in time-domain indices or rest HR.</td></tr><tr><td>Rantanen et al. 2018</td><td>Patients on Chronic Dialysis (n=85)</td><td>n-3 PUFAs</td><td>12 weeks</td><td>2 g/day PUFA (1 g EPA + 1 g DHA)</td><td>Placebo capsules with olive oil</td><td>62.3 (14.3)</td><td>Increased SDNN and decreased HR</td></tr><tr><td>Carter et al. 2012</td><td>Individuals with prehypertension (n=67)</td><td>n-3 PUFAs</td><td>8 weeks</td><td>9 g of fish oil (1.6 g EPA, 1.1 g DHA)</td><td>Placebo (9 g of olive oils)</td><td>23.0 ± 1.0</td><td>Improved HR and muscle sympathetic nerve activity</td></tr><tr><td>Carney et al. 2010</td><td>Patients with coronary heart diseases (n=72)</td><td>n-3 PUFAs</td><td>10 weeks</td><td>2 g (930 mg of EPA and 750 mg of DHA)</td><td>Placebo</td><td>57.9 ± 8.5</td><td>Improved VLF and HR</td></tr><tr><td>Buchhorn, Baumann and Willaschek, 2019</td><td>Children with frequent idiopathic premature ventricular contractions (n=17)</td><td>n-3 PUFAs</td><td>143 days</td><td>1-2 g of fish oil</td><td>Without control group in the intervention</td><td>11.6 ± 4.9</td><td>Reduced premature ventricular contraction, and HR; Increased SDNN and RMSSD</td></tr><tr><td>Sjoberg et al. 2010</td><td>Individuals with overweight and obesity (n=67)</td><td>n-3 PUFAs</td><td>12 weeks</td><td>2, 4 or 6 g/day (260 mg DHA+60 mg EPA/g)</td><td>Placebo capsules with sunola oil</td><td>53.0 (2.0)</td><td>Improved LF, HF and LF/HF ratio</td></tr><tr><td>Kristensen et al. 2016</td><td>Individuals with psoriatic arthritis (n=133)</td><td>n-3 PUFAs</td><td>24 weeks</td><td>Six capsules containing either 3 g of n-3 PUFA (50% EPA and 50% DHA)</td><td>3 g of olive oil</td><td>52.0 ± 11.5</td><td>Reduced HR and increased RR intervals</td></tr><tr><td>Zanini et al., 2020</td><td>Individuals with multiple sclerosis (n=3)</td><td>L-carnosine</td><td>8 weeks</td><td>2 g/day</td><td>Without control group in the intervention</td><td>37, 48 and 48 each individual</td><td>Normalized parasympathetic modulation and balanced sympathetic function; increased in serum total antioxidant capacity; reduced blood lactate; increased brain choline-contained compounds, total creatine and myo-inositol levels</td></tr><tr><td>Tsujita et al. 2019</td><td>Young adults with subclinical depression (n=30)</td><td>Tryptophan, vitamin B6 and nicotinamide</td><td>7 days</td><td>100 mg, 4 mg, and 4 mg, respectively twice daily</td><td>Placebo capsules</td><td>Between 18.0 and 22.0</td><td>Improved mood, but there was no significant change in ANS activity or plasma total tryptophan</td></tr><tr><td>Fukuda et al. 2015</td><td>Patients with end-stage renal disease (n=172)</td><td>Vitamins B1, B2, B6, B12, C, niacin, folic acid, carnitine, coenzyme Q10, naive galacto-oligosaccharide, and zinc</td><td>12 weeks</td><td>50 mL of liquid beverage</td><td>50 mL of placebo beverage</td><td>55.6 ± 10.0</td><td>Improved LF/HF ratio and decrease in HHV7 reactivation after intervention.</td></tr><tr><td>Massa et al. 2016</td><td>Prehypertensive and hypertensive individuals (n=40)</td><td>Watermelon extract</td><td>6 weeks</td><td>6 g/day</td><td>Placebo</td><td>48.7 ± 1.9</td><td>Decreased SBP and DBP, but there was no significant change in the cardiac autonomic function</td></tr></tbody></table>

Table organized by composition of nutraceuticals.

NR: Not Reported; n-3 PUFAs: n-3 polyunsaturated fatty acids; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid; ANS: autonomic nervous system; HHV7: Human herpes virus 7; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR; heart rate; HRV: heart rate variability; LF: low-frequency; HF: high-frequency; RMSSD: root mean square of NN intervals; SDNN: standard deviation of NN intervals.

This study analyzed young individuals, and perhaps studies evaluating older individuals may reveal more robust sympathoinhibitory effects, since autonomic dysfunction increases with age and is related to the duration of the disease and, consequently, the adverse effects caused by hypertension [139]. A randomized clinical trial with patients with coronary artery disease showed that supplementation with 2 g (930 mg EPA and 750 mg DHA) for ten weeks improved VLF and HR indices of

HRV [140]. The intervention with 1-2 g of fish oil for 143 days reduced premature ventricular contractions and increased SDNN and RMSSD in a non-placebo-controlled trial with children with frequent idiopathic premature ventricular contractions [61].

In a randomized, double-blind, placebo-controlled, parallel dose-response supplementation trial, the consumption of 6 g/day for 12 weeks of DHA-rich fish oil improved LF, HF, and LF/HF ratio in
individuals with overweight and obesity, while the doses of 4 g/day reduced LF/HF without affecting the other measured variables [3]. A randomized, placebo-controlled clinical trial with the administration of n-3 PUFAs (50 % EPA and 50 % DHA) during 24 weeks to individuals with psoriatic arthritis reported changes in autonomic cardiac functioning, with decreased HR and increased RR intervals, but with no difference in HRV indices [126].

A pilot trial conducted with three individuals with multiple sclerosis receiving 2 g/day of l-carnosine for eight weeks detected a normalization of parasympathetic modulation and sympathetic function, an increased serum total antioxidant capacity, brain choline-contained compounds, total creatine, and myo-inositol levels, and reduced blood lactate. However, although the study was conducted to investigate people with a rare condition, conducting it with only 3 individuals and without a placebo group may not represent the true effects of L-carnosine, highlighting the need for more robust studies in humans [49].

Nutraceutical formulation may involve combining isolated nutrients. A randomized, double-blind, and placebo-controlled trial investigated the effects of a nutraceutical containing tryptophan (100 mg), vitamin B6 (4 mg), and nicotinamide (4 mg) on patients with subclinical depression ingesting the product twice a day between meals for eight days. The results showed improvement in mood, with no change in plasma tryptophan levels or ANS activity, which was linked to the relatively low dose of tryptophan provided and attenuation of ANS reactivity due to depressive symptoms, respectively [52]. The consumption of a beverage (50 mL) with varying amounts of micronutrients for 12 weeks improved the LF/HF ratio in patients with end-stage renal disease in a multicenter, randomized, placebo-controlled, parallel-group trial [51]. Nutritional deficiencies can occur in these clinical conditions, and correction using nutraceuticals may be beneficial for ANS dysfunctions. A negative point of providing multiple micronutrients in beverages is that the isolated effects of each compound or the synergy between them cannot be demonstrated, making it impossible to understand the contribution of each compound.

A randomized, double-blind, placebo-controlled trial demonstrated that the consumption of 6 g/day of watermelon extract for 6 weeks in prehypertensive and hypertensive subjects reduced SBP and DBP. However, there were no changes in autonomic control between individuals, demonstrating that the mechanism of BP reduction could not be linked to autonomic control, but instead to vascular reactivity. This study shows interesting results, but some limitations may have prevented the occurrence of effects at the autonomic level. The first of these is that the duration of the intervention may have been relatively short, in addition to the fact that at baseline the experimental group had consumed more calories and had changes in lipoproteins compared to the control group [141]. Considering the available evidence, it each compound can exert distinct effects on different systems in the body. The following section will discuss the main mechanisms involved in improving autonomic function using nutraceuticals.

## 7. Mechanisms that improves autonomic control through nutraceuticals

Based on the results reported in the studies presented above, it could be assumed that the effects of nutraceuticals on autonomic function may vary depending on their nature and composition. For instance, probiotics can positively influence the gut microbiota and enhance the interaction between the gut and the brain, particularly with the brain regions responsible for autonomic control, including cardiovascular control. In addition, certain compounds, such as nitrate, could promote positive autonomic responses by increasing NO production. NO produced by the neuronal NO synthase acts as an inhibitory neurotransmitter in the PVN leading to sympathoinhibition [142,143]. Additionally, n-3 PUFAs could enhance the physical and chemical makeup of cell membranes in cardiac and neural tissues, improving electrophysiological responses and reducing inflammation through

different pathways. Other compounds, such as resveratrol, quercetin, inositol, curcumin, and L-carnosine, could reduce oxidative stress and inflammation in autonomic control areas (Fig. 5).

### 7.1. Probiotics

Probiotics act by modulating the gut microbiota, improving the communication between the gut and brain through different pathways. However, some clinical studies have not established this connection due to the absence of evaluation regarding the composition and function of gut microbiota. Studies performed in experimental animal models with evaluation of the gut microbiota have shown improvements in *Firmicutes/Bacteroidetes* ratio, decreased abundance of *Proteobacteria* and *Epsilonbacteraeota* phyla, normalization of abundance of *Prevotella*, improved gut barrier permeability, and increased production of SCFAs [144,145]. Therefore, further studies, particularly in humans, are needed to better understand this pathway.

Gut bacteria metabolize fiber and other compounds, including some nutraceuticals, increasing the production of metabolites beneficial to health, such as SCFAs. These SCFAs consist mostly of acetate, butyrate, and propionate and can exert beneficial effects on the gut-brain axis by interacting with G-protein-coupled receptors GPR41 and GPR43 [146]. Several studies indicate the contribution of SCFAs to maintaining physical barriers such as BBB or intestinal barrier by impacting the tight junctions between cells, reducing oxidative stress and inflammation [112,113,147]. There is also evidence of the beneficial effects of butyrate on cardiac tissue, attenuating inflammation, cardiac hypertrophy, and sympathetic neural remodeling in rats after myocardial infarction [148]. Acetate acts as a modulator of microglial and astrocyte morphological changes and improves BBB integrity, attenuating neuroinflammation and reducing sympathetic tone [149].

Furthermore, the production of SCFAs resulting from a well-balanced gut microbiota leads to a reduction in the production of endotoxins, such as LPS, which reduces local inflammation and improves vagal communication through the production of specific neurotransmitters [100]. A stronger gut barrier, characterized by improved interaction between microorganisms, metabolites, and mucus production, reduces the passage of harmful substances, such as LPS, into the bloodstream, reducing systemic inflammation and hindering the perception of inflammatory processes by brain regions [117–119]. Therefore, nutraceuticals modulating gut microbiota could be important in preventing neuroinflammation by exerting direct or indirect communication with the brain.

### 7.2. Nitrate

Bioactive compounds, such as nitrate, have been investigated as strategies for improving autonomic nervous system. Administration of inorganic nitrate increases plasma and tissue levels of NO, and L-arginine-like effect. Increased availability of NO to the pre-sympathetic neurons of the RVLM could reduce the negative effects of reactive oxygen species (ROS) production and improve autonomic control. Additionally, NO enhances GABAergic stimuli, with inhibitory effects on presympathetic neurons in the PVN and RVLM. The reduction of AT1 and AT2 receptors induced by the nutraceutical suggests a decrease in HR, as well as of BP in cases of angiotensin-dependent hypertension [47, 150].

### 7.3. *n*-3 polyunsaturated fatty acids

Studies have focused on the effects of n-3 PUFAs on improving autonomic control. n-3 PUFAs can modulate the physical and chemical properties of cell membranes and organelles, particularly in cardiac and neural tissues. Therefore, it is important to understand their role in neural and cardiovascular autonomic control [151]. Furthermore, there is evidence that intestinal bacteria can metabolize n-3 PUFAs into
<figure><img src="image_9.png" /><figcaption>**Fig. 5.** Mechanisms involved in amelioration of the autonomic nervous system induced by different nutraceuticals. Probiotics and other bioactive compounds, such as curcumin, contribute to beneficial gut microbiota modulation, increasing the production of SCFAs, improving gut barrier integrity, reducing the production and translocation of LPS, and improving vagal reflex response. SCFAs, resveratrol, quercetin, inositol, and l-carnosine can reach (via the bloodstream) the brain regions responsible for autonomic control and reduce oxidative stress and inflammation, improving autonomic function and reducing sympathetic activity. Nitrate can increase NO production and cause vasodilatation. n-3 PUFAs improve the fluidity of neuronal and cardiac cell membranes, reducing inflammation and improving cardiac electrophysiology. Furthermore, gut bacteria can metabolize n-3 PUFAs into SCFAs, which confer the beneficial effects discussed above. **Abbreviations:** LPS: Lipopolysaccharides; SCFAs: short-chain fatty acids; n-3 PUFAs: Omega-3 polyunsaturated fatty acids.</figcaption></figure>

SCFAs, which confer the beneficial effects discussed above [152,153].

There is evidence that n-3 PUFAs act directly on cardiac electro-
physiology, interacting directly with ion channels and membrane pro-
teins, such as sodium, potassium, and calcium channels, which may
explain their antiarrhythmic effects. In addition, the interaction of n-3
PUFAs with G-protein-coupled receptor 120 (GPR 120) may modulate
inflammation in innate immune defense cells, such as monocytes and
macrophages, by decreasing the generation of intracellular ROS and
reducing the activation of redox-sensitive transcription factors, such as
NF-κB system, modifying the expression of pro-inflammatory genes. n-3
PUFAs may attenuate the dimerization and recruitment of TLR4 and
help reduce the activation of NF-κB, thereby reducing LPS-associated
inflammation [151,154].

In addition, the role of n-3 PUFAs as regulators of gene expression
has been investigated, and several nuclear receptors and transcription
factors have been implicated in these processes. n-3 PUFAs can modulate
peroxisome proliferator-activated receptors and sterol regulatory
element binding protein-1c (SREBP-1c), improving lipid metabolism
and anti-inflammatory pathways. n-3 PUFAs may reduce translocation
of NF-κB to the nucleus and generation of inflammatory cytokines
through activation of peroxisome proliferator-activated receptor gamma
(PPAR-γ) or reduced translocation of protein kinase C to the plasma
membrane [155].

n-3 PUFAs could also induce an alteration in the eicosanoid profile
and consequently reduce inflammation, thrombosis, and vascular

function by decreasing the production of eicosanoids derived from
arachidonic acids, such as prostaglandin, thromboxane, and leukotriene
while increasing the production of eicosanoids derived from n-3 PUFAs
via oxygenase (COX and LOX) and cytochrome p450. COX and LOX
produce metabolites of n-3 PUFAs called specialized pro-resolving me-
diators (SPMs), which play an important role in alleviating inflamma-
tion, especially chronic inflammation [151].

In addition to the direct effects of n-3 PUFAs on neural and cardiac
cells, it is reasonable to assume that they may play an indirect role in
improving autonomic function. Although there are still gaps, some
studies show that n-3 PUFAs are substrates for gut bacteria to produce
SCFAs, whose beneficial effects on autonomic function were discussed
above [152,153,156].

7.4. Resveratrol, curcumin, inositol, quercetin, and L-carnosine

Several isolated compounds have positive effects on autonomic
function in different diseases, including resveratrol, curcumin, inositol,
quercetin, and L-carnosine. These compounds can act mainly in
reducing oxidative stress and inflammation.

Resveratrol acts in both cardiac and vascular autonomic modulation, and many of its beneficial effects are strictly related to endothelial NO synthesis [39], which acts on endothelial cells through various mechanisms, such as activation of SIRT 1 (silent mating type information regulation 2 homologs) and KLF2 (Krüppel -like factor 2),
phosphorylation mediated by AMPK (adenosine monophosphate (AMP)-activated protein kinase), and ERK1/2 (extracellular signal-regulated kinase). Resveratrol may increase the expression of antioxidant enzymes and reduce reactive oxygen species [157].

Quercetin may act by reducing oxidative stress, inhibiting angiotensin-converting enzyme activity, and improving endothelium-dependent and -independent function [158]. Reducing oxidative stress and scavenging free radicals could improve baroreflex sensitivity, leading to improved autonomic response [135,158].

Inositol may not only improve cardiac electromechanics [50] but its effects may also occur in other insulin-sensitive tissues and organs since inositol metabolites could act as insulin mimetics [159]. Inositol could correct the deficiency of pathophysiological tissue to produce phosphatidylinositol, an important compound contributing to maintaining endoplasmic reticulum membrane homeostasis [160]. Curcumin may act through various effects to improve autonomic function. In addition to the well-known effects of curcumin as a compound with the capacity to reduce inflammation and oxidative stress, its effects could be mediated through the vagus nerve by improving the vagal reflex, increasing the activity of choline acetyltransferase (ChAT), regulating the function of the cholinergic system, and reducing sympathetic and increasing parasympathetic tone [136,161]. These beneficial effects of curcumin on the vagal reflex may be related to its modulatory effects on gut microbiota [162,163]. Finally, L-carnosine could be an important compound to treat autonomic dysfunction, acting as an anti-oxidative, anti-inflammatory, chelating, anti-apoptotic, signaling, and anti-glycating agent, which are linked to neuroprotective effects [164].

## 8. Important considerations on nutraceutical safety and future perspectives

Although the effects of nutraceuticals are increasingly being studied, there is still a need to develop more clinical trials aimed at evaluating safety and understanding more about the regulation of these compounds. Regarding the regulation of probiotics, although there is no global standard for the use of probiotics for therapeutic purposes, both the Food and Drug Administration (FDA) of the United States and the European Food Safety Authority (EFSA) of the European Union provide important guidance, listing certain probiotic strains as Generally Recognized as Safe (GRAS) and assigning species-level Qualified Pre-sumption of Safety (QPS) status, indicating which bacteria are considered safe for consumption [165]. Probiotic strains, such as members of the Lactobacilli family, the *Lactococcus* genus, the *Bifidobacterium* genus, and the *Streptococcus thermophilus* strain, have a long history of safe use and receive GRAS status [165]. The EFSA considers all common probiotic species as safe [166]. It is worth mentioning that the EFSA is stringent in accepting the term "probiotic", but in Italy, the term is widely used [23].

Nevertheless, currently marketed probiotics are derived from fermented foods with a long history of safe consumption and are indicated for a healthy target population [167,168]. In general, clinical trials investigating the effects of probiotics do not have safety issues as their primary objective, as in the vast majority of cases, the safety profile is based on the history of safe use of probiotics in food products and the results of clinical trials investigating the health benefits of probiotics use [169]. Furthermore, the studies to be developed on the safety of probiotics must emphasize that effective and safe doses depend on some important factors such as clinical condition, age, evaluated strains, route of administration, delivery vehicle, and drug interactions [170].

This concern regarding the safety of probiotics becomes even more important since some cases of serious adverse effects have already been documented, regardless of dosage, formulation, and daily intake. These effects include an increased risk of infection and/or morbidity in vulnerable groups, including infants [171] and very low birthweight neonates [172]. Patients with severe acute pancreatitis showed an increased risk of mortality related to treatment with a probiotic

formulation [173], and adult patients with severe heart failure hospitalized in intensive care units [174]. Therefore, a broad analysis is also needed to support the safety of probiotic use in vulnerable individuals, including those with compromised intestinal mucosa or immunosuppressed individuals, such as patients with inflammatory bowel disease, severe liver disease, and people living with human immunodeficiency virus (HIV) [165].

Regarding the regulation and safety of other bioactive compounds, it is observed in the literature that it varies from one compound to another. Given the growing investigation into the health benefits of polyphenols, the efficacy and safety of resveratrol and quercetin are being increasingly being evaluated [175-180]. Resveratrol has been shown to be safe at doses up to 5 g/day, and it can be used alone or in combination therapy [176,177], while quercetin has been shown to be effective and safe at doses up to 1000 mg/day [178-180]. Although these compounds are considered dietary supplements by the FDA, their use as a therapeutic modality has not been approved so far, reinforcing the need for more robust clinical evidence on the safety of quercetin and resveratrol [180,181].

In recent years, the effects of n-3 PUFAs have been increasingly studied, with doses around 200-500 mg varying by country [182,183]. It is worth noting that n-3 PUFAs supplements can be classified as prescription formulations and dietary supplements, and have similarities in terms of composition, production, development, efficacy, and quality [182,183]. Despite these similarities, only prescription formulations have been regulated by the FDA and the European Medicines Agency (EMA). It is important to identify the classification of the compounds used in the studies developed [44,183].

Other bioactive compounds included in the present study, such as curcumin, nitrate, and inositol, are considered safe. According to the World Health Organization (WHO), the recommended concentration of nitrate allowed in drinking water is 44 mg/L in the United States and 50 mg/L in Europe. Additionally, according to the Joint FAO/WHO Expert Committee on Food Additives, the acceptable daily intake of nitrate is 3.7 mg/kg of body weight [184,185]. Although not approved for therapeutic purposes, curcumin is recognized as GRAS and is considered safe at doses of 6-8 g/day [186-188]). Regarding L-carnosine, there are still few studies investigating the safety of this compound [189].

Therefore, it can be concluded that most nutraceuticals are safe when used in appropriate doses and the benefits outweigh the risks based on the available evidence. However, when studying the effects of nutraceuticals in populations with pre-existing disorders, it is important to consider the potential interactions between the components forming the nutraceuticals and medications, which can lead to undesirable side effects [2,190]. Furthermore, safety tests to evaluate adverse effects, such as toxicity, do not yet have well-established techniques, due to the high variability of the matrix from which the compound was extracted. Additionally, different compounds forming a nutraceutical can act synergistically or antagonistically, leading to erroneous measurements of the real effect [191].

Nutraceuticals containing different isolated or combined compounds, which act through different mechanisms, could be useful to control autonomic dysfunction and improving related conditions. There is a lack of studies in this area, making it an important future strategy. The effects of nutraceuticals can occur through gut microbiota modulation, improving gut-brain communication, as well as through other mechanisms, such as reducing oxidative stress and inflammation in the brain and heart tissues. The relationship between gut microbiota modulation and autonomic function in humans is not well clarified since many of these compounds were studied only in animal models. Future investigations should advance in understanding this relationship in humans.
## 9. Conclusion

The evidence from available literature indicates that various nutraceuticals exert beneficial effects on autonomic dysfunction, and the mechanisms underlying these effects could be related to the nature and function of the bioactive compound forming the nutraceuticals. Probiotics, nitrate, resveratrol, quercetin, inositol, curcumin, L-carnosine, and n-3 PUFAs improve the composition and function of the gut microbiota, reduce oxidative stress and inflammation, and improve the structure and function of neuronal and cardiac cell membranes, resulting in signaling that culminates in improved autonomic dysfunction (Fig. 5). Given the well-established safety of the compounds comprising the examined nutraceuticals, these bioactive products could represent an important adjuvant treatment strategy in diseases associated with autonomic dysfunctions. The current challenge is to address potential compounds that may be promising nutraceuticals and the effects of combined compounds with different mechanisms of action in the same nutraceutical. Finally, the combination of scientific advances and financial feasibility holds promising prospects for the practical use of nutraceuticals in both preventing and treating a range of clinical conditions, including those related to autonomic dysfunction, such as psoariatic arthritis, kidney disease, mental disorders, arterial hypertension, and obesity.

## Financial support

The research was supported by the CAPES-COFECUB collaboration (88881.711922/2022-01). M. Magnani, V. R. Antunes, E. L. de Souza, and J. L. de Brito Alves thank the National Council for Scientific and Technological Development (CNPq) for their research productivity grant.

## CRediT authorship contribution statement

**Paulo César Trindade da Costa:** Writing – original draft, Conceptualization. **Jose Luiz de Brito Alves:** Writing – review & editing, Writing – original draft, Investigation, Funding acquisition, Conceptualization. **Hubert Vidal:** Writing – review & editing. **Evandro Leite de Souza:** Writing – review & editing. **Vagner Roberto Antunes:** Writing – review & editing. **Marciane Magnani:** Writing – review & editing. **Murielle Godet:** Writing – review & editing. **Daniella de Oliveira Coutinho:** Writing – original draft. **Micaelle Oliveira de Luna Freire:** Writing – original draft.

## Declaration of Competing Interest

The research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

## Data Availability

No data was used for the research described in the article.

## References

[1] A. Santini, E. Novellino, Nutraceuticals - shedding light on the grey area between pharmaceuticals and food, Expert Rev. Clin. Pharm. 11 (6) (2018) 545-547.

[2] M. AlAli, et al., Nutraceuticals: Transformation of Conventional Foods into Health Promoters/Disease Preventers and Safety Considerations, Molecules 26 (9) (2021).

[3] N.J. Sjoberg, et al., Dose-dependent increases in heart rate variability and arterial compliance in overweight and obese adults with DHA-rich fish oil supplementation, Br. J. Nutr. 103 (2) (2010) 243-248.

[4] L.F. Romao da Silva, et al., Effects of probiotic therapy on cardio-metabolic parameters and autonomic modulation in hypertensive women: a randomized, triple-blind, placebo-controlled trial, Food Funct. 11 (8) (2020) 7152-7163.

[5] E.A. Wehrwein, H.S. Oer, S.M. Barman, Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System, Compr. Physiol. 6 (3) (2016) 1239-1278.

[6] J.B. Furness, The organisation of the autonomic nervous system: peripheral connections, Auton. Neurosci. 130 (1-2) (2006) 1-5.

[7] F. Roche, et al., Anatomy and physiology of the autonomic nervous system: Implication on the choice of diagnostic/monitoring tools in 2023, Rev. Neurol. (Paris) 180 (1-2) (2024) 42-52.

[8] J. Zubcevic, et al., Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension, Circ. Res 125 (1) (2019) 104-116.

[9] R.A. Dampney, et al., Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states, Am. J. Physiol. Heart Circ. Physiol. 315 (5) (2018) H1200-H1214.

[10] P. Valensi, Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications, Cardiovasc Diabetol. 20 (1) (2021) 170.

[11] R.M. Bruno, et al., Sympathetic regulation of vascular function in health and disease, Front Physiol. 3 (2012) 284.

[12] S. Lee, et al., Human milk oligosaccharide 2'-fucosyllactose supplementation improves gut barrier function and signaling in the vagal afferent pathway in mice, Food Funct. 12 (18) (2021) 8507-8521.

[13] G.S. Reginato, et al., Differential benefits of physical training associated or not with l-arginine supplementation in rats with metabolic syndrome: Evaluation of cardiovascular, autonomic and metabolic parameters, Physiol. Behav. 268 (2023) 114251.

[14] T. Rajapakse, A.R. Gantenbein, Nutraceuticals in migraine, Handb. Clin. Neurol. 199 (2024) 125-144.

[15] S. Benvenga, et al., Nutraceutical Supplements in the Thyroid Setting: Health Benefits beyond Basic Nutrition, Nutrients 11 (9) (2019).

[16] J.Y.P. da Silva, et al., Revealing the Potential Impacts of Nutraceuticals Formulated with Freeze-Dried Jabuticaba Peel and Limosilactobacillus fermentum Strains Candidates for Probiotic Use on Human Intestinal Microbiota, Probiotics Antimicrob. Proteins (2023).

[17] R.G.S. Cavalcante, et al., The probiotic Lactobacillus fermentum 296 attenuates cardiometabolic disorders in high fat diet-treated rats, Nutr. Metab. Cardiovasc Dis. 29 (12) (2019) 1408-1417.

[18] A. Pongchaidecha, et al., Effects of curcuminoid supplement on cardiac autonomic status in high-fat-induced obese rats, Nutrition 25 (7-8) (2009) 870-878.

[19] A. Radaelli, et al., Enhanced baroreceptor control of the cardiovascular system by polyunsaturated Fatty acids in heart failure patients, J. Am. Coll. Cardiol. 48 (8) (2006) 1600-1606.

[20] L. Das, et al., Role of nutraceuticals in human health, J. Food Sci. Technol. 49 (2) (2012) 173-183.

[21] M.R. Damian, et al., Functional Foods, Nutraceuticals and Probiotics: A Focus on Human Health, Microorganisms 10 (5) (2022).

[22] S.H. Zeisel, Regulation of "nutraceuticals, Science 285 (5435) (1999) 1853-1855.

[23] C. Hill, et al., Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic, Nat. Rev. Gastroenterol. Hepatol. 11 (8) (2014) 506-514.

[24] Y. Xiao, et al., Gut Colonization Mechanisms of Lactobacillus and Bifidobacterium: An Argument for Personalized Designs, Annu Rev. Food Sci. Technol. 12 (2021) 213-233.

[25] E.F. Garcia, et al., Identification of Lactic Acid Bacteria in Fruit Pulp Processing Byproducts and Potential Probiotic Properties of Selected Lactobacillus Strains, Front Microbiol 7 (2016) 1371.

[26] M. Takada, et al., Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models, Neurogastroenterol. Motil. 28 (7) (2016) 1027-1036.

[27] A. De Mauri, et al., Probiotics-Supplemented Low-Protein Diet for Microbiota Modulation in Patients with Advanced Chronic Kidney Disease (ProLowCKD): Results from a Placebo-Controlled Randomized Trial, Nutrients 14 (8) (2022).

[28] Y.T. Ho, et al., Effects of Lactobacillus plantarum PS128 on Depressive Symptoms and Sleep Quality in Self-Reported Insomniacs: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial, Nutrients 13 (8) (2021).

[29] I. Robles-Vera, et al., The Probiotic Lactobacillus fermentum Prevents Dysbiosis and Vascular Oxidative Stress in Rats with Hypertension Induced by Chronic Nitric Oxide Blockade, Mol. Nutr. Food Res 62 (19) (2018) e1800298.

[30] G. de Araujo Henriques Ferreira, et al., Potentially Probiotic Limosilactobacillus fermentum Fruit-Derived Strains Alleviate Cardiometabolic Disorders and Gut Microbiota Impairment in Male Rats Fed a High-Fat Diet, Probiotics Antimicrob. Proteins 14 (2) (2022) 349-359.

[31] M.O. de Luna Freire, et al., Limosilactobacillus fermentum Strains with Claimed Probiotic Properties Exert Anti-oxidant and Anti-inflammatory Properties and Prevent Cardiometabolic Disorder in Female Rats Fed a High-Fat Diet, Probiotics Antimicrob. Proteins 15 (3) (2023) 601-613.

[32] M.O. de Luna Freire, et al., Effects of a Mixed Limosilactobacillus fermentum Formulation with Claimed Probiotic Properties on Cardiometabolic Variables, Biomarkers of Inflammation and Oxidative Stress in Male Rats Fed a High-Fat Diet, Foods 10 (9) (2021).

[33] L.C.P. do Nascimento, et al., Limosilactobacillus fermentum prevents gut-kidney oxidative damage and the rise in blood pressure in male rat offspring exposed to a maternal high-fat diet, J. Dev. Orig. Health Dis. 13 (6) (2022) 719-726.

[34] Y. de Oliveira, et al., Oral administration of Lactobacillus fermentum post-weaning improves the lipid profile and autonomic dysfunction in rat offspring exposed to maternal dyslipidemia, Food Funct. 11 (6) (2020) 5581-5594.
[35] Y.L. Tain, C.N. Hsu, Novel Insights on Dietary Polyphenols for Prevention in Early-Life Origins of Hypertension: A Review Focusing on Preclinical Animal Models, Int J. Mol. Sci. 23 (12) (2022).

[36] H. Liu, et al., Dietary polyphenols regulate appetite mechanism via gut-brain axis and gut homeostasis, Food Chem. 446 (2024) 138739.

[37] G.B. Fanaro, et al., New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy, Antioxid. (Basel) 12 (6) (2023).

[38] S.O. Aloo, K. Barathikannan, D.H. Oh, Polyphenol-rich fermented hempseed ethanol extracts improve obesity, oxidative stress, and neural health in high-glucose diet-induced Caenorhabditis elegans, Food Chem. X 21 (2024) 101233.

[39] D.R. Dillenburg, et al., Resveratrol and grape juice differentially ameliorate cardiovascular autonomic modulation in L-NAME-treated rats, Auton. Neurosci. 179 (1-2) (2013) 9-13.

[40] M.L. Chen, et al., Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota, mBio 7 (2) (2016) e02210-15.

[41] J.L. de Brito Alves, et al., New Insights on the Use of Dietary Polyphenols or Probiotics for the Management of Arterial Hypertension, Front Physiol. 7 (2016) 448.

[42] W. Zhang, et al., Research progress of quercetin in cardiovascular disease, Front Cardiovasc Med 10 (2023) 1203713.

[43] F. Ali, et al., Quercetin attenuates angiotensin II-induced proliferation of vascular smooth muscle cells and p53 pathway activation in vitro and in vivo, Bio factors 49 (4) (2023) 956-970.

[44] !!! INVALID CITATION !!! {}.

[45] K.B. Sampaio, et al., Development and in vitro evaluation of novel nutraceutical formulations composed of Limosilactobacillus fermentum, quercetin and/or resveratrol, Food Chem. 342 (2021) 128264.

[46] V. Sorrenti, et al., Cocoa Polyphenols and Gut Microbiota Interplay: Bioavailability, Prebiotic Effect, and Impact on Human Health, Nutrients 12 (7) (2020).

[47] D.D. Guimaraes, et al., Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II-Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity, Hypertension 73 (4) (2019) 839-848.

[48] Y. Han, et al., Curcumin attenuates migration of vascular smooth muscle cells via inhibiting NfκappaB-mediated NLRP3 expression in spontaneously hypertensive rats, J. Nutr. Biochem 72 (2019) 108212.

[49] D. Zanini, et al., Dietary supplementation with L-carnosine improves patient-reported outcomes, autonomic nervous system performance, and brain metabolism in 3 adult patients with multiple sclerosis, Nutr. Res 84 (2020) 63-69.

[50] S. L'Abbate, et al., Myo-inositol and d-chiro-inositol oral supplementation ameliorate cardiac dysfunction and remodeling in a mouse model of diet-induced obesity, Pharm. Res 159 (2020) 105047.

[51] S. Fukuda, et al., Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: a randomized, double-blind, placebo-controlled, multicenter trial, PLoS One 10 (3) (2015) e0119578.

[52] N. Tsujita, et al., Effect of Tryptophan, Vitamin B(6), and Nicotinamide-Containing Supplement Loading between Meals on Mood and Autonomic Nervous System Activity in Young Adults with Subclinical Depression: A Randomized, Double-Blind, and Placebo-Controlled Study. J. Nutr. Sci. Vitam. (Tokyo) 65 (6) (2019) 507-514.

[53] G. Brosolo, et al., Omega-3 Fatty Acids in Arterial Hypertension: Is There Any Good News? Int J. Mol. Sci. 24 (11) (2023).

[54] R.L. Weinberg, et al., Cardiovascular Impact of Nutritional Supplementation With Omega-3 Fatty Acids: JACC Focus Seminar, J. Am. Coll. Cardiol. 77 (5) (2021) 593-608.

[55] Q.K. Liu, Triglyceride-lowering and anti-inflammatory mechanisms of omega-3 polyunsaturated fatty acids for atherosclerotic cardiovascular risk reduction, J. Clin. Lipido 15 (4) (2021) 556-568.

[56] L. Huang, et al., Effect of Omega-3 Polyunsaturated Fatty Acids on Cardiovascular Outcomes in Patients with Diabetes: A Meta-analysis of Randomized Controlled Trials, Adv. Nutr. 14 (4) (2023) 629-636.

[57] J. Backes, et al., The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia, Lipids Health Dis. 15 (1) (2016) 118.

[58] P. Safaei, G. Bayat, A. Mohajer, Comparison of fish oil supplements and corn oil effects on serum lipid profile: a systematic review and meta-analysis of randomized controlled trials, Syst. Rev. 13 (1) (2024) 54.

[59] K.A. Sauder, et al., Effects of omega-3 fatty acid supplementation on heart rate variability at rest and during acute stress in adults with moderate hypertriglyceridemia, Psychosom. Med 75 (4) (2013) 382-389.

[60] T.M. Harrison, et al., Omega-3 fatty acids and autonomic function in adolescents with anorexia: A randomized trial, Pedia Res 92 (4) (2022) 1042-1050.

[61] R. Buchhorn, C. Baumann, C. Willaschek, Alleviation of arrhythmia burden in children with frequent idiopathic premature ventricular contractions by omega-3-fatty acid supplementation, Int J. Cardiol. 291 (2019) 52-56.

[62] G.R. Gibson, et al., Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (iAPP) consensus statement on the definition and scope of prebiotics, Nat. Rev. Gastroenterol. Hepatol. 14 (8) (2017) 491-502.

[63] M.E. Sanders, et al., Probiotics and prebiotics in intestinal health and disease: from biology to the clinic, Nat. Rev. Gastroenterol. Hepatol. 16 (10) (2019) 605-616.

[64] E.B. Oliveira-Sales, et al., Oxidative stress contributes to renovascular hypertension, Am. J. Hypertens. 21 (1) (2008) 98-104.

[65] K.K. Griendling, et al., Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells, Circ. Res 74 (6) (1994) 1141-1148.

[66] S. Taddei, et al., Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension, Circulation 100 (16) (1999) 1680-1683.

[67] S.S. Jaradeh, T.E. Prieto, Evaluation of the autonomic nervous system, Phys. Med Rehabil. Clin. N. Am. 14 (2) (2003) 287-305.

[68] R.A. Dampney, Functional organization of central pathways regulating the cardiovascular system, Physiol. Rev. 74 (2) (1994) 323-364.

[69] A.M. Allen, Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone, Hypertension 39 (2) (2002) 275-280.

[70] P.G. Guyenet, et al., Rostral Ventrolateral Medulla and Hypertension, Hypertension 72 (3) (2018) 559-566.

[71] B. Savic, D. Murphy, N. Japundzic-Zigon, The Paraventricular Nucleus of the Hypothalamus in Control of Blood Pressure and Blood Pressure Variability, Front Physiol. 13 (2022) 858941.

[72] D.B. Zoccal, et al., The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities, Front Physiol. 5 (2014) 238.

[73] A. Murtazina, I. Adameyko, The peripheral nervous system, Development 150 (9) (2023).

[74] R.A. Dampney, et al., Central mechanisms underlying short- and long-term regulation of the cardiovascular system, Clin. Exp. Pharm. Physiol. 29 (4) (2002) 261-268.

[75] T.E. Lohmeier, R. Iliescu, The baroreflex as a long-term controller of arterial pressure, Physiol. (Bethesda) 30 (2) (2015) 148-158.

[76] P.A. Lanfranchi, V.K. Somers, Arterial baroreflex function and cardiovascular variability: interactions and implications, Am. J. Physiol. Regul. Integr. Comp. Physiol. 283 (4) (2002) R815-R826.

[77] P.M. Pilowsky, A.K. Goodchild, Baroreceptor reflex pathways and neurotransmitters: 10 years on, J. Hypertens. 20 (9) (2002) 1675-1688.

[78] N. Honzikova, E. Zavodna, Baroreflex sensitivity in children and adolescents: physiology, hypertension, obesity, diabetes mellitus, Physiol. Res 65 (6) (2016) 879-889.

[79] I.S.A. Felippe, et al., The sympathetic nervous system exacerbates carotid body sensitivity in hypertension, Cardiovasc Res 119 (1) (2023) 316-331.

[80] J.L. de Brito Alves, et al., Maternal protein restriction increases respiratory and sympathetic activities and sensitizes peripheral chemoreflex in male rat offspring, J. Nutr. 145 (5) (2015) 907-914.

[81] P. Ortega-Saenz, J. Lopez-Barneo, Physiology of the Carotid Body: From Molecules to Disease, Annu Rev. Physiol. 82 (2020) 127-149.

[82] R. Iturriaga, et al., Carotid body chemoreceptors: physiology, pathology, and implications for health and disease, Physiol. Rev. 101 (3) (2021) 1177-1235.

[83] F. Brognara, et al., Physiological Sympathetic Activation Reduces Systemic Inflammation: Role of Baroreflex and Chemoreflex, Front Immunol. 12 (2021) 637845.

[84] I.S.A. Felippe, et al., Commonalities and differences in carotid body dysfunction in hypertension and heart failure, J. Physiol. 601 (24) (2023) 5527-5551.

[85] J.P. Cunha-Guimaraes, et al., Carotid body chemosensitivity: early biomarker of dysmetabolism in humans, Eur. J. Endocrinol. 182 (6) (2020) 549-557.

[86] G. Grassi, The Sympathetic Nervous System in Hypertension: Roadmap Update of a Long Journey, Am. J. Hypertens. 34 (12) (2021) 1247-1254.

[87] D. Thorsdottir, Z. Einwag, B. Erdos, BDNF shifts excitatory-inhibitory balance in the paraventricular nucleus of the hypothalamus to elevate blood pressure, J. Neurophysiol. 126 (4) (2021) 1209-1220.

[88] M.J. Kenney, et al., Paraventricular nucleus bicuculline alters frequency components of sympathetic nerve discharge bursts, Am. J. Physiol. Heart Circ. Physiol. 281 (3) (2001) H1233-H1241.

[89] J.F. Cryan, et al., The Microbiota-Gut-Brain Axis, Physiol. Rev. 99 (4) (2019) 1877-2013.

[90] Y. Xiong, et al., The Role of Gut Microbiota in Hypertension Pathogenesis and the Efficacy of Antihypertensive Drugs, Curr. Hypertens. Rep. 23 (8) (2021) 40.

[91] S. Carding, et al., Dysbiosis of the gut microbiota in disease, Micro Ecol. Health Dis. 26 (2015) 26191.

[92] J. Li, et al., Dynamic role of macrophage CX3CR1 expression in inflammatory bowel disease, Immunol. Lett. 232 (2021) 39-44.

[93] T.C. Fung, C.A. Olson, E.Y. Hsiao, Interactions between the microbiota, immune and nervous systems in health and disease, Nat. Neurosci. 20 (2) (2017) 145-155.

[94] A.M. Mowat, W.W. Agace, Regional specialization within the intestinal immune system, Nat. Rev. Immunol. 14 (10) (2014) 667-685.

[95] J. Bruning, et al., Gut Microbiota and Short Chain Fatty Acids: Influence on the Autonomic Nervous System, Neurosci. Bull. 36 (1) (2020) 91-95.

[96] W.M. de Vos, et al., Gut microbiome and health: mechanistic insights, Gut 71 (5) (2022) 1020-1032.

[97] H. Ahmed, et al., Microbiota-derived metabolites as drivers of gut-brain communication, Gut Microbes 14 (1) (2022) 2102878.

[98] E.M. Richards, et al., Gut Microbiome and Neuroinflammation in Hypertension, Circ. Res 130 (3) (2022) 401-417.

[99] S. Calabro, et al., Impact of Gut Microbiota on the Peripheral Nervous System in Physiological, Regenerative and Pathological Conditions, Int J. Mol. Sci. 24 (9) (2023).

[100] P. Strandwitz, Neurotransmitter modulation by the gut microbiota, Brain Res 1693 (Pt B)) (2018) 128-133.

[101] X. Wang, et al., The Bidirectional Signal Communication of Microbiota-Gut-Brain Axis in Hypertension, Int J. Hypertens. 2021 (2021) 8174789.
[102] B. Bonaz, V. Sinniger, S. Pellissier, Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease, J. Intern Med 282 (1) (2017) 46-63.

[103] S. Breit, et al., Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders, Front Psychiatry 9 (2018) 44.

[104] L.E. Goehler, et al., Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain communication, Brain Res Bull. 43 (3) (1997) 357-364.

[105] L.R. Watkins, et al., Blockade of interleukin-1 induced hyperthermia by subdiaphractic vagotomy: evidence for vagal mediation of immune-brain communication, Neurosci. Lett. 183 (1-2) (1995) 27-31.

[106] B.E. Steinberg, et al., Cytokine-specific Neurograms in the Sensory Vagus Nerve, Bioelectron. Med 3 (2016) 7-17.

[107] B. Bonaz, V. Sinniger, S. Pellissier, The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract, Front Immunol. (8) (2017) 1452.

[108] L.E. Goehler, et al., Vagal immune-to-brain communication: a visceral chemosensory pathway, Auton. Neurosci. 85 (1-3) (2000) 49-59.

[109] L.V. Borovikova, et al., Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin, Nature 405 (6785) (2000) 458-462.

[110] P.E. Sawchenko, Central connections of the sensory and motor nuclei of the vagus nerve, J. Auton. Nerv. Syst. 9 (1) (1983) 13-26.

[111] A.E. Coutinho, K.E. Chapman, The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights, Mol. Cell Endocrinol. 335 (1) (2011) 2-13.

[112] M.M. Santisteban, et al., Hypertension-Linked Pathophysiological Alterations in the Gut, Circ. Res 120 (2) (2017) 312-323.

[113] S. Kim, et al., Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure, Clin. Sci. (Lond.) 132 (6) (2018) 701-718.

[114] H.B. Li, et al., Curcumin ameliorates hypertension via gut-brain communication in spontaneously hypertensive rat, Toxicol. Appl. Pharm. 429 (2021) 115701.

[115] N. Alhajri, et al., Cardiovascular Health and The Intestinal Microbial Ecosystem: The Impact of Cardiovascular Therapies on The Gut Microbiota, Microorganisms 9 (10) (2021).

[116] A. Nesci, et al., Gut Microbiota and Cardiovascular Disease: Evidence on the Metabolic and Inflammatory Background of a Complex Relationship, Int J. Mol. Sci. 24 (10) (2023).

[117] M. Toral, et al., Critical Role of the Interaction Gut Microbiota - Sympathetic Nervous System in the Regulation of Blood Pressure, Front Physiol. 10 (2019) 231.

[118] R. Abdel-Haq, et al., Microbiome-microglia connections via the gut-brain axis, J. Exp. Med 216 (1) (2019) 41-59.

[119] S.G. Wei, et al., Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat, Hypertension 65 (5) (2015) 1126-1133.

[120] K.L. Wu, S.H. Chan, J.Y. Chan, Neuroinflammation and oxidative stress in rostral ventrolateral medulla contribute to neurogenic hypertension induced by systemic inflammation, J. Neuroinflamm. 9 (2012) 212.

[121] R.K. Sharma, et al., Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin II-Induced Hypertension, Circ. Res 124 (5) (2019) 727-736.

[122] H. Ishinaga, et al., Synergistic induction of nuclear factor-kappaB by transforming growth factor-beta and tumour necrosis factor-alpha is mediated by protein kinase A-dependent RelA acetylation, Biochem. J. 417 (2) (2009) 583-591.

[123] B. Viviani, et al., Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases, J. Neurosci. 23 (25) (2003) 8692-8700.

[124] M. de Almeida Silva, et al., Kefir ameliorates hypertension via gut-brain mechanisms in spontaneously hypertensive rats, J. Nutr. Biochem 77 (2020) 108318.

[125] G.T. Lai, et al., Production of Lactobacillus brevis ProGA28 attenuates stress-related sleep disturbance and modulates the autonomic nervous system and the motor response in anxiety/depression behavioral tests in Wistar-Kyoto rats, Life Sci. 288 (2022) 120165.

[126] S. Kristensen, et al., The effect of marine n-3 polyunsaturated fatty acids on cardiac autonomic and hemodynamic function in patients with psoriatic arthritis: a randomised, double-blind, placebo-controlled trial, Lipids Health Dis. 15 (1) (2016) 216.

[127] J.M. Rantanen, et al., Effects of Marine n-3 Polyunsaturated Fatty Acids on Heart Rate Variability and Heart Rate in Patients on Chronic Dialysis: A Randomized Controlled Trial, Nutrients 10 (9) (2018).

[128] A. Ait-Belgnaoui, et al., Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice, Neurogastroenterol. Motil. 26 (4) (2014) 510-520.

[129] P. Bercik, et al., The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication, Neurogastroenterol. Motil. 23 (12) (2011) 1132-1139.

[130] M. Nishimura, et al., Eicosapentaenoic acid stimulates nitric oxide production and decreases cardiac noradrenaline in diabetic rats, Clin. Exp. Pharm. Physiol. 27 (8) (2000) 618-624.

[131] M. Hashimoto, et al., The hypotensive effect of docosahexaenoic acid is associated with the enhanced release of ATP from the caudal artery of aged rats, J. Nutr. 129 (1) (1999) 70-76.

[132] V.X. Farias, et al., Chronic treatment with D-chiro-inositol prevents autonomic and somatic neuropathy in STZ-induced diabetic mice, Diabetes Obes. Metab. 13 (3) (2011) 243-250.

[133] D. Menichini, et al., Maternal Supplementation of Inositol, Fucoxanthin, and Hydroxytyrosol in Pregnant Murine Models of Hypertension, Am. J. Hypertens. 33 (7) (2020) 652-659.

[134] M. Mozafari, et al., The effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension: a study of antihypertensive mechanisms, Iran. J. Med Sci. 40 (2) (2015) 152-160.

[135] M.M. Monteiro, et al., Quercetin improves baroreflex sensitivity in spontaneously hypertensive rats, Molecules 17 (11) (2012) 12997-13008.

[136] Y. Dou, et al., Curcumin attenuates collagen-induced inflammatory response through the "gut-brain axis, J. Neuroinflamm. 15 (1) (2018) 6.

[137] X.J. Kong, J. Kang, K. Liu, Probiotic and intra-nasal oxytocin combination therapy on autonomic function and gut-brain axis signaling in young children and teens with autism spectrum disorder, J. Psychiatr. Res 166 (2023) 1-9.

[138] H.S. Lilleberg, et al., The Effect of Marine n-3 Polyunsaturated Fatty Acids on Heart Rate Variability in Renal Transplant Recipients: A Randomized Controlled Trial, Nutrients 11 (12) (2019).

[139] J.R. Carter, et al., Fish oil and neurovascular control in humans, Am. J. Physiol. Heart Circ. Physiol. 303 (4) (2012) H450-H456.

[140] R.M. Carney, et al., Effect of omega-3 fatty acids on heart rate variability in depressed patients with coronary heart disease, Psychosom. Med 72 (8) (2010) 748-754.

[141] N.M. Massa, et al., Watermelon extract reduces blood pressure but does not change sympathovagal balance in prehypertensive and hypertensive subjects, Blood Press 25 (4) (2016) 244-248.

[142] F.Z. Wang, et al., Adrenomedullin in paraventricular nucleus attenuates adipose afferent reflex and sympathoexcitation via receptors mediated nitric oxide-gamma-aminobutyric acid A type receptor pathway in rats with obesity-related hypertension, J. Hypertens. 41 (2) (2023) 233-245.

[143] N.M. Sharma, et al., Central angiotensin II-Protein inhibitor of neuronal nitric oxide synthase (PIN) axis contribute to neurogenic hypertension, Nitric Oxide 94 (2020) 54-62.

[144] L.A. Carneiro Dos Santos, et al., A Mix of Potentially Probiotic Limosilactobacillus fermentum Strains Alters the Gut Microbiota in a Dose- and Sex-Dependent Manner in Wistar Rats, Microorganisms 12 (4) (2024).

[145] M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharm. Res 130 (2018) 152-163.

[146] M.K. Nohr, et al., Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia, Neuroscience 290 (2015) 126-137.

[147] G. Caspani, J. Swann, Small talk: microbial metabolites involved in the signaling from microbiota to brain, Curr. Opin. Pharm. 48 (2019) 99-106.

[148] X. Jiang, et al., Butyrate improves cardiac function and sympathetic neural remodeling following myocardial infarction in rats, Can. J. Physiol. Pharm. 98 (6) (2020) 391-399.

[149] X. Yin, et al., Microbiota-derived acetate attenuates neuroinflammation in rostral ventrolateral medulla of spontaneously hypertensive rats, J. Neuroinflamm. 21 (1) (2024) 101.

[150] Y. Li, W. Zhang, J.E. Stern, Nitric oxide inhibits the firing activity of hypothalamic paraventricular neurons that innervate the medulla oblongata: role of GABA, Neuroscience 118 (3) (2003) 585-601.

[151] D. Mozaffarian, J.H. Wu, Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events, J. Am. Coll. Cardiol. 58 (20) (2011) 2047-2067.

[152] P. Zhuang, et al., Eicosapentaenoic and docosahexaenoic acids attenuate hyperglycemia through the microbiome-gut-organs axis in db/db mice, Microbiome 9 (1) (2021) 185.

[153] H. Watson, et al., A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota, Gut 67 (11) (2018) 1974-1983.

[154] D.Y. Oh, et al., GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects, Cell 142 (5) (2010) 687-698.

[155] H. Li, et al., EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism, Kidney Int 67 (3) (2005) 867-874.

[156] R.C. Robertson, et al., Deficiency of essential dietary n-3 PUFA disrupts the caecal microbiome and metabolome in mice, Br. J. Nutr. 118 (11) (2017) 959-970.

[157] C.A. Schmitt, E.H. Heiss, V.M. Dirsch, Effect of resveratrol on endothelial cell function: Molecular mechanisms, Biofactors 36 (5) (2010) 342-349.

[158] A.J. Larson, J.D. Symons, T. Jalili, Therapeutic potential of quercetin to decrease blood pressure: review of efficacy and mechanisms, Adv. Nutr. 3 (1) (2012) 39-46.

[159] M.L. Croze, C.O. Soulage, Potential role and therapeutic interests of myo-inositol in metabolic diseases, Biochimie 95 (10) (2013) 1811-1827.

[160] R.H. Michell, Do inositol supplements enhance phosphatidylinositol supply and thus support endoplasmic reticulum function? Br. J. Nutr. 120 (3) (2018) 301-316.

[161] P.S. Olofsson, et al., Rethinking inflammation: neural circuits in the regulation of immunity, Immunol. Rev. 248 (1) (2012) 188-204.

[162] Z. Zhang, et al., Effect of Curcumin on the Diversity of Gut Microbiota in Ovariectomized Rats, Nutrients 9 (10) (2017).

[163] R.M. McFadden, et al., The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer Prevention, Inflamm. Bowel Dis. 21 (11) (2015) 2483-2494.

[164] M. Schon, et al., The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence, Nutrients 11 (6) (2019).
[165] T.F. da Silva, et al., Unlocking the Potential of Probiotics: A Comprehensive Review on Research, Production, and Regulation of Probiotics, Probiotics Antimicrob. Proteins (2024).

[166] E.Po.B. Hazards, et al., Update of the list of QPS-recommended biological agents intentionally added to food or feed as notified to EFSA 15: suitability of taxonomic units notified to EFSA until September 2021, EFSA J. 20 (1) (2022) e07045.

[167] F. Guarner, et al., World Gastroenterology Organisation Global Guidelines: Probiotics and Prebiotics, J. Clin. Gastroenterol. 58 (6) (2024) 533-553.

[168] M. Cordaillat-Simmons, A. Rouanet, B. Pot, Live biotherapeutic products: the importance of a defined regulatory framework, Exp. Mol. Med 52 (9) (2020) 1397-1406.

[169] J. Suez, et al., The pros, cons, and many unknowns of probiotics, Nat. Med 25 (5) (2019) 716-729.

[170] A.C. Ouwehand, A review of dose-responses of probiotics in human studies, Benef. Microbes 8 (2) (2017) 143-151.

[171] C. Quin, et al., Probiotic supplementation and associated infant gut microbiome and health: a cautionary retrospective clinical comparison, Sci. Rep. 8 (1) (2018) 8283.

[172] S. Topcuoglu, et al., A new risk factor for neonatal vancomycin-resistant Enterococcus colonisation: bacterial probiotics, J. Matern Fetal Neonatal Med 28 (12) (2015) 1491-1494.

[173] M.G. Besselink, et al., Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial, Lancet 371 (9613) (2008) 651-659.

[174] M.L. Carvour, et al., Predictors of Clostridium difficile infection and predictive impact of probiotic use in a diverse hospital-wide cohort, Am. J. Infect. Control 47 (1) (2019) 2-8.

[175] S. Yadegar, et al., Effects and safety of resveratrol supplementation in older adults: A comprehensive systematic review, Phytother. Res 38 (5) (2024) 2448-2461.

[176] A.P. Singh, et al., Health benefits of resveratrol: Evidence from clinical studies, Med Res Rev. 39 (5) (2019) 1851-1891.

[177] V.A. Brown, et al., Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis, Cancer Res 70 (22) (2010) 9003-9011.

[178] S. Andres, et al., Safety Aspects of the Use of Quercetin as a Dietary Supplement, Mol. Nutr. Food Res 62 (1) (2018).

[179] V. Devi, et al., Therapeutic Potential and Clinical Effectiveness of Quercetin: A Dietary Supplement, Recent Adv. Food Nutr. Agric. 15 (1) (2024) 13-32.

[180] O. Dagher, et al., Therapeutic Potential of Quercetin to Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases, Front Cardiovasc Med 8 (2021) 658400.

[181] M. Salla, et al., Enhancing the Bioavailability of Resveratrol: Combine It, Derivatize It, or Encapsulate It? Pharmaceutics 16 (4) (2024).

[182] J. Yan, et al., Efficacy and Safety of Omega-3 Fatty Acids in the Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis, Cardiovasc Drugs Ther. 38 (4) (2024) 799-817.

[183] J.P. Chang, et al., Safety of Supplementation of Omega-3 Polyunsaturated Fatty Acids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials, Adv. Nutr. 14 (6) (2023) 1326-1336.

[184] O.M. Shannon, et al., Dietary Inorganic Nitrate as an Ergogenic Aid: An Expert Consensus Derived via the Modified Delphi Technique, Sports Med 52 (10) (2022) 2537-2558.

[185] N.S. Bryan, J.L. Ivy, Inorganic nitrite and nitrate: evidence to support consideration as dietary nutrients, Nutr. Res 35 (8) (2015) 643-654.

[186] V. Soleimani, A. Sahebkar, H. Hosseinzadeh, Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review, Phytother. Res 32 (6) (2018) 985-995.

[187] H. Mirzaei, et al., Phytosomal curcumin: A review of pharmacokinetic, experimental and clinical studies, Biomed. Pharm. 85 (2017) 102-112.

[188] J. Sharifi-Rad, et al., Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications, Front Pharm. 11 (2020) 01021.

[189] B. Araminia, et al., L-Carnosine combination therapy for major depressive disorder: A randomized, double-blind, placebo-controlled trial, J. Affect Disord. 267 (2020) 131-136.

[190] K. Gul, A.K. Singh, R. Jabeen, Nutraceuticals and Functional Foods: The Foods for the Future World, Crit. Rev. Food Sci. Nutr. 56 (16) (2016) 2617-2627.

[191] R.C. Gupta, A. Srivastava, R. Lall, Toxicity Potential of Nutraceuticals, Methods Mol. Biol. 1800 (2018) 367-394.