Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : December 31, 2021
Accepted : January 30, 2022
Published online : March 31, 2022
doi:10.24659/gsr.9.1_1

Review article

The power of gut-brain interaction as a promising target for healthy longevity
Hiroaki Masuzaki, Tsugumi Uema, Jasmine F. Millman, Shiki Okamoto
Division of Endocrinology, Diabetes and Metabolism, Hematology and Rheumatology,(Second Department of Internal Medicine), Graduate School of Medicine,
University of the Ryukyus, Nishihara, Okinawa, Japan

Abstract

Hippocrates, the sage of medicine, famously said, "All disease begins in the gut," The gut-brain axis plays an extremely
important role in a high-quality strategy for anti-aging throughout the roughly 100-year life span of humans. When the gutbrain axis is functioning properly, it is possible to maintain a healthy body, mind, and cognitive function, while dysfunction in
the gut-brain axis can lead to increased risks of a variety of diseases and subsequent deterioration. From this point of view, wecall the unlimited power of the gut-brain interaction "gut-brain axis power" and have focused our attention on the molecular
medicine of diet and exercise to enhance gut-brain axis power. The degree of gut-brain power varies greatly from person
to person, and the power of gut-brain axis is greatly affected by one's lifestyle, including diet, exercise habits, sleep quality,
and stress management. Based on this notion, gut brain power is highlighted as a possible factor X to explain individualand constitutional differences in the development and worsening of complications as well as differences in response todiet, exercise, and drug therapy, all of which have occasionally been overlooked in preventive and clinical medicine. The
ingested dietary contents are sensed by enteroendocrine cells (EECs) as nutrients, bile acids, or fermentation metabolites ofgut microbiota, and are involved in the regulation of secretion of gut-derived peptide hormones, i.e. CCK, GLP-1, PYY, andghrelin. These gastrointestinal hormones then act on the central nervous system (brain) to exert a considerable influence on thecontrol of appetite and food preference. In addition to sensing by EEC, the various bioactive substances in the gastrointestinal
tracts send information to the brain via blood and lymph flow or directly via spinal afferents, and determine all modesof behaviour, including eating habits and physical activity, whether consciously or unconsciously. The ultimate key to the"behavioural modification" that is being discussed in various aspects of society can be said to be gut brain axis power.

KEY WORDS: the gut-brain axis power, gut microbiota, gut-derived peptide hormone, brain function,		food preference, behavioural modification

Introduction

power. In addition to sensing by EEC, a variety of humoral
bioactive substances in the gastrointestinal tract send a vast
amount of information to the brain via blood and lymphatic
flow or directly via spinal afferents, and determine all modesof behaviour, including eating habits and physical activity,
whether consciously or unconsciously ( Fig. 1, quoted andmodified from Ref. 1) 1).
In the field of glycative stress research, imbalance ofintestinal microflora (microbiota) has attracted attention ofscientists as a factor that hampers the success of various
treatments for type 2 diabetes mellitus (T2DM). The alterationof gut microbiota has been found to play an important role inthe dramatic improvement of glucose metabolism by weight-

The brain and gut are closely related through theautonomic nervous system and humoral factors, i.e. hormones,
cytokines, and bioactive substances which is called the gutbrain interaction (gut-brain axis). When the gut-brain axis
is functioning properly, it is possible to maintain a healthy
body, mind, and cognitive functions, while dysfunction in
the gut-brain axis would lead to increased risks of a variety
of diseases and subsequent deterioration. From this point ofview, we call the unlimited power of the gut-brain interaction"gut-brain axis power" and have focused our attention on
the molecular medicine of diet and exercise to enhance this

Corresponding to: Hiroaki Masuzaki, MD, PhD.
Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology,
Department of Medicine, Graduate School of Medicine, University of the Ryukyus
Uehara 207, Nakagami-gun Nishihara-cho, Okinawa, 903-0215 Japan
TEL : + 81-98-895-1146 FAX: +81-98-895-1415 e-mail: hiroaki@med.u-ryukyu.ac.jp
Co-authors; Uema T, ma2.ky8.26@gmail.com; Millman JF, jasmine.f.millman@gmail.com;
Okamoto S, shiki@med.u-ryukyu.ac.jp_ 1 _Glycative Stress Research 2022; 9 (1) : 1- 6(c) Society for Glycative Stress Research

The Power of Gut-Brain Interaction and Healthy Longevity

Brain• ER Stress• Lipotoxicity/Free Fatty Acids• Bacterial LPS• Hypoxia

LeptinHypothalamus
NTS

White
Adipocytes

Behaviors are Largely Determinedby the Gut-Brain Interaction
Paracrine via
SpinalAfferents andEnteric
Nervous
SystemBrown
Adipocytes• Adiponectin• Growth Factors• Immune Cells-TNF-a-IL-6-IL-18-PAI-1↑Energy
Expenditure• Environmental• Epigenetic• Genetic• Psycho-Social

Inflammation
TissueDamageGut Peptides Derived EECs
（CCK, GLP1, PYY, Ghrelin）
EECs Senses Luminal Factors

Endocrine via
Blood and Lymph• Food Intake• Energy Dissipation• Satiety• Glucose Homeostasis• Gut Secretion• Nutrient Utilization• Gut Mortality• Gastric Emptying

Luminal Factors● Pre-Absorptive
Nutrients● Bile Acids● Fermented
Products

Gut

Lumen

Fig. 1. A panorama of gut-brain axis.

EEC, entero-endocrine cell; ENS, enteric nervous system; NTS, nucleus tractus solitarius; CCK, cholecystokinin; GLP-1, glucagonlike peptide 1; LPS, lipopolysaccharide; PYY, peptide tyrosine (Y) tyrosine (Y); TNF, tumor necrosis factor; IL, interleukin; PAI,
plasminogen activator inhibitor. Quoted and modified from Reference 1.

reduction and metabolic surgery (bariatric surgery, i. e. sleeve
gastrectomy, bypass surgery) 1) and also in the mechanism ofaction of metformin, a drug for T2DM 2). It has been pointed
out that in many patients with T2DM and obesity, even if
they consume a lot of dietary fiber, their energy consumption
efficiency is reduced due to accelerated degradation offlavonoid, and that dysbiosis is associated with impaired
gastrointestinal mucosal barriers and resultant production ofa variety of pro-inflammatory substances, which subsequently
enter the systemic circulation and cause chronic inflammationin organs involved in glucose metabolism including the brain 3).
We have recently reported a novel mechanism bywhich extra virgin olive oil (EVOO) effectively ameliorates
gastrointestinal barrier dysfunction and impaired
gastrointestinal immune function observed in obese anddiabetic mice fed an animal fat 4). The polyphenols andoleic acid abundantly contained in EVOO reduce microglial
inflammation in the central nervous system (CNS), while
enhancing the expression of amyloid-β transport protein andpromoting amyloid-β clearance. In the circulation, they lower
LDL-cholesterol levels and elevate HDL-cholesterol levels,
thus reducing the risk of cardiovascular events. Furthermore,in the gut microbiota, they also increase the ratio of short-chain fatty acid (SCFA)-producing bacteria, thereby
increasing the blood concentration of SCFAs, and induce
the differentiation and maturation of regulatory T cells, andsuppress inflammation of the gastrointestinal tract 5).
Our recent studies have shown that oral administrationof γ-oryzanol, a functional component found only in highconcentrations in brown rice (rice bran), to genetically obese
mice dose-dependently increased the ratio of Bacteroidetes/
Firmicutes (B/F) ratio, which is closely associated withrestoration of intestinal bacterial diversity and improvementof glucose metabolism 6). In addition, our study demonstrated
that consumption of a brown rice-fermented beveragecontaining high levels of γ- oryzanol increased the B/ F ratio
in humans as well 7), and also significantly increased intestinalbacteria classified as Lactobacillus and Clostridium, which
are involved in the production of SCFAs and reduction of
inflammation, compared to a control brown rice-fermented
beverage that did not contain γ - oryzanol (Akamine Y,
Masuzaki H, et al., manuscript in minor revision 2022).
Based on the fact that a variety of fermentation
metabolites, i.e. SCFAs, considerably impact brain function,
it is highly expected that food choice such as EVOO andγ-oryzanol contributes to improve the gut-brain axis power.

_ 2 _Glycative Stress ResearchMechanisms of appetite loss with aging
from the viewpoint of gut-brain axis

anorexia nervosa (AN), and it is hoped that fMRI approaches
will reveal the entire picture of underlying mechanisms ofappetite loss with aging in appetite-regulating brain regions
including the insula.
On the other hand, a couple of mechanisms whereby
dysfunctions in the gut-brain axis lead to age-related
appetite loss have also been clarified (Fig. 1 ). It is known
that secretion of cholecystokinin (CCK), a potent appetitesuppressing peptide produced in the duodenum andjejunum, increases with age, and is considered as one of thepathological causes of appetite loss in the elderly 10). Also,
secretion of ghrelin, which is produced by the stomachand exerts a strong orexigenic action, decreases with age,suggesting its role in the pathogenesis of decreased appetite
in the elderly (Fig. 2) 11). Impact of aging on the production
and secretion of other gut-derived hormones of the appetite
suppressive system, i. e. amylin, glucagon-like peptide 1(GLP-1), and bombesin, have not yet been reported.
The frequency of malignancies also increases in theelderly. It is known that lactate, whose production is increasedin many cancer cells, reaches the CNS and suppresses
methylmalonyl CoA, which potently acts as an appetite
stimulant in the hypothalamus 12).
Methylmalonyl CoA is synthesized into fatty acids such as
palmitate by fatty acid synthase (FAS) in microsomes. In
fact, inhibitors of FAS and carnitine O-palmitoyltransferase
1 (CPT-1) involved in this pathway are known to cause
hyperphasia and resultant obesity in mice 13).

An appetite loss with aging decreases physical strength,
and immunity, thereby causing sarcopenia and frailty, andeventually worsens quality of life (QOL) over a long periodof time. This is in a sharp contrast to the current situation
where obesity and metabolic syndrome associated withovernutrition are being highlighted in middle-aged andmature generations. The term "frail" refers to a decline
in spare capacity in daily life, and encompasses not only
frailty in the narrow sense of musculoskeletal weakness,but also social frailty and mental frailty including cognitive
impairment and depression. In the elderly, frailty, sarcopenia,
and T2DM are recognized as a triad that exacerbates eachother, and overseas data have shown that the progression of
sarcopenia is definitely faster in elderly people with T2DM
than in those without T2DM 8).
The mechanism of appetite loss with aging involves
two types of functional abnormalities: one in the brain itself,
which is the center of appetite regulation, and the other inthe gut-brain axis. Although the mechanism of appetite loss
with aging of the CNS is still not fully elucidated, functional
magnetic resonance imaging (fMRI) analyses suggest that theinsula, one of the key regions in enhancing eating behaviour,
is sometimes dysfunctional in the elderly 9). Notably, it has
been reported that the dysfunction of the insular cortex
is deeply involved in the pathogenesis of a severe form of

Psychogenic and Cognitive
Appetite Loss

Dysfunction of
InsulaOrexigenic
Methyl Malonyl CoA ⇊Appetite Loss due to
Impaired Vision

Anorectic
PeptideCCK ⇈Orexigenic
PeptideGhrerin ⇊Olfaction ⇊Taste ⇊

LactateMastication ⇊Swallowing ⇊Salivation ⇊Missing Teeth ⇊OccultCancers

Appetite Loss
Exercise ⇊Muscle Volume ⇊Energy Dissipation ⇊Appetite Loss

Poor Digestion, Poor Absorption
Constipation
Appetite Loss

Fig. 2. Plausible mechanisms on aging-related appetite loss in relation to the dysfunction of gut-brain axis.
CCK, cholesystokinin.

_ 3 _The Power of Gut-Brain Interaction and Healthy Longevity

The mechanism of age-related appetite loss also includes
factors related to brain function in a broad sense, such as
psychogenic appetite loss, loss of appetite due to cognitive
decline, dysfunctions in the appetite center itself as well as in
the gut-brain axis. In addition, as shown in Fig. 2, there is acomplex involvement of factors including impaired sense invision, smell, and taste, as well as masticatory and swallowing
functions, oral functions, digestive functions, and also
impaired appetite due to decreased physical activity.

and other factors, and promotes the secretion of gutderived hormones, i.e. Peptide YY (PYY), GLP-1, thereby
contributing to improve glucose metabolism, suppress
excessive appetite, and exert anti-inflammatory effects in awide variety of tissues.
While a series of short-chain fatty acids produced byfermentation by beneficial intestinal bacteria exemplify avariety of health-promoting effects, when certain intestinalbacteria proliferate due to unhealthy lifestyle or dietary
disturbances, gut microbiota-derived toxic substances(ammonia, nitroso compounds, hydrogen sulfide, amines,
indole) and inflammatory cytokines (IL - 6, TNF - α, I L 23, IL-17, etc.) induce liver cancer and colon cancer 14). For
example, imidazolpropionic acid derived from histidine
induces insulin resistance, and it has also attracted attention
that part of the insulin sensitizing effect of metformin ismediated by its suppressive impact on the imidazolpropionicacid. Furthermore, choline and carnitine derived fromred meat and liver are converted into trimethylamine byfermentation, and when metabolized to trimethylamineoxide (TMAO) in the liver, they act as potent inflammatory
stimulants and are also deeply involved in the progressionof atherosclerosis and cardiovascular diseases, tissue
fibrosis, and mitochondrial dysfunction. In fact, TMAO,
acting as an intravascular inflammatory agent, increases
platelet aggregation, inhibits the reverse transport of HDLcholesterol, and eventually contributes to the accumulation ofcholesterol-phagocytosed foam macrophages (foam cells) in
vessel walls.
On the other hand, 4-cresol, which has recently been
attracting attention as a beneficial fermentation metabolite,
is derived from tyrosine and phenylalanine, and contributes
to the alleviation of hyperglycemia and liver steatosis via
increased insulin secretion. Experimentally, subcutaneousadministration of 4-cresol to obese-diabetic mice on ahigh-fat diet was shown to increase insulin secretion andameliorate hyperglycemia via promoting proliferation of
pancreatic β cells. Furthermore, some bile acids that escapereabsorption from the gastrointestinal tract are metabolized
into secondary and tertiary bile acids, and secondary bile
acids in particular activate bile acid receptors distributed
throughout the body, namely the farnesoid X- activatedreceptor (FXR) and G protein-coupled bile acid receptor(TGR5). FXR signaling is accompanied by increased
secretion of FGF15 and FGF19, and TGR5 signaling isaccompanied by increased secretion of GLP-1, both of which
act on the brain to suppress food intake, increase energy
expenditure, and contribute to a line of anti-inflammatory
effects ( Fig. 3, quoted and modified from Ref. 14) 14).

The key to gut-brain axis:
Functions and pathological significanceof fermentation metabolites
Some intestinal bacteria have enzymes that break downplant-derived fibrous polysaccharides, which were originallyunable to be used as nutrition. Humans have a long historyof forming a symbiosis that promotes energy reserves for
starvation with the help of intestinal bacteria. In fact, germfree mice in which intestinal bacteria were removed byadministering high doses of antibiotics are remarkably thinand do not become obese. Moreover, they are characterized
by a marked deterioration in kidney function. This notion
shows that the inability to produce sufficient amounts of aseries of SCFAs due to insufficient fermentation of intestinalbacteria causes enormous adverse effects on the physiologicalaccumulation of body fat and the maintenance of renal
function 1). Conversely, when the intestinal bacteria of healthy
mice were transplanted into the digestive tract of germ-freemice, the thin germ-free mice began to gain weight. The ecosystem formed between the intestinal bacteria and the hostworked favorably in times of starvation, but it also poses arisk of inducing obesity under conditions of insatiable dietand imbalanced gut microbiota (dysbiosis) 3).
For example, the acetic acid produced by fermentationacts on the brain to decrease appetite and promote
neurogenesis. It also acts on adipose tissue, gastrointestinal
tract, lungs, and cells responsible for immunity, i.e.
regulatory T cells (Treg), exerting anti-inflammatory andanti-carcinogenic effects, degradation of triglycerides inadipose tissue (protection against obesity and alleviation ofexcessive insulin sensitivity in adipose tissue), inhibitionof epigenetic enzymes, i. e. histone deacetylase (HDAC9),and activation of Treg (alleviation of bronchial asthma). A
line of mechanisms include a combination of intracellularsignaling of fatty acid receptors that use acetic acid as aligand (G protein-coupled seven transmembrane receptors(GPCRs), i.e. GPR41, GPR43) and inhibition of HDACs
involved in epigenetic modification.
Butyric acid also acts on immunocompetent cells, i.e.
Treg, distributed in the gastrointestinal tract, suppresses
HDACs, and promotes secretion of interleukin-18 (IL-18)
via SCFA receptors such as GPR109A, thereby suppressing
inflammation and carcinogenesis in the gastrointestinal tract.
Of note, butyrate plays an extremely important role as amajor nutrient source for gastrointestinal epithelial cells andis also essential for the construction of the gastrointestinal
barrier.
Propionic acid also enhances Treg function via GPR43

Dysfunction of the gut-brain axis:
A plausible mechanism of fermentation
failureExperiments in rodents have shown that continuous
intake of animal fat increases obesity-prone gut microbiota,
while continuous intake of fish oil and polyunsaturated
fatty acids contributes to the maintenance of a less fattening
microbiota 15). Importantly, continuous overconsumption of_ 4 _Glycative Stress Research

Colon

ILCs

IL-22

Anti-Inflammatory

Tryptophan
Indoles

GLP-1

2°BA

1°BA

Anti-Inflammatory

Barrier Function

FibersSCFA

Browning
Adipose Tissue
Fat Storage
Energy Expenditure

GNG

Satiety

GLP-1
PYY

Histidine

ImP

Tyrosine

4-Cresol

CholineBrain

Gluconeogenesis
Lipogenesis

InsulinResistanceFatty liver

TMA

Liver

TMAO
Pro-Inflammatory
IECs L cell

Atherosclerosis
Cardiovascular Diseases

Fig. 3. Role of gut-derived microbial metabolites in metabolic health and disease.

1°BA, primary bile acids; 2°BA, secondary bile acids; SCFA, short chain fatty acids; GNG, gluconeogenesis in theintestinal tissue; IECs, intestinal epithelial cells; ILCs, innate lymphoid cells; IL, interleukin; GLP-1, glucagonlike prptide-1; PYY, peptide tyrosine (Y) tyrosine (Y); ImP, imidazole propionate; TMA, trimethyl amine; TMAO,
trimethyl amine oxide. Quoted and modified from Reference 14.

animal fat reduces the fermentation power of beneficial
intestinal bacteria, leading to a substantial drop in intestinal
immune function mainly due to decreased production of
SCFAs, and also a marked shrink in epigenomic regulatory
functions mediated by SCFAs, which predisposes tometabolic derangement such as T2DM and obesity disease 16).
The gut microbiota of humans and mice with sustained
and substantial intake of animal fats is markedly alteredin a short period of time, inducing inflammation of thegastrointestinal tract, impairment of acquired as well as
innate immune system, and barrier dysfunction in thegastrointestinal mucosa. Concurrently, a reduction in thesize of the cecum and considerable shortening of thegastrointestinal tract occur. Disruption of the gastrointestinal
barrier increases the concentration of lipopolysaccharide(LPS) and other endotoxins in the circulation, causing mild
but chronic invisible inflammation throughout the body,leading to insulin resistance and obesity. In addition toexcessive intake of animal fat, other triggers for dysfunctionof gastrointestinal mucosal barrier have been suggested to berelated to excessive intake of preservatives and colorants infoods, caffeine, and alcohol, and also abuse of antibacterial
drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), andproton pump inhibitors (PPIs).

There are two types of gut microbiota: those that are
inherited from the mother and remain largely unchanged
throughout the life, and those that can be easily altered by life
circumstances. Compared to vaginally delivered infants, theintestinal flora of infants via the cesarean section (C-section)is considerably altered, with a predominance of metabolicallyand immunologically beneficial Lactobacillus species in
the former and an increase in pathogenic staphylococci inthe latter. It has been reported that the risk of a variety of
metabolic, allergic and neuropsychiatric diseases is apparently
increased in C -section infants compared to vaginallydelivered infants (allergic diseases: 5 times, attention deficit
hyperactivity disorder (ADHD): 3 times, autism: 2 times,
obesity: 1. 5 times, type 1 diabetes mellitus: 1. 7 times), andthe mechanistic link with abnormal balance of intestinal
flora has attracted attention in scientists and clinicians 17).
In addition to this notion, an interesting finding wasreported comparing the gut microbiota of thin children
living in the suburbs of central Africa on a cereal staple dietwith that of children living in urban Italy. In the former,
Bacteroidetes (B) accounted for 75% of the microbiota
and Firmicutes (F) for only 10 %, whereas in the latter,
Bacteroidetes accounted for 25% and Firmicutes for 50 % 18).

_ 5 _The Power of Gut-Brain Interaction and Healthy Longevity

Conclusion

Acknowledgments

Although diet and nutritional guidance up to now havemechanically determined caloric intake based on blood
glucose level, body fat mass, body mass index (BMI), andlevel of physical activities, huge individual differences doexist in the risk of obesity and hyperglycemia even wheneating similar foods. Based on these observations, evaluationof gut microbiota has recently begun to be actively utilized
as part of prevention and monitoring of therapeutic effects in
T2DM and obesity. The development of pharmaceuticals andfunctional foods targeting the improvement of microbiotabalance is expeditiously exploding, and ”the power of gutbrain axis” will be no doubt an increasingly key concept in
the future medical field.

This work was supported in part by a JSPS KAKENHI
grant (20K08912, 2020-2022), The Uehara Memorial
Foundation (2020) and The Tojuro Iijima Foundation for
Food Science and Technology (2020). The publication ofthis study was supported by the Isyoku-Dogen Research
Foundation (IDF#22001).

Author Contributions:
Writing, Masuzaki H; Analysis of intestinal flora inobese and diabetic patients, Uema T; Analysis of intestinal
flora in obese and diatetic mice, Millman JF; Analysis of brain
functions related to food preference, addictive behaviors, andcognitive functions, Okamoto S.

Conflicts of Interest
All authors state that they have no conflicts of interest.

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