Qiseng strongly supported the distinct chemotherapy mechanisms on fatigue and cognition. In fact, the dorsal dentate gyrus contained more immature neurons (doublecortin+) than the ventral dentate gyrus while being composed of more mature neurons (NeuN+) [56], and the maturation of adult-born neurons differed between the ventral and the dorsal dentate gyrus [85], explaining differential susceptibilities to cytotoxic drugs. In addition, studies showing that i.p. LPS or traumatic brain injury induces acute and/or sustained cytokines mRNA expression in the dHp and vHp, respectively [86,87], suggest that the dHp develops this neuroinflammation first and transiently, which then spreads to the vHp over a longer time. While 5-FU administration drastically altered neurogenesis in the dHp and VHp, Qiseng®, and potentially its components, such as ginsenosides or *P. qfolius* metabolites, would be more specific to the neuroinflammatory pathway recruited in the vHp.

The specific impact of Qiseng® administered *per os* on fatigue should be closely linked to the primary impact of chemotherapy with intestinal inflammation. Chemotherapy adversely affects the gut microbiota [88], and a modification of the intestinal microbiota plays an important role in the development of inflammatory intestinal diseases [59]. It is known that intestinal microbiota plays a fundamental role in the structuring and functioning of the brain [89] and that dysbiosis of the gut microbiota would control the brain functions through a gut-brain axis involving the immune system, the ascending vagal nerve pathway or plasma metabolites and neurotransmitters [90]. At the phylum level, 5-FU treatment has been shown to increase Verrucomicrobia and decrease Firmicutes in BALB/c mouse cecum [61]. Contrary to the results of this paper, in the present study, 5-FU did not impact Firmicutes, and a decrease in Verrucomicrobia was only identified in the 5-FU/Qiseng® group.

A human study interested in Panax ginseng metabolism revealed that a low level of Proteobacteria in feces was associated with high metabolism of Rb1 ginsenosides present in ginseng to compound K [91]. Indeed, some ginsenosides such as Rb1 and Rc, were digested by gastric acid and/or intestinal bacteria into smaller compounds, such as Rd and compound K, and further into Protopanaxadiol [58]. In our chemotherapy mouse model, we established for the first time the role of 5-FU in increasing Lactobacillus, and more specifically, L. reuteri, L. acidophilus and L. johnsonii/gasseri, and decreasing L. murinus/animalis. This chemotherapy-induced elevation of Lactobacillus species dysbiosis was mainly prevented by Qiseng® but also vitamin C, but concomitantly, in all Qiseng® mice, a specific diminution of Beta-, Gamma- and Delta-proteobacteria was observed. Thus, Qiseng® modified the gut microbiota equilibrium through a decrease in proteobacteria while preventing the increase in Lactobacillus induced by 5-FU. Similarly, ginsenoside supplementation can restore the composition of the microbiota altered by chemotherapy [92]. Additionally, it was shown that a decoction of Ginseng could restore D-galactose-induced memory deficits in rats by up-regulating Bacteroidetes and down-regulating Lactobacillus [93].

These preclinical data are in agreement with a randomized clinical trial concluding that probiotic supplementation during chemotherapy could reduce the incidence of CRCI, by means of an increase in the plasma metabolite p-Mentha-1,8-dien-7-ol and potentially reduced inflammation in breast cancer patients [94]. Although several Lactobacillus species are currently used as probiotics to improve gastrointestinal health, increased levels of Lactobacilli are not always associated with healthy conditions. For example, higher levels of Lactobacilli were reported in obese individuals [95], as well as in mouse models of undernutrition [96]. Lactobacilli may, in some instances, activate the immune system by engaging host pattern-recognition receptors and trigger inflammation [97], playing a role in bowel inflammation disease [93]. Indeed, the oral administration of L. reuteri to Lactobacillus-free mice resulted in an inflammatory reaction of the intestinal mucosa 6 days after inoculation, correlated with IL-1α and IL-6 mRNA expression in small intestine enterocytes [98]. Moreover, L. acidophilus can promote cell reactive oxygen species (ROS) in cultured intestinal epithelial cells [99], whose production likely contributes to intestinal tissue damage and triggers NF-κB, leading to pro-inflammatory cytokines, such as TNF-α,
Qiseng strongly supported the distinct chemotherapy mechanisms on fatigue and cognition. In fact, the dorsal dentate gyrus contained more immature neurons (doublecortin+) than the ventral dentate gyrus while being composed of more mature neurons (NeuN+) [56], and the maturation of adult-born neurons differed between the ventral and the dorsal dentate gyrus [85], explaining differential susceptibilities to cytotoxic drugs. In addition, studies showing that i.p. LPS or traumatic brain injury induces acute and/or sustained cytokines mRNA expression in the dHp and vHp, respectively [86,87], suggest that the dHp develops this neuroinflammation first and transiently, which then spreads to the vHp over a longer time. While 5-FU administration drastically altered neurogenesis in the dHp and VHp, Qiseng®, and potentially its components, such as ginsenosides or *P. qfolius* metabolites, would be more specific to the neuroinflammatory pathway recruited in the vHp.

The specific impact of Qiseng® administered *per os* on fatigue should be closely linked to the primary impact of chemotherapy with intestinal inflammation. Chemotherapy adversely affects the gut microbiota [88], and a modification of the intestinal microbiota plays an important role in the development of inflammatory intestinal diseases [59]. It is known that intestinal microbiota plays a fundamental role in the structuring and functioning of the brain [89] and that dysbiosis of the gut microbiota would control the brain functions through a gut-brain axis involving the immune system, the ascending vagal nerve pathway or plasma metabolites and neurotransmitters [90]. At the phylum level, 5-FU treatment has been shown to increase Verrucomicrobia and decrease Firmicutes in BALB/c mouse cecum [61]. Contrary to the results of this paper, in the present study, 5-FU did not impact Firmicutes, and a decrease in Verrucomicrobia was only identified in the 5-FU/Qiseng® group.

A human study interested in Panax ginseng metabolism revealed that a low level of Proteobacteria in feces was associated with high metabolism of Rb1 ginsenosides present in ginseng to compound K [91]. Indeed, some ginsenosides such as Rb1 and Rc, were digested by gastric acid and/or intestinal bacteria into smaller compounds, such as Rd and compound K, and further into Protopanaxadiol [58]. In our chemotherapy mouse model, we established for the first time the role of 5-FU in increasing Lactobacillus, and more specifically, L. reuteri, L. acidophilus and L. johnsonii/gasseri, and decreasing L. murinus/animalis. This chemotherapy-induced elevation of Lactobacillus species dysbiosis was mainly prevented by Qiseng® but also vitamin C, but concomitantly, in all Qiseng® mice, a specific diminution of Beta-, Gamma- and Delta-proteobacteria was observed. Thus, Qiseng® modified the gut microbiota equilibrium through a decrease in proteobacteria while preventing the increase in Lactobacillus induced by 5-FU. Similarly, ginsenoside supplementation can restore the composition of the microbiota altered by chemotherapy [92]. Additionally, it was shown that a decoction of Ginseng could restore D-galactose-induced memory deficits in rats by up-regulating Bacteroidetes and down-regulating Lactobacillus [93].

These preclinical data are in agreement with a randomized clinical trial concluding that probiotic supplementation during chemotherapy could reduce the incidence of CRCI, by means of an increase in the plasma metabolite p-Mentha-1,8-dien-7-ol and potentially reduced inflammation in breast cancer patients [94]. Although several Lactobacillus species are currently used as probiotics to improve gastrointestinal health, increased levels of Lactobacilli are not always associated with healthy conditions. For example, higher levels of Lactobacilli were reported in obese individuals [95], as well as in mouse models of undernutrition [96]. Lactobacilli may, in some instances, activate the immune system by engaging host pattern-recognition receptors and trigger inflammation [97], playing a role in bowel inflammation disease [93]. Indeed, the oral administration of L. reuteri to Lactobacillus-free mice resulted in an inflammatory reaction of the intestinal mucosa 6 days after inoculation, correlated with IL-1α and IL-6 mRNA expression in small intestine enterocytes [98]. Moreover, L. acidophilus can promote cell reactive oxygen species (ROS) in cultured intestinal epithelial cells [99], whose production likely contributes to intestinal tissue damage and triggers NF-κB, leading to pro-inflammatory cytokines, such as TNF-α,
IL-1β and IL-6 [16,17]. Thus Qiseng® but also vitamin C may control intestinal mucosa
inflammation during chemotherapy.

Here, we evaluated the serum levels of ginsenosides in the control and 5-FU mice after two weeks of Qiseng® administration and mainly found Rb1, Rd and Rc, and also the compound K metabolite [20], Protopanaxadiol. The absence of compound K can be explained by a rapid metabolization. Indeed, in rats, it was shown that compound K was detectable in blood from 4 h to 7 h post-oral-administration of Rb1 [100]. Since we collected blood samples at least 24 h post-Qiseng® oral treatment, the absence of compound K can be correlated to its metabolization into Protopanaxadiol, here detected in some samples. The levels of ginsenosides found after 24 h are, nevertheless, in agreement with previous studies showing a proportion of Rb1 and Rc ginsenosides unmetabolized by bacteria after their administration [100,101]. In our study, Rc was even detected in higher concentrations in the serum of 5-FU mice, suggesting less metabolization, possibly due to the chemotherapy-induced dysbiosis. Interestingly, the ginsenoside Rc would possess the highest antioxidant activity, followed by Rb1, then Rd, preventing the formation of ROS, whose elevation is involved in inflammatory processes and production of pro-inflammatory cytokines [102]. Thus, Qiseng®-derived ginsenosides should contribute to reducing the 5-FU impact on intestinal mucosa and the intestinal wall, while the ginsenosides available in the bloodstream may, in addition, play neuroprotective roles.

Intestinal damages following 5-FU treatment were characterized here by a decrease in the intestinal surface and villi height, correlated with an increase in intestinal inflammation corroborated by the infiltration of MOMA+ macrophages. In complete agreement, a decrease in intestinal villi height and increased inflammatory cell infiltration in both mucosal and sub-mucosal intestines have been attributed to chemotherapy [103]. Interestingly, the American ginseng polysaccharide and ginsenosides can relieve cyclophosphamide-induced damage by protecting mucosal surfaces against infection [92]. Our results showed that Qiseng® only partially protected the intestinal surface, while the 5-FU-induced diminished height of the villi was not significantly prevented. However, Qiseng® compared to vitamin C lowered monocyte/macrophage infiltration caused by chemotherapy. Intestine-activated macrophages may produce pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 but also ROS [104]. In particular, IL-6 has been shown to increase the epithelium tight junction permeability of Caco-2 monolayers [105], potentially responsible for bloodstream diffusion of microbial products triggering systemic inflammation and increased serum IL-6 level [106].

Changes in the composition of the cecal microbiota and intestinal inflammation have been associated with elevation of pro-inflammatory cytokines [59]. In a mouse model of colonic mucositis induced by 5-FU, the increased serum levels of IL-6 and TNF-α were already described [61]. In the present study, 5-FU also evoked plasma levels of IL-6 and TNF-α as well as IL-2, IL-4, IL-12p70, IL-17 and MCP-1 while decreasing RANTES. We demonstrated positive correlations between enhanced IL-6 and MCP-1 with increased proportion of Lactobacilli, and more specifically, L. acidophilus. Interestingly, L. acidophilus could upregulate a number of effector genes, such as IL-6 and CCL2 (MCP-1) in mice, involving NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK) signaling pathways in intestinal epithelial cell lines [65]. We also observed that the co-administration of vitamin C with 5-FU suppressed plasma IL-2, IL-4, IL-12p70, IL-17 and TNF-α cytokines but did not prevent increased IL-6 and MCP-1 as well as decreased RANTES levels. Such data closely corroborate a partial but not complete prevention of IL-6 expression by vitamin C supplementation in a mouse model of colon cancer [107]. A remarkable effect of Qiseng® was thus detected, since all the measured cytokines were found at the level of the NaCl mice, possibly due to the Rb1, Rd and Protopanaxadiol ginsenosides resulting from Qiseng® metabolization. Indeed, the administration of Rb1 for 23 days in a cancer-induced cachexia mouse model led to diminished TNF-α and IL-6 levels in serum evoked by cancer [26]. Similarly, Rd was able to alleviate the colitis induced by E. Coli, in particular by suppressing the increased expression of IL-6, thus normalizing the anxiety/depression behaviors [108],
IL-1β and IL-6 [16,17]. Thus Qiseng® but also vitamin C may control intestinal mucosa
inflammation during chemotherapy.

Here, we evaluated the serum levels of ginsenosides in the control and 5-FU mice after two weeks of Qiseng® administration and mainly found Rb1, Rd and Rc, and also the compound K metabolite [20], Protopanaxadiol. The absence of compound K can be explained by a rapid metabolization. Indeed, in rats, it was shown that compound K was detectable in blood from 4 h to 7 h post-oral-administration of Rb1 [100]. Since we collected blood samples at least 24 h post-Qiseng® oral treatment, the absence of compound K can be correlated to its metabolization into Protopanaxadiol, here detected in some samples. The levels of ginsenosides found after 24 h are, nevertheless, in agreement with previous studies showing a proportion of Rb1 and Rc ginsenosides unmetabolized by bacteria after their administration [100,101]. In our study, Rc was even detected in higher concentrations in the serum of 5-FU mice, suggesting less metabolization, possibly due to the chemotherapy-induced dysbiosis. Interestingly, the ginsenoside Rc would possess the highest antioxidant activity, followed by Rb1, then Rd, preventing the formation of ROS, whose elevation is involved in inflammatory processes and production of pro-inflammatory cytokines [102]. Thus, Qiseng®-derived ginsenosides should contribute to reducing the 5-FU impact on intestinal mucosa and the intestinal wall, while the ginsenosides available in the bloodstream may, in addition, play neuroprotective roles.

Intestinal damages following 5-FU treatment were characterized here by a decrease in the intestinal surface and villi height, correlated with an increase in intestinal inflammation corroborated by the infiltration of MOMA+ macrophages. In complete agreement, a decrease in intestinal villi height and increased inflammatory cell infiltration in both mucosal and sub-mucosal intestines have been attributed to chemotherapy [103]. Interestingly, the American ginseng polysaccharide and ginsenosides can relieve cyclophosphamide-induced damage by protecting mucosal surfaces against infection [92]. Our results showed that Qiseng® only partially protected the intestinal surface, while the 5-FU-induced diminished height of the villi was not significantly prevented. However, Qiseng® compared to vitamin C lowered monocyte/macrophage infiltration caused by chemotherapy. Intestine-activated macrophages may produce pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 but also ROS [104]. In particular, IL-6 has been shown to increase the epithelium tight junction permeability of Caco-2 monolayers [105], potentially responsible for bloodstream diffusion of microbial products triggering systemic inflammation and increased serum IL-6 level [106].

Changes in the composition of the cecal microbiota and intestinal inflammation have been associated with elevation of pro-inflammatory cytokines [59]. In a mouse model of colonic mucositis induced by 5-FU, the increased serum levels of IL-6 and TNF-α were already described [61]. In the present study, 5-FU also evoked plasma levels of IL-6 and TNF-α as well as IL-2, IL-4, IL-12p70, IL-17 and MCP-1 while decreasing RANTES. We demonstrated positive correlations between enhanced IL-6 and MCP-1 with increased proportion of Lactobacilli, and more specifically, L. acidophilus. Interestingly, L. acidophilus could upregulate a number of effector genes, such as IL-6 and CCL2 (MCP-1) in mice, involving NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK) signaling pathways in intestinal epithelial cell lines [65]. We also observed that the co-administration of vitamin C with 5-FU suppressed plasma IL-2, IL-4, IL-12p70, IL-17 and TNF-α cytokines but did not prevent increased IL-6 and MCP-1 as well as decreased RANTES levels. Such data closely corroborate a partial but not complete prevention of IL-6 expression by vitamin C supplementation in a mouse model of colon cancer [107]. A remarkable effect of Qiseng® was thus detected, since all the measured cytokines were found at the level of the NaCl mice, possibly due to the Rb1, Rd and Protopanaxadiol ginsenosides resulting from Qiseng® metabolization. Indeed, the administration of Rb1 for 23 days in a cancer-induced cachexia mouse model led to diminished TNF-α and IL-6 levels in serum evoked by cancer [26]. Similarly, Rd was able to alleviate the colitis induced by E. Coli, in particular by suppressing the increased expression of IL-6, thus normalizing the anxiety/depression behaviors [108],
suggesting obvious links between dysbiosis, intestinal inflammation, circulating cytokines, and more specifically, IL-6.

In cancer patients, cytokine circulating levels, particularly IL-6, have been positively correlated with scores of cognition and somatic fatigue [14,62]. In mice, a single intravenous injection of IL-6 produced an increased immobility time [63] and a significant decrease in locomotor activity [15]. We demonstrated that 5-FU mice receiving placebo or vitamin C and exhibiting at least an increased plasma IL-6 level show marked decrease in locomotor activity and exploration behavior. Because the anxiety-like (EPM test) and depressive-like (TST/FST) behaviors were not significantly modified when 5-FU was administered, we propose that 5-FU evoked symptoms of neurofatigue associated, at least in part, with IL-6. Qiseng® supplementation during chemotherapy notably extinguished IL-6 in serum and rehabilitated mouse locomotor activity and exploration. While BBB can selectively transport several circulating cytokines, such as TNF-α or IL-6, leading to neuroinflammation [109], it should be noticed that IL-6 tg⁺/⁺ mice with a high level of IL-6 expressed by astrocytes presented a reduced activity/exploration in OFT and LDB compared with IL-6 tg⁻/⁻ mice [110]. Some studies already reported a role of the glycoprotein 130 (gp130) receptor for IL-6 in astrocytes but also in neurons. For example, in a mouse model of autoimmune encephalomyelitis, mice with astrocytes expressing the gp130 receptor were shown to develop astrogliosis [111]. In our study, we observed in chemotherapy mice a net immunolabeling of gp130 detected both in mature neurons but also in astrocytes within the Hp correlated with decreased neural precursor cell proliferation in the dentate gyrus. Similar results indicate that overexpression of IL-6 by astrocytes decreased neurogenesis by 63% in the Hp dentate gyrus of adult mice [112]. Here, Qiseng® administered with chemotherapy blocked serum IL-6 and attenuated the expression of IL-6 gp130 receptor in the dHp and vHp through mechanisms potentially involving ginsenosides. This control of 5-FU-induced neuroinflammatory processes is likely more specifically associated with diminished neurogenesis in the vHp and alteration of locomotor activity.

We recognize, however, that this work has several limits. First, we are fully aware that we interpreted “fatigue” in animals through the association of exploratory and motivation behaviors and spontaneous activity and that we cannot claim that these behaviors reflect fatigue. Among patients, cancer-related fatigue (CRF), as defined by the National Comprehensive Cancer Network (NCCN), is “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” [113]. Interestingly, it has been shown in humans that decreased motivation and fatigue are both related to alterations in the basal ganglia and reduced neuronal activation of the reward signals [114,115], suggesting similar neurological substrates. Thus, we and others focused on cancer-related fatigue in animals related to tumor growth [116], chemotherapy [117] or radiation [118] by using a common physical activity criterion by means of OFT [119] also involving motivation. Second, this work was exclusively conducted on C57Bl/6 male mice to avoid behavioral issues due to the estrous cycle in female mice. Accordingly, it was shown in female mice that the estrus cycle has a robust effect on anxiety, low anxiety being associated with a high estradiol level (proestrus and estrus phase) [120]. Nevertheless, a very important study in young mice exposed to a combination of chemotherapy established that males, and not females, exhibited deficits in short memory and executive functions 4–5 weeks after chemotherapy [121]. Interestingly, this early exposure to chemotherapy led to an increased MCP-1 expression only in males, while the oligodendrocyte markers were altered in both males and females. Thus, the present work should be reproduced in female mice.

**5. Conclusions**

Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. To better understand the pathophysiology and neurobiological mechanisms of CRCI and the
suggesting obvious links between dysbiosis, intestinal inflammation, circulating cytokines, and more specifically, IL-6.

In cancer patients, cytokine circulating levels, particularly IL-6, have been positively correlated with scores of cognition and somatic fatigue [14,62]. In mice, a single intravenous injection of IL-6 produced an increased immobility time [63] and a significant decrease in locomotor activity [15]. We demonstrated that 5-FU mice receiving placebo or vitamin C and exhibiting at least an increased plasma IL-6 level show marked decrease in locomotor activity and exploration behavior. Because the anxiety-like (EPM test) and depressive-like (TST/FST) behaviors were not significantly modified when 5-FU was administered, we propose that 5-FU evoked symptoms of neurofatigue associated, at least in part, with IL-6. Qiseng® supplementation during chemotherapy notably extinguished IL-6 in serum and rehabilitated mouse locomotor activity and exploration. While BBB can selectively transport several circulating cytokines, such as TNF-α or IL-6, leading to neuroinflammation [109], it should be noticed that IL-6 tg⁺/⁺ mice with a high level of IL-6 expressed by astrocytes presented a reduced activity/exploration in OFT and LDB compared with IL-6 tg⁻/⁻ mice [110]. Some studies already reported a role of the glycoprotein 130 (gp130) receptor for IL-6 in astrocytes but also in neurons. For example, in a mouse model of autoimmune encephalomyelitis, mice with astrocytes expressing the gp130 receptor were shown to develop astrogliosis [111]. In our study, we observed in chemotherapy mice a net immunolabeling of gp130 detected both in mature neurons but also in astrocytes within the Hp correlated with decreased neural precursor cell proliferation in the dentate gyrus. Similar results indicate that overexpression of IL-6 by astrocytes decreased neurogenesis by 63% in the Hp dentate gyrus of adult mice [112]. Here, Qiseng® administered with chemotherapy blocked serum IL-6 and attenuated the expression of IL-6 gp130 receptor in the dHp and vHp through mechanisms potentially involving ginsenosides. This control of 5-FU-induced neuroinflammatory processes is likely more specifically associated with diminished neurogenesis in the vHp and alteration of locomotor activity.

We recognize, however, that this work has several limits. First, we are fully aware that we interpreted “fatigue” in animals through the association of exploratory and motivation behaviors and spontaneous activity and that we cannot claim that these behaviors reflect fatigue. Among patients, cancer-related fatigue (CRF), as defined by the National Comprehensive Cancer Network (NCCN), is “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” [113]. Interestingly, it has been shown in humans that decreased motivation and fatigue are both related to alterations in the basal ganglia and reduced neuronal activation of the reward signals [114,115], suggesting similar neurological substrates. Thus, we and others focused on cancer-related fatigue in animals related to tumor growth [116], chemotherapy [117] or radiation [118] by using a common physical activity criterion by means of OFT [119] also involving motivation. Second, this work was exclusively conducted on C57Bl/6 male mice to avoid behavioral issues due to the estrous cycle in female mice. Accordingly, it was shown in female mice that the estrus cycle has a robust effect on anxiety, low anxiety being associated with a high estradiol level (proestrus and estrus phase) [120]. Nevertheless, a very important study in young mice exposed to a combination of chemotherapy established that males, and not females, exhibited deficits in short memory and executive functions 4–5 weeks after chemotherapy [121]. Interestingly, this early exposure to chemotherapy led to an increased MCP-1 expression only in males, while the oligodencrocyte markers were altered in both males and females. Thus, the present work should be reproduced in female mice.

**5. Conclusions**

Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. To better understand the pathophysiology and neurobiological mechanisms of CRCI and the
direct impact of the different cancer treatments, animal models have been developed to investigate the selective effects of the disease and/or treatment on the neurocognitive function and the influence of stress, mood and aging on cognitive impairment. It must be said that growing demands for CRCI management from patients led to studies testing cognitive rehabilitation in cancer patients but that animal models should provide cues of efficacy of pharmacological and non-pharmacological care and support of CRCI and fatigue.

Here, we proved that frequent administrations of 5-FU, in the absence of cancer, induced the loss of locomotor/exploratory activity that we associated with neurofatigue, coupled with cognitive deficits (spatial learning and memory and flexibility). In these 5-FU mice, the gut microbiota composition was altered and the intestinal mucosa was inflamed, both associated with proinflammatory serum cytokines, notably IL-6. Vitamin C did not compensate for the effects of 5-FU on activity/fatigue, alteration of the microbiota and elevation of IL-6.

A *P. qfolius*-based solution (Qiseng®) completely prevented the deleterious effect of 5-FU on locomotor and exploration activity while preventing microbiota dysbiosis and elevation of all cytokines. This preclinical study established that Qiseng® supplementation could prevent chemotherapy-induced neurofatigue but not cognitive impairment. These data provide an important validation of the beneficial effect of a Qiseng® supplementation on fatigue in cancer patients treated with chemotherapy, while this type of non-pharmacologic intervention should be more accepted by patients. Accordingly, a recent clinical trial "Evaluation of the Impact of Taking American Ginseng for 8 weeks on Fatigue in Patients Treated for Localized Breast Cancer (QISEIN)" (NCT05241405) was initiated very recently, with the objective of improving cancer patients' QoL. We think that the Qiseng®-induced benefit is not trivial, since mental fatigue affects large-scale network connectivity in the brain during high cognitive demands associated with effort [122]. In fact, preventing neurofatigue should enable optimal cognitive functions or acceptance of the effort required in a cognitive rehabilitation protocol.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers14184403/s1, Table S1: Primer sequences used to quantify intestinal bacteria. Table S2: Summary of the behavioral phenotypes of NaCl vs. 5-FU mice treated with placebo, vitamin C or Qiseng®. Table S3: Impact of chemotherapy injection on plasma pro-inflammatory, pluripotent, chemotactic and leukocyte growth cytokines.

**Author Contributions:** Conceptualization, H.C., M.D. and F.J.; methodology, H.C., M.D., R.P., L.D., C.G. and D.R., software, R.P. and P.H.; validation, H.C. and M.D.; formal analysis, R.P.; investigation, R.P., N.B., A.M., K.-P.D., M.D. and H.C.; data curation, R.P.; writing—original draft preparation, R.P. and H.C.; writing—review and editing, D.R., M.C., C.F. and H.C.; visualization, R.P. and H.C.; supervision, V.C. and H.C.; project administration, L.T., H.C.; funding acquisition, H.C., L.T., F.J. and C.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was independently funded by Laboratoire Natsuca. This work was also supported by The Ligue Nationale contre le Cancer (Plate-forme Cancer and cognition), Normandy Rouen University and Inserm.

**Institutional Review Board Statement:** The study did not involve humans. The number and the suffering of animals were minimized in accordance with the guidelines of the European Parliament and Council Directive (2010/63/EU) 3/EU) and ARRIVE (Animal Research: Reporting of In Vivo Experiments) 2.0 guidelines. This project was approved by the "Comité d'Ethique Normandie en Matière d'Expérimentation Animale" and the French Research Minister (#20779-201902001322662 v7) and carried out under the supervision of authorized operators (H.C. and M.D.).

**Data Availability Statement:** Data supporting the reported results are available upon request.
direct impact of the different cancer treatments, animal models have been developed to investigate the selective effects of the disease and/or treatment on the neurocognitive function and the influence of stress, mood and aging on cognitive impairment. It must be said that growing demands for CRCI management from patients led to studies testing cognitive rehabilitation in cancer patients but that animal models should provide cues of efficacy of pharmacological and non-pharmacological care and support of CRCI and fatigue.

Here, we proved that frequent administrations of 5-FU, in the absence of cancer, induced the loss of locomotor/exploratory activity that we associated with neurofatigue, coupled with cognitive deficits (spatial learning and memory and flexibility). In these 5-FU mice, the gut microbiota composition was altered and the intestinal mucosa was inflamed, both associated with proinflammatory serum cytokines, notably IL-6. Vitamin C did not compensate for the effects of 5-FU on activity/fatigue, alteration of the microbiota and elevation of IL-6.

A *P. qfolius*-based solution (Qiseng®) completely prevented the deleterious effect of 5-FU on locomotor and exploration activity while preventing microbiota dysbiosis and elevation of all cytokines. This preclinical study established that Qiseng® supplementation could prevent chemotherapy-induced neurofatigue but not cognitive impairment. These data provide an important validation of the beneficial effect of a Qiseng® supplementation on fatigue in cancer patients treated with chemotherapy, while this type of non-pharmacologic intervention should be more accepted by patients. Accordingly, a recent clinical trial "Evaluation of the Impact of Taking American Ginseng for 8 weeks on Fatigue in Patients Treated for Localized Breast Cancer (QISEIN)" (NCT05241405) was initiated very recently, with the objective of improving cancer patients' QoL. We think that the Qiseng®-induced benefit is not trivial, since mental fatigue affects large-scale network connectivity in the brain during high cognitive demands associated with effort [122]. In fact, preventing neurofatigue should enable optimal cognitive functions or acceptance of the effort required in a cognitive rehabilitation protocol.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers14184403/s1, Table S1: Primer sequences used to quantify intestinal bacteria. Table S2: Summary of the behavioral phenotypes of NaCl vs. 5-FU mice treated with placebo, vitamin C or Qiseng®. Table S3: Impact of chemotherapy injection on plasma pro-inflammatory, pluripotent, chemotactic and leukocyte growth cytokines.

**Author Contributions:** Conceptualization, H.C., M.D. and F.J.; methodology, H.C., M.D., R.P., L.D., C.G. and D.R., software, R.P. and P.H.; validation, H.C. and M.D.; formal analysis, R.P.; investigation, R.P., N.B., A.M., K.-P.D., M.D. and H.C.; data curation, R.P.; writing—original draft preparation, R.P. and H.C.; writing—review and editing, D.R., M.C., C.F. and H.C.; visualization, R.P. and H.C.; supervision, V.C. and H.C.; project administration, L.T., H.C.; funding acquisition, H.C., L.T., F.J. and C.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was independently funded by Laboratoire Natsuca. This work was also supported by The Ligue Nationale contre le Cancer (Plate-forme Cancer and cognition), Normandy Rouen University and Inserm.

**Institutional Review Board Statement:** The study did not involve humans. The number and the suffering of animals were minimized in accordance with the guidelines of the European Parliament and Council Directive (2010/63/EU) 3/EU) and ARRIVE (Animal Research: Reporting of In Vivo Experiments) 2.0 guidelines. This project was approved by the "Comité d'Ethique Normandie en Matière d'Expérimentation Animale" and the French Research Minister (#20779-201902001322662 v7) and carried out under the supervision of authorized operators (H.C. and M.D.).

**Data Availability Statement:** Data supporting the reported results are available upon request.
**Acknowledgments:** This study was made possible by the free access to the deep-learning framework Chainer used in the Python program for the evaluation and classification of learning strategies in the Morris water maze test. Images were obtained from PRIMACEN (http://www.primacen.fr; accessed on 21 July 2022), the Cell Imaging Platform of Normandy, IRIB, Normandy Rouen University, France. We thank Arnaud Arabo and Julie Maucotel for animal housing and care and for access to the behavioral equipment of the Biological Resources Department (Normandie Rouen University, France).

**Conflicts of Interest:** Renaud Parment, Martine Dubois, Laurence Desrues, Alexandre Mutel, Kléouforo-Paul Dembélé, Nicolas Belin, Laure Tron, Pascal Hilber, Moïse Coëffier, Vincent Compère and David Ribet have no biomedical financial interests or no conflicts of interest to declare. Pr Florence Joly reports having received lecture and consulting fees from Janssen-Cilag, Astellas Pharma, Bayer, Sanofi and research funding from Astellas Pharma. Hélène Castel reports having received research funding from Laboratoire Natsuca. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results". Céline Féger provided expert review of the written paper.

## References

1. Joly, F.; Heutte, N.; Duclos, B.; Noal, S.; Léger-Hardy, I.; Dauchy, S.; Longato, N.; Desrues, L.; Houede, N.; Lange, M.; et al. Prospective Evaluation of the Impact of Antiangiogenic Treatment on Cognitive Functions in Metastatic Renal Cancer. *Eur. Urol. Focus* **2016**, *2*, 642–649. [CrossRef] [PubMed]

2. Lange, M.; Rigal, O.; Clarisse, B.; Giffard, B.; Sevin, E.; Barillet, M.; Eustache, F.; Joly, F. Cognitive dysfunctions in elderly cancer patients: A new challenge for oncologists. *Cancer Treat. Rev.* **2014**, *40*, 810–817. [CrossRef] [PubMed]

3. Lange, M.; Joly, F.; Vardy, J.; Ahles, T.; Dubois, M.; Tron, L.; Winocur, G.; De Ruiter, M.B.; Castel, H. Cancer-related cognitive impairment: An update on state of the art, detection, and management strategies in cancer survivors. *Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.* **2019**, *30*, 1925–1940. [CrossRef] [PubMed]

4. Ferguson, R.J.; McDonald, B.C.; Saykin, A.J.; Ahles, T.A. Brain structure and function differences in monozygotic twins: Possible effects of breast cancer chemotherapy. *J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.* **2007**, *25*, 3866–3870. [CrossRef]

5. Silverman, D.H.S.; Dy, C.J.; Castellon, S.A.; Lai, J.; Pio, B.S.; Abraham, L.; Waddell, K.; Petersen, L.; Phelps, M.E.; Ganz, P.A. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. *Breast Cancer Res. Treat.* **2007**, *103*, 303–311. [CrossRef]

6. Gibson, E.M.; Nagaraja, S.; Ocampo, A.; Tam, L.T.; Wood, L.S.; Pallegar, P.N.; Greene, J.J.; Geraghty, A.C.; Goldstein, A.K.; Ni, L.; et al. Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. *Cell* **2019**, *176*, 43–55.e13. [CrossRef]

7. Castel, H.; Denouel, A.; Lange, M.; Tonon, M.-C.; Dubois, M.; Joly, F. Biomarkers Associated with Cognitive Impairment in Treated Cancer Patients: Potential Predisposition and Risk Factors. *Front. Pharmacol.* **2017**, *8*, 138. [CrossRef]

8. Naser, A.Y.; Hameed, A.N.; Mustafa, N.; Alwafi, H.; Dahmash, E.Z.; Alyami, H.S.; Khalil, H. Depression and Anxiety in Patients with Cancer: A Cross-Sectional Study. *Front. Psychol.* **2021**, *12*, 585534. [CrossRef]

9. Himmerich, H.; Patsalos, O.; Lichtblau, N.; Ibrahim, M.A.A.; Dalton, B. Cytokine Research in Depression: Principles, Challenges, and Open Questions. *Front. Psychiatry* **2019**, *10*, 30. [CrossRef]

10. Köhler, C.A.; Freitas, T.H.; Stubbs, B.; Maes, M.; Solmi, M.; Veronese, N.; de Andrade, N.Q.; Morris, G.; Fernandes, B.S.; Brunoni, A.R.; et al. Peripheral Alterations in Cytokine and Chemokine Levels after Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis. *Mol. Neurobiol.* **2018**, *55*, 4195–4206. [CrossRef]

11. Scuric, Z.; Carroll, J.E.; Bower, J.E.; Ramos-Perlberg, S.; Petersen, L.; Esquivel, S.; Hogan, M.; Chapman, A.M.; Irwin, M.R.; Breen, E.C.; et al. Biomarkers of aging associated with past treatments in breast cancer survivors. *NPJ Breast Cancer* **2017**, *3*, 50. [CrossRef]

12. Barton, D.L.; Liu, H.; Dakhil, S.R.; Linquist, B.; Sloan, J.A.; Nichols, C.R.; McGinn, T.W.; Stella, P.J.; Seeger, G.R.; Sood, A.; et al. Wisconsin Ginseng (*Panax quinquefolius*) to improve cancer-related fatigue: A randomized, double-blind trial, N07C2. *J. Natl. Cancer Inst.* **2013**, *105*, 1230–1238. [CrossRef]

13. Barton, D.L.; Soori, G.S.; Bauer, B.A.; Sloan, J.A.; Johnson, P.A.; Figueras, C.; Duane, S.; Mattar, B.; Liu, H.; Atherton, P.J.; et al. Pilot study of *Panax quinquefolius* (American ginseng) to improve cancer-related fatigue: A randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA. *Supportive Care Cancer Off. J. Multinatl. Assoc. Supportive Care Cancer* **2010**, *18*, 179–187. [CrossRef]

14. Schubert, C.; Hong, S.; Natarajan, L.; Mills, P.J.; Dimsdale, J.E. The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review. *Brain Behav. Immun.* **2007**, *21*, 413–427. [CrossRef]

15. Skelly, D.T.; Hennessy, E.; Dansereau, M.-A.; Cunningham, C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, TNF-α and IL-6 challenges in C57BL/6 mice. *PLoS ONE* **2013**, *8*, e69123. [CrossRef]
**Acknowledgments:** This study was made possible by the free access to the deep-learning framework Chainer used in the Python program for the evaluation and classification of learning strategies in the Morris water maze test. Images were obtained from PRIMACEN (http://www.primacen.fr; accessed on 21 July 2022), the Cell Imaging Platform of Normandy, IRIB, Normandy Rouen University, France. We thank Arnaud Arabo and Julie Maucotel for animal housing and care and for access to the behavioral equipment of the Biological Resources Department (Normandie Rouen University, France).

**Conflicts of Interest:** Renaud Parment, Martine Dubois, Laurence Desrues, Alexandre Mutel, Kléouforo-Paul Dembélé, Nicolas Belin, Laure Tron, Pascal Hilber, Moïse Coëffier, Vincent Compère and David Ribet have no biomedical financial interests or no conflicts of interest to declare. Pr Florence Joly reports having received lecture and consulting fees from Janssen-Cilag, Astellas Pharma, Bayer, Sanofi and research funding from Astellas Pharma. Hélène Castel reports having received research funding from Laboratoire Natsuca. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results". Céline Féger provided expert review of the written paper.

## References

1. Joly, F.; Heutte, N.; Duclos, B.; Noal, S.; Léger-Hardy, I.; Dauchy, S.; Longato, N.; Desrues, L.; Houede, N.; Lange, M.; et al. Prospective Evaluation of the Impact of Antiangiogenic Treatment on Cognitive Functions in Metastatic Renal Cancer. *Eur. Urol. Focus* **2016**, *2*, 642–649. [CrossRef] [PubMed]

2. Lange, M.; Rigal, O.; Clarisse, B.; Giffard, B.; Sevin, E.; Barillet, M.; Eustache, F.; Joly, F. Cognitive dysfunctions in elderly cancer patients: A new challenge for oncologists. *Cancer Treat. Rev.* **2014**, *40*, 810–817. [CrossRef] [PubMed]

3. Lange, M.; Joly, F.; Vardy, J.; Ahles, T.; Dubois, M.; Tron, L.; Winocur, G.; De Ruiter, M.B.; Castel, H. Cancer-related cognitive impairment: An update on state of the art, detection, and management strategies in cancer survivors. *Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.* **2019**, *30*, 1925–1940. [CrossRef] [PubMed]

4. Ferguson, R.J.; McDonald, B.C.; Saykin, A.J.; Ahles, T.A. Brain structure and function differences in monozygotic twins: Possible effects of breast cancer chemotherapy. *J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.* **2007**, *25*, 3866–3870. [CrossRef]

5. Silverman, D.H.S.; Dy, C.J.; Castellon, S.A.; Lai, J.; Pio, B.S.; Abraham, L.; Waddell, K.; Petersen, L.; Phelps, M.E.; Ganz, P.A. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. *Breast Cancer Res. Treat.* **2007**, *103*, 303–311. [CrossRef]

6. Gibson, E.M.; Nagaraja, S.; Ocampo, A.; Tam, L.T.; Wood, L.S.; Pallegar, P.N.; Greene, J.J.; Geraghty, A.C.; Goldstein, A.K.; Ni, L.; et al. Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. *Cell* **2019**, *176*, 43–55.e13. [CrossRef]

7. Castel, H.; Denouel, A.; Lange, M.; Tonon, M.-C.; Dubois, M.; Joly, F. Biomarkers Associated with Cognitive Impairment in Treated Cancer Patients: Potential Predisposition and Risk Factors. *Front. Pharmacol.* **2017**, *8*, 138. [CrossRef]

8. Naser, A.Y.; Hameed, A.N.; Mustafa, N.; Alwafi, H.; Dahmash, E.Z.; Alyami, H.S.; Khalil, H. Depression and Anxiety in Patients with Cancer: A Cross-Sectional Study. *Front. Psychol.* **2021**, *12*, 585534. [CrossRef]

9. Himmerich, H.; Patsalos, O.; Lichtblau, N.; Ibrahim, M.A.A.; Dalton, B. Cytokine Research in Depression: Principles, Challenges, and Open Questions. *Front. Psychiatry* **2019**, *10*, 30. [CrossRef]

10. Köhler, C.A.; Freitas, T.H.; Stubbs, B.; Maes, M.; Solmi, M.; Veronese, N.; de Andrade, N.Q.; Morris, G.; Fernandes, B.S.; Brunoni, A.R.; et al. Peripheral Alterations in Cytokine and Chemokine Levels after Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis. *Mol. Neurobiol.* **2018**, *55*, 4195–4206. [CrossRef]

11. Scuric, Z.; Carroll, J.E.; Bower, J.E.; Ramos-Perlberg, S.; Petersen, L.; Esquivel, S.; Hogan, M.; Chapman, A.M.; Irwin, M.R.; Breen, E.C.; et al. Biomarkers of aging associated with past treatments in breast cancer survivors. *NPJ Breast Cancer* **2017**, *3*, 50. [CrossRef]

12. Barton, D.L.; Liu, H.; Dakhil, S.R.; Linquist, B.; Sloan, J.A.; Nichols, C.R.; McGinn, T.W.; Stella, P.J.; Seeger, G.R.; Sood, A.; et al. Wisconsin Ginseng (*Panax quinquefolius*) to improve cancer-related fatigue: A randomized, double-blind trial, N07C2. *J. Natl. Cancer Inst.* **2013**, *105*, 1230–1238. [CrossRef]

13. Barton, D.L.; Soori, G.S.; Bauer, B.A.; Sloan, J.A.; Johnson, P.A.; Figueras, C.; Duane, S.; Mattar, B.; Liu, H.; Atherton, P.J.; et al. Pilot study of *Panax quinquefolius* (American ginseng) to improve cancer-related fatigue: A randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA. *Supportive Care Cancer Off. J. Multinatl. Assoc. Supportive Care Cancer* **2010**, *18*, 179–187. [CrossRef]

14. Schubert, C.; Hong, S.; Natarajan, L.; Mills, P.J.; Dimsdale, J.E. The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review. *Brain Behav. Immun.* **2007**, *21*, 413–427. [CrossRef]

15. Skelly, D.T.; Hennessy, E.; Dansereau, M.-A.; Cunningham, C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, TNF-α and IL-6 challenges in C57BL/6 mice. *PLoS ONE* **2013**, *8*, e69123. [CrossRef]
16. Sonis, S.T.; Elting, L.S.; Keefe, D.; Peterson, D.E.; Schubert, M.; Hauer-Jensen, M.; Bekele, B.N.; Raber-Durlacher, J.; Donnelly, J.P.; Rubenstein, E.B.; et al. Perspectives on cancer therapy-induced mucosal injury: Pathogenesis, measurement, epidemiology, and consequences for patients. *Cancer* **2004**, *100*, 1995–2025. [CrossRef]

17. Sonis, S.T.; O'Donnell, K.E.; Popat, R.; Bragdon, C.; Phelan, S.; Cocks, D.; Epstein, J.B. The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis. *Oral Oncol.* **2004**, *40*, 170–176. [CrossRef]

18. Iop, A.; Manfredi, A.M.; Bonura, S. Fatigue in cancer patients receiving chemotherapy: An analysis of published studies. *Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.* **2004**, *15*, 712–720. [CrossRef]

19. Vollbracht, C.; Schneider, B.; Leendert, V.; Weiss, G.; Auerbach, L.; Beuth, J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: Results of a retrospective, multicentre, epidemiological cohort study in Germany. *In Vivo* **2011**, *25*, 983–990.

20. Mancuso, C.; Santangelo, R. *Panax ginseng* and *Panax quinquefolius*: From pharmacology to toxicology. *Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc.* **2017**, *107*, 362–372. [CrossRef]

21. Kennedy, D.O.; Scholey, A.B. Ginseng: Potential for the enhancement of cognitive performance and mood. *Pharmacol. Biochem. Behav.* **2003**, *75*, 687–700. [CrossRef]

22. Smith, I.; Williamson, E.M.; Putnam, S.; Farrimond, J.; Whalley, B.J. Effects and mechanisms of ginseng and ginsenosides on cognition. *Nutr. Rev.* **2014**, *72*, 319–333. [CrossRef] [PubMed]

23. Yuan, Q.-L.; Yang, C.-X.; Xu, P.; Gao, X.-Q.; Deng, L.; Chen, P.; Sun, Z.-L.; Chen, Q.-Y. Neuroprotective effects of ginsenoside Rb1 on transient cerebral ischemia in rats. *Brain Res.* **2007**, *1167*, 1–12. [CrossRef] [PubMed]

24. Ye, R.; Li, N.; Han, J.; Kong, X.; Cao, R.; Rao, Z.; Zhao, G. Neuroprotective effects of ginsenoside Rd against oxygen-glucose deprivation in cultured hippocampal neurons. *Neurosci. Res.* **2009**, *64*, 306–310. [CrossRef]

25. Zhao, H.; Li, Q.; Zhang, Z.; Pei, X.; Wang, J.; Li, Y. Long-term ginsenoside consumption prevents memory loss in aged SAMP8 mice by decreasing oxidative stress and up-regulating the plasticity-related proteins in hippocampus. *Brain Res.* **2009**, *1256*, 111–122. [CrossRef]

26. Lu, S.; Zhang, Y.; Li, H.; Zhang, J.; Ci, Y.; Han, M. Ginsenoside Rb1 can ameliorate the key inflammatory cytokines TNF-α and IL-6 in a cancer cachexia mouse model. *BMC Complement. Med. Ther.* **2020**, *20*, 11. [CrossRef]

27. Hussien, M.; Yousef, M.I. Impact of ginseng on neurotoxicity induced by cisplatin in rats. *Environ. Sci. Pollut. Res.* **2022**, *29*, 62042–62054. [CrossRef]

28. Prut, L.; Belzung, C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. *Eur. J. Pharmacol.* **2003**, *463*, 3–33. [CrossRef]

29. Seibenhener, M.L.; Wooten, M.C. Use of the Open Field Maze to Measure Locomotor and Anxiety-Like Behavior in Mice. *J. Vis. Exp. JoVE* **2015**, *96*, e52434. [CrossRef]

30. Lister, R.G. The use of a plus-maze to measure anxiety in the mouse. *Psychopharmacology* **1987**, *92*, 180–185. [CrossRef]

31. Hascoët, M.; Bourin, M.; Nic Dhonnchadha, B.A. The mouse light-dark paradigm: A review. *Prog. Neuro-Psychopharmacol. Biol. Psychiatry* **2001**, *25*, 141–166. [CrossRef]

32. Porsolt, R.D.; Bertin, A.; Jalfre, M. Behavioral despair in mice: A primary screening test for antidepressants. *Arch. Int. Pharmacodyn. Ther.* **1977**, *229*, 327–336.

33. Steru, L.; Chermat, R.; Thierry, B.; Simon, P. The tail suspension test: A new method for screening antidepressants in mice. *Psychopharmacology* **1985**, *85*, 367–370. [CrossRef]

34. Graziano, A.; Petrosini, L.; Bartoletti, A. Automatic recognition of explorative strategies in the Morris water maze. *J. Neurosci. Methods* **2003**, *130*, 33–44. [CrossRef]

35. Higaki, A.; Mogi, M.; Iwanami, J.; Min, L.-J.; Bai, H.-Y.; Shan, B.-S.; Kan-No, H.; Ikeda, S.; Higaki, J.; Horiuchi, M. Recognition of early stage thigmotaxis in Morris water maze test with convolutional neural network. *PLoS ONE* **2018**, *13*, e0197003. [CrossRef]

36. Illouz, T.; Madar, R.; Louzoun, Y.; Griffioen, K.J.; Okun, E. Corrigendum to “Unraveling cognitive traits using the Morris water maze unbiased strategy classification (MUST-C) algorithm”. *Brain Behav. Immun.* **2017**, *61*, 386. [CrossRef]

37. Nicola, C.; Dubois, M.; Campart, C.; Al Sagheer, T.; Desrues, L.; Schapman, D.; Galas, L.; Lange, M.; Joly, F.; Castel, H. The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice. *Cancers* **2021**, *13*, 3518. [CrossRef]

38. Liu, M.-Y.; Yin, C.-Y.; Zhu, L.-J.; Zhu, X.-H.; Xu, C.; Luo, C.-X.; Chen, H.; Zhu, D.-Y.; Zhou, Q.-G. Sucrose preference test for measurement of stress-induced anhedonia in mice. *Nat. Protoc.* **2018**, *13*, 1686–1698. [CrossRef]

39. Dore, J.; Ehrlich, S.; Levenez, F.; Pelletier, E.; Alberti, A.; Bertrand, L. *IHMS_SOP 06 V1*; Standard Operating Procedure for Fecal Samples DNA Extraction, Protocol Q. International Human Microbiome Standards, 2015. Available online: http://www.human-microbiome.org/index.php?id=Sop&num=006.

40. Fierer, N.; Jackson, J.A.; Vilgalys, R.; Jackson, R.B. Assessment of soil microbial community structure by use of taxon-specific quantitative PCR assays. *Appl. Environ. Microbiol.* **2005**, *71*, 4117–4120. [CrossRef]

41. Mühling, M.; Woolven-Allen, J.; Murrell, J.C.; Joint, I. Improved group-specific PCR primers for denaturing gradient gel electrophoresis analysis of the genetic diversity of complex microbial communities. *ISME J.* **2008**, *2*, 379–392. [CrossRef]

42. Bindels, L.B.; Beck, R.; Schakman, O.; Martin, J.C.; De Backer, F.; Sohet, F.M.; Dewulf, E.M.; Pachikian, B.D.; Neyrinck, A.M.; Thissen, J.P.; et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. *PLoS ONE* **2012**, *7*, e37971. [CrossRef]
16. Sonis, S.T.; Elting, L.S.; Keefe, D.; Peterson, D.E.; Schubert, M.; Hauer-Jensen, M.; Bekele, B.N.; Raber-Durlacher, J.; Donnelly, J.P.; Rubenstein, E.B.; et al. Perspectives on cancer therapy-induced mucosal injury: Pathogenesis, measurement, epidemiology, and consequences for patients. *Cancer* **2004**, *100*, 1995–2025. [CrossRef]

17. Sonis, S.T.; O'Donnell, K.E.; Popat, R.; Bragdon, C.; Phelan, S.; Cocks, D.; Epstein, J.B. The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis. *Oral Oncol.* **2004**, *40*, 170–176. [CrossRef]

18. Iop, A.; Manfredi, A.M.; Bonura, S. Fatigue in cancer patients receiving chemotherapy: An analysis of published studies. *Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.* **2004**, *15*, 712–720. [CrossRef]

19. Vollbracht, C.; Schneider, B.; Leendert, V.; Weiss, G.; Auerbach, L.; Beuth, J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: Results of a retrospective, multicentre, epidemiological cohort study in Germany. *In Vivo* **2011**, *25*, 983–990.

20. Mancuso, C.; Santangelo, R. *Panax ginseng* and *Panax quinquefolius*: From pharmacology to toxicology. *Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc.* **2017**, *107*, 362–372. [CrossRef]

21. Kennedy, D.O.; Scholey, A.B. Ginseng: Potential for the enhancement of cognitive performance and mood. *Pharmacol. Biochem. Behav.* **2003**, *75*, 687–700. [CrossRef]

22. Smith, I.; Williamson, E.M.; Putnam, S.; Farrimond, J.; Whalley, B.J. Effects and mechanisms of ginseng and ginsenosides on cognition. *Nutr. Rev.* **2014**, *72*, 319–333. [CrossRef] [PubMed]

23. Yuan, Q.-L.; Yang, C.-X.; Xu, P.; Gao, X.-Q.; Deng, L.; Chen, P.; Sun, Z.-L.; Chen, Q.-Y. Neuroprotective effects of ginsenoside Rb1 on transient cerebral ischemia in rats. *Brain Res.* **2007**, *1167*, 1–12. [CrossRef] [PubMed]

24. Ye, R.; Li, N.; Han, J.; Kong, X.; Cao, R.; Rao, Z.; Zhao, G. Neuroprotective effects of ginsenoside Rd against oxygen-glucose deprivation in cultured hippocampal neurons. *Neurosci. Res.* **2009**, *64*, 306–310. [CrossRef]

25. Zhao, H.; Li, Q.; Zhang, Z.; Pei, X.; Wang, J.; Li, Y. Long-term ginsenoside consumption prevents memory loss in aged SAMP8 mice by decreasing oxidative stress and up-regulating the plasticity-related proteins in hippocampus. *Brain Res.* **2009**, *1256*, 111–122. [CrossRef]

26. Lu, S.; Zhang, Y.; Li, H.; Zhang, J.; Ci, Y.; Han, M. Ginsenoside Rb1 can ameliorate the key inflammatory cytokines TNF-α and IL-6 in a cancer cachexia mouse model. *BMC Complement. Med. Ther.* **2020**, *20*, 11. [CrossRef]

27. Hussien, M.; Yousef, M.I. Impact of ginseng on neurotoxicity induced by cisplatin in rats. *Environ. Sci. Pollut. Res.* **2022**, *29*, 62042–62054. [CrossRef]

28. Prut, L.; Belzung, C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. *Eur. J. Pharmacol.* **2003**, *463*, 3–33. [CrossRef]

29. Seibenhener, M.L.; Wooten, M.C. Use of the Open Field Maze to Measure Locomotor and Anxiety-Like Behavior in Mice. *J. Vis. Exp. JoVE* **2015**, *96*, e52434. [CrossRef]

30. Lister, R.G. The use of a plus-maze to measure anxiety in the mouse. *Psychopharmacology* **1987**, *92*, 180–185. [CrossRef]

31. Hascoët, M.; Bourin, M.; Nic Dhonnchadha, B.A. The mouse light-dark paradigm: A review. *Prog. Neuro-Psychopharmacol. Biol. Psychiatry* **2001**, *25*, 141–166. [CrossRef]

32. Porsolt, R.D.; Bertin, A.; Jalfre, M. Behavioral despair in mice: A primary screening test for antidepressants. *Arch. Int. Pharmacodyn. Ther.* **1977**, *229*, 327–336.

33. Steru, L.; Chermat, R.; Thierry, B.; Simon, P. The tail suspension test: A new method for screening antidepressants in mice. *Psychopharmacology* **1985**, *85*, 367–370. [CrossRef]

34. Graziano, A.; Petrosini, L.; Bartoletti, A. Automatic recognition of explorative strategies in the Morris water maze. *J. Neurosci. Methods* **2003**, *130*, 33–44. [CrossRef]

35. Higaki, A.; Mogi, M.; Iwanami, J.; Min, L.-J.; Bai, H.-Y.; Shan, B.-S.; Kan-No, H.; Ikeda, S.; Higaki, J.; Horiuchi, M. Recognition of early stage thigmotaxis in Morris water maze test with convolutional neural network. *PLoS ONE* **2018**, *13*, e0197003. [CrossRef]

36. Illouz, T.; Madar, R.; Louzoun, Y.; Griffioen, K.J.; Okun, E. Corrigendum to “Unraveling cognitive traits using the Morris water maze unbiased strategy classification (MUST-C) algorithm”. *Brain Behav. Immun.* **2017**, *61*, 386. [CrossRef]

37. Nicola, C.; Dubois, M.; Campart, C.; Al Sagheer, T.; Desrues, L.; Schapman, D.; Galas, L.; Lange, M.; Joly, F.; Castel, H. The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice. *Cancers* **2021**, *13*, 3518. [CrossRef]

38. Liu, M.-Y.; Yin, C.-Y.; Zhu, L.-J.; Zhu, X.-H.; Xu, C.; Luo, C.-X.; Chen, H.; Zhu, D.-Y.; Zhou, Q.-G. Sucrose preference test for measurement of stress-induced anhedonia in mice. *Nat. Protoc.* **2018**, *13*, 1686–1698. [CrossRef]

39. Dore, J.; Ehrlich, S.; Levenez, F.; Pelletier, E.; Alberti, A.; Bertrand, L. *IHMS_SOP 06 V1*; Standard Operating Procedure for Fecal Samples DNA Extraction, Protocol Q. International Human Microbiome Standards, 2015. Available online: http://www.human-microbiome.org/index.php?id=Sop&num=006.

40. Fierer, N.; Jackson, J.A.; Vilgalys, R.; Jackson, R.B. Assessment of soil microbial community structure by use of taxon-specific quantitative PCR assays. *Appl. Environ. Microbiol.* **2005**, *71*, 4117–4120. [CrossRef]

41. Mühling, M.; Woolven-Allen, J.; Murrell, J.C.; Joint, I. Improved group-specific PCR primers for denaturing gradient gel electrophoresis analysis of the genetic diversity of complex microbial communities. *ISME J.* **2008**, *2*, 379–392. [CrossRef]

42. Bindels, L.B.; Beck, R.; Schakman, O.; Martin, J.C.; De Backer, F.; Sohet, F.M.; Dewulf, E.M.; Pachikian, B.D.; Neyrinck, A.M.; Thissen, J.P.; et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. *PLoS ONE* **2012**, *7*, e37971. [CrossRef]
43. Klindworth, A.; Pruesse, E.; Schweer, T.; Peplies, J.; Quast, C.; Horn, M.; Glöckner, F.O. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. *Nucleic Acids Res.* **2013**, *41*, e1. [CrossRef]

44. Queipo-Ortuño, M.I.; Seoane, L.M.; Murri, M.; Pardo, M.; Gomez-Zumaquero, J.M.; Cardona, F.; Casanueva, F.; Tinahones, F.J. Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels. *PLoS ONE* **2013**, *8*, e65465. [CrossRef]

45. Hermann-Bank, M.L.; Skovgaard, K.; Stockmarr, A.; Larsen, N.; Mølbak, L. The Gut Microbiotassay: A high-throughput qPCR approach combinable with next generation sequencing to study gut microbial diversity. *BMC Genom.* **2013**, *14*, 788. [CrossRef]

46. Kim, H.-J.; Cho, C.-W.; Hwang, J.-T.; Son, N.; Choi, J.H.; Shim, G.-S.; Han, C.-K. LC-MS-based metabolomic analysis of serum and livers from red ginseng-fed rats. *J. Ginseng Res.* **2013**, *37*, 371–378. [CrossRef]

47. Park, H.-W.; In, G.; Han, S.-T.; Lee, M.-W.; Kim, S.-Y.; Kim, K.-T.; Cho, B.-G.; Han, G.-H.; Chang, I.-M. Simultaneous determination of 30 ginsenosides in *Panax ginseng* preparations using ultra performance liquid chromatography. *J. Ginseng Res.* **2013**, *37*, 457–467. [CrossRef]

48. Motulsky, H.J.; Brown, R.E. Detecting outliers when fitting data with nonlinear regression—A new method based on robust nonlinear regression and the false discovery rate. *BMC Bioinform.* **2006**, *7*, 123. [CrossRef]

49. Dubois, M.; Lapinte, N.; Villier, V.; Lecointre, C.; Roy, V.; Tonon, M.-C.; Gandolfo, P.; Joly, F.; Hilber, P.; Castel, H. Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: Role of glucose as adjuvant. *Neuropharmacology* **2014**, *79*, 234–248. [CrossRef]

50. Bower, J.E.; Ganz, P.A.; Desmond, K.A.; Rowland, J.H.; Meyerowitz, B.E.; Belin, T.R. Fatigue in breast cancer survivors: Occurrence, correlates, and impact on quality of life. *J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.* **2000**, *18*, 743–753. [CrossRef]

51. Jones, J.M.; Olson, K.; Catton, P.; Catton, C.N.; Fleshner, N.E.; Krzyzanowska, M.K.; McCready, D.R.; Wong, R.K.S.; Jiang, H.; Howell, D. Cancer-related fatigue and associated disability in post-treatment cancer survivors. *J. Cancer Surviv.* **2016**, *10*, 51–61. [CrossRef]

52. Loos, M.; Koopmans, B.; Aarts, E.; Maroteaux, G.; Sluis, S.v.d.; Consortium, N.-B.M.P.; Verhage, M.; Smit, A.B. Sheltering Behavior and Locomotor Activity in 11 Genetically Diverse Common Inbred Mouse Strains Using Home-Cage Monitoring. *PLoS ONE* **2014**, *9*, e108563. [CrossRef] [PubMed]

53. Kitamura, Y.; Hattori, S.; Yoneda, S.; Watanabe, S.; Kanemoto, E.; Sugimoto, M.; Kawai, T.; Machida, A.; Kanzaki, H.; Miyazaki, I.; et al. Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. *Behav. Brain Res.* **2015**, *292*, 184–193. [CrossRef] [PubMed]

54. Joly, F.; Giffard, B.; Rigal, O.; De Ruiter, M.B.; Small, B.J.; Dubois, M.; LeFel, J.; Schagen, S.B.; Ahles, T.A.; Wefel, J.S.; et al. Impact of Cancer and Its Treatments on Cognitive Function: Advances in Research from the Paris International Cognition and Cancer Task Force Symposium and Update Since 2012. *J. Pain Symptom Manag.* **2015**, *50*, 830–841. [CrossRef] [PubMed]

55. ELBeltagy, M.; Mustafa, S.; Umka, J.; Lyons, L.; Salman, A.; Dormon, K.; Allcock, C.; Bennett, G.; Wigmore, P. The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus. *Brain Res. Bull.* **2012**, *88*, 514–518. [CrossRef]

56. Anacker, C.; Hen, R. Adult hippocampal neurogenesis and cognitive flexibility—Linking memory and mood. *Nat. Rev. Neurosci.* **2017**, *18*, 335–346. [CrossRef]

57. Kim, D.-H. Chemical Diversity of *Panax ginseng*, *Panax quinquifolium*, and *Panax notoginseng*. *J. Ginseng Res.* **2012**, *36*, 1–15. [CrossRef]

58. Oh, J.; Kim, J.-S. Compound K derived from ginseng: Neuroprotection and cognitive improvement. *Food Funct.* **2016**, *7*, 4506–4515. [CrossRef]

59. Rangel, I.; Ganda Mall, J.P.; Willén, R.; Sjöberg, F.; Hultgren-Hörnquist, E. Degree of colitis correlates with microbial composition and cytokine responses in colon and caecum of Gαi2-deficient mice. *FEMS Microbiol. Ecol.* **2016**, *92*, fiw098. [CrossRef]

60. Margolis, K.G.; Cryan, J.F.; Mayer, E.A. The Microbiota-Gut-Brain Axis: From Motility to Mood. *Gastroenterology* **2021**, *160*, 1486–1501. [CrossRef]

61. Li, H.-L.; Lu, L.; Wang, X.-S.; Qin, L.-Y.; Wang, P.; Qiu, S.-P.; Wu, H.; Huang, F.; Zhang, B.-B.; Shi, H.-L.; et al. Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis. *Front. Cell. Infect. Microbiol.* **2017**, *7*, 455. [CrossRef]

62. Pedraz-Petrozzi, B.; Neumann, E.; Sammer, G. Pro-inflammatory markers and fatigue in patients with depression: A case-control study. *Sci. Rep.* **2020**, *10*, 9494. [CrossRef]

63. Bazovkina, D.V.; Tibeikina, M.A.; Kulikov, A.V.; Popova, N.K. Effects of lipopolysaccharide and interleukin-6 on cataleptic immobility and locomotor activity in mice. *Neurosci. Lett.* **2011**, *487*, 302–304. [CrossRef]

64. Potrykus, M.; Czaja-Stolc, S.; Stankiewicz, M.; Kaska, Ł.; Małgorzewicz, S. Intestinal Microbiota as a Contributor to Chronic Inflammation and Its Potential Modifications. *Nutrients* **2021**, *13*, 3839. [CrossRef]

65. Jiang, Y.; Lü, X.; Man, C.; Han, L.; Shan, Y.; Qu, X.; Liu, Y.; Yang, S.; Xue, Y.; Zhang, Y. Lactobacillus acidophilus Induces Cytokine and Chemokine Production via NF-κB and p38 Mitogen-Activated Protein Kinase Signaling Pathways in Intestinal Epithelial Cells. *Clin. Vaccine Immunol.* **CVI 2012**, *19*, 603–608. [CrossRef]
43. Klindworth, A.; Pruesse, E.; Schweer, T.; Peplies, J.; Quast, C.; Horn, M.; Glöckner, F.O. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. *Nucleic Acids Res.* **2013**, *41*, e1. [CrossRef]

44. Queipo-Ortuño, M.I.; Seoane, L.M.; Murri, M.; Pardo, M.; Gomez-Zumaquero, J.M.; Cardona, F.; Casanueva, F.; Tinahones, F.J. Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels. *PLoS ONE* **2013**, *8*, e65465. [CrossRef]

45. Hermann-Bank, M.L.; Skovgaard, K.; Stockmarr, A.; Larsen, N.; Mølbak, L. The Gut Microbiotassay: A high-throughput qPCR approach combinable with next generation sequencing to study gut microbial diversity. *BMC Genom.* **2013**, *14*, 788. [CrossRef]

46. Kim, H.-J.; Cho, C.-W.; Hwang, J.-T.; Son, N.; Choi, J.H.; Shim, G.-S.; Han, C.-K. LC-MS-based metabolomic analysis of serum and livers from red ginseng-fed rats. *J. Ginseng Res.* **2013**, *37*, 371–378. [CrossRef]

47. Park, H.-W.; In, G.; Han, S.-T.; Lee, M.-W.; Kim, S.-Y.; Kim, K.-T.; Cho, B.-G.; Han, G.-H.; Chang, I.-M. Simultaneous determination of 30 ginsenosides in *Panax ginseng* preparations using ultra performance liquid chromatography. *J. Ginseng Res.* **2013**, *37*, 457–467. [CrossRef]

48. Motulsky, H.J.; Brown, R.E. Detecting outliers when fitting data with nonlinear regression—A new method based on robust nonlinear regression and the false discovery rate. *BMC Bioinform.* **2006**, *7*, 123. [CrossRef]

49. Dubois, M.; Lapinte, N.; Villier, V.; Lecointre, C.; Roy, V.; Tonon, M.-C.; Gandolfo, P.; Joly, F.; Hilber, P.; Castel, H. Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: Role of glucose as adjuvant. *Neuropharmacology* **2014**, *79*, 234–248. [CrossRef]

50. Bower, J.E.; Ganz, P.A.; Desmond, K.A.; Rowland, J.H.; Meyerowitz, B.E.; Belin, T.R. Fatigue in breast cancer survivors: Occurrence, correlates, and impact on quality of life. *J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.* **2000**, *18*, 743–753. [CrossRef]

51. Jones, J.M.; Olson, K.; Catton, P.; Catton, C.N.; Fleshner, N.E.; Krzyzanowska, M.K.; McCready, D.R.; Wong, R.K.S.; Jiang, H.; Howell, D. Cancer-related fatigue and associated disability in post-treatment cancer survivors. *J. Cancer Surviv.* **2016**, *10*, 51–61. [CrossRef]

52. Loos, M.; Koopmans, B.; Aarts, E.; Maroteaux, G.; Sluis, S.v.d.; Consortium, N.-B.M.P.; Verhage, M.; Smit, A.B. Sheltering Behavior and Locomotor Activity in 11 Genetically Diverse Common Inbred Mouse Strains Using Home-Cage Monitoring. *PLoS ONE* **2014**, *9*, e108563. [CrossRef] [PubMed]

53. Kitamura, Y.; Hattori, S.; Yoneda, S.; Watanabe, S.; Kanemoto, E.; Sugimoto, M.; Kawai, T.; Machida, A.; Kanzaki, H.; Miyazaki, I.; et al. Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. *Behav. Brain Res.* **2015**, *292*, 184–193. [CrossRef] [PubMed]

54. Joly, F.; Giffard, B.; Rigal, O.; De Ruiter, M.B.; Small, B.J.; Dubois, M.; LeFel, J.; Schagen, S.B.; Ahles, T.A.; Wefel, J.S.; et al. Impact of Cancer and Its Treatments on Cognitive Function: Advances in Research from the Paris International Cognition and Cancer Task Force Symposium and Update Since 2012. *J. Pain Symptom Manag.* **2015**, *50*, 830–841. [CrossRef] [PubMed]

55. ELBeltagy, M.; Mustafa, S.; Umka, J.; Lyons, L.; Salman, A.; Dormon, K.; Allcock, C.; Bennett, G.; Wigmore, P. The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus. *Brain Res. Bull.* **2012**, *88*, 514–518. [CrossRef]

56. Anacker, C.; Hen, R. Adult hippocampal neurogenesis and cognitive flexibility—Linking memory and mood. *Nat. Rev. Neurosci.* **2017**, *18*, 335–346. [CrossRef]

57. Kim, D.-H. Chemical Diversity of *Panax ginseng*, *Panax quinquifolium*, and *Panax notoginseng*. *J. Ginseng Res.* **2012**, *36*, 1–15. [CrossRef]

58. Oh, J.; Kim, J.-S. Compound K derived from ginseng: Neuroprotection and cognitive improvement. *Food Funct.* **2016**, *7*, 4506–4515. [CrossRef]

59. Rangel, I.; Ganda Mall, J.P.; Willén, R.; Sjöberg, F.; Hultgren-Hörnquist, E. Degree of colitis correlates with microbial composition and cytokine responses in colon and caecum of Gαi2-deficient mice. *FEMS Microbiol. Ecol.* **2016**, *92*, fiw098. [CrossRef]

60. Margolis, K.G.; Cryan, J.F.; Mayer, E.A. The Microbiota-Gut-Brain Axis: From Motility to Mood. *Gastroenterology* **2021**, *160*, 1486–1501. [CrossRef]

61. Li, H.-L.; Lu, L.; Wang, X.-S.; Qin, L.-Y.; Wang, P.; Qiu, S.-P.; Wu, H.; Huang, F.; Zhang, B.-B.; Shi, H.-L.; et al. Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis. *Front. Cell. Infect. Microbiol.* **2017**, *7*, 455. [CrossRef]

62. Pedraz-Petrozzi, B.; Neumann, E.; Sammer, G. Pro-inflammatory markers and fatigue in patients with depression: A case-control study. *Sci. Rep.* **2020**, *10*, 9494. [CrossRef]

63. Bazovkina, D.V.; Tibeikina, M.A.; Kulikov, A.V.; Popova, N.K. Effects of lipopolysaccharide and interleukin-6 on cataleptic immobility and locomotor activity in mice. *Neurosci. Lett.* **2011**, *487*, 302–304. [CrossRef]

64. Potrykus, M.; Czaja-Stolc, S.; Stankiewicz, M.; Kaska, Ł.; Małgorzewicz, S. Intestinal Microbiota as a Contributor to Chronic Inflammation and Its Potential Modifications. *Nutrients* **2021**, *13*, 3839. [CrossRef]

65. Jiang, Y.; Lü, X.; Man, C.; Han, L.; Shan, Y.; Qu, X.; Liu, Y.; Yang, S.; Xue, Y.; Zhang, Y. Lactobacillus acidophilus Induces Cytokine and Chemokine Production via NF-κB and p38 Mitogen-Activated Protein Kinase Signaling Pathways in Intestinal Epithelial Cells. *Clin. Vaccine Immunol.* **CVI 2012**, *19*, 603–608. [CrossRef]
66. Choi, J.-S.; Kim, S.-Y.; Cha, J.-H.; Choi, Y.-S.; Sung, K.-W.; Oh, S.T.; Kim, O.N.; Chung, J.-W.; Chun, M.-H.; Lee, S.B.; et al. Upregulation of gp130 and STAT3 activation in the rat hippocampus following transient forebrain ischemia. *Glia* **2003**, *41*, 237–246. [CrossRef]

67. Joly, F.; Lange, M.; Dos Santos, M.; Vaz-Luis, I.; Di Meglio, A. Long-Term Fatigue and Cognitive Disorders in Breast Cancer Survivors. *Cancers* **2019**, *11*, 1896. [CrossRef]

68. Abrahams, H.J.G.; Gielissen, M.F.M.; Schmits, I.C.; Verhagen, C.A.H.H.V.M.; Rovers, M.M.; Knoop, H. Risk factors, prevalence, and course of severe fatigue after breast cancer treatment: A meta-analysis involving 12 327 breast cancer survivors. *Ann. Oncol.* **2016**, *27*, 965–974. [CrossRef]

69. Wolff, B.S.; Raheem, S.A.; Saligan, L.N. Comparing passive measures of fatigue-like behavior in mice. *Sci. Rep.* **2018**, *8*, 14238. [CrossRef]

70. Sánchez-Lara, K.; Ugalde-Morales, E.; Motola-Kuba, D.; Green, D. Gastrointestinal symptoms and weight loss in cancer patients receiving chemotherapy. *Br. J. Nutr.* **2013**, *109*, 894–897. [CrossRef]

71. Guindon, J.; Deng, L.; Fan, B.; Wager-Miller, J.; Hohmann, A.G. Optimization of a cisplatin model of chemotherapy-induced peripheral neuropathy in mice: Use of vitamin C and sodium bicarbonate pretreatments to reduce nephrotoxicity and improve animal health status. *Mol. Pain* **2014**, *10*, 56. [CrossRef]

72. Du, X.F.; Jiang, C.Z.; Wu, C.F.; Won, E.K.; Choung, S.Y. Synergistic immunostimulating activity of pidotimod and red ginseng acidic polysaccharide against cyclophosphamide-induced immunosuppression. *Arch. Pharmacal Res.* **2008**, *31*, 1153–1159. [CrossRef] [PubMed]

73. Zhang, S.; Liu, Y.; Xiang, D.; Yang, J.; Liu, D.; Ren, X.; Zhang, C. Assessment of dose-response relationship of 5-fluorouracil to murine intestinal injury. *Biomed. Pharmacother.* **2018**, *106*, 910–916. [CrossRef] [PubMed]

74. Dougherty, J.P.; Springer, D.A.; Cullen, M.J.; Gershengorn, M.C. Evaluation of the effects of chemotherapy-induced fatigue and pharmacological interventions in multiple mouse behavioral assays. *Behav. Brain Res.* **2019**, *360*, 255–261. [CrossRef] [PubMed]

75. Hsu, T.-H.; Hung, S.-W.; Wu, C.-Y.; Chiu, C.-C.; Hong, H.-T.; Lee, G.-C.; Chen, C.-C.; Lin, J.-S.; Wu, C.-P. Supplementation of beef extract improves chemotherapy-induced fatigue and toxic effects in mice. *J. Funct. Foods* **2020**, *75*, 104232. [CrossRef]

76. Arantes-Rodrigues, R.; Henriques, A.; Pinto-Leite, R.; Faustino-Rocha, A.; Pinho-Oliveira, J.; Teixeira-Guedes, C.; Seixas, F.; Gama, A.; Colaço, B.; Colaço, A.; et al. The effects of repeated oral gavage on the health of male CD-1 mice. *Lab. Anim.* **2012**, *41*, 129–134. [CrossRef] [PubMed]

77. Jones, C.P.; Boyd, K.L.; Wallace, J.M. Evaluation of Mice Undergoing Serial Oral Gavage While Awake or Anesthetized. *J. Am. Assoc. Lab. Anim. Sci.* **JAALAS** **2016**, *55*, 805–810.

78. Wu, Y.; Qin, C.; Lu, X.; Marchiori, J.; Feng, Q. North American ginseng inhibits myocardial NOX2-ERK1/2 signaling and tumor necrosis factor-α expression in endotoxemia. *Pharmacol. Res.* **2016**, *111*, 217–225. [CrossRef]

79. Chanana, P.; Kumar, A. GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety Like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation. *Front. Neurosci.* **2016**, *10*, 84. [CrossRef]

80. Gulyaeva, N.V. Functional Neurochemistry of the Ventral and Dorsal Hippocampus: Stress, Depression, Dementia and Remote Hippocampal Damage. *Neurochem. Res.* **2019**, *44*, 1306–1322. [CrossRef]

81. Akazawa, K.-h.; Cui, Y.; Tanaka, M.; Kataoka, Y.; Yoneda, Y.; Watanabe, Y. Mapping of regional brain activation in response to fatigue-load and recovery in rats with c-Fos immunohistochemistry. *Neurosci. Res.* **2010**, *66*, 372–379. [CrossRef]

82. Anacker, C.; Luna, V.M.; Stevens, G.S.; Millette, A.; Shores, R.; Jimenez, J.C.; Chen, B.; Hen, R. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. *Nature* **2018**, *559*, 98–102. [CrossRef]

83. John, J.; Kinra, M.; Mudgal, J.; Viswanatha, G.L.; Nandakumar, K. Animal models of chemotherapy-induced cognitive decline in preclinical drug development. *Psychopharmacology* **2021**, *238*, 3025–3053. [CrossRef]

84. Groves, T.R.; Farris, R.; Anderson, J.E.; Alexander, T.C.; Kiffer, F.; Carter, G.; Wang, J.; Boerma, M.; Allen, A.R. 5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice. *Behav. Brain Res.* **2017**, *316*, 215–224. [CrossRef]

85. Snyder, J.S.; Ferrante, S.C.; Cameron, H.A. Late maturation of adult-born neurons in the temporal dentate gyrus. *PLoS ONE* **2012**, *7*, e48757. [CrossRef]

86. Onufriev, M.V.; Uzakov, S.S.; Freiman, S.V.; Stepanichev, M.Y.; Moiseeva, Y.V.; Lazareva, N.A.; Markevich, V.A.; Gulyaeva, N.V. The Dorsal and Ventral Hippocampus Have Different Reactivities to Proinflammatory Stress: Corticosterone Levels, Cytokine Expression, and Synaptic Plasticity. *Neurosci. Behav. Physiol.* **2018**, *48*, 1024–1031. [CrossRef]

87. Komoltsev, I.G.; Tretyakova, L.V.; Frankevich, S.O.; Shirobokova, N.I.; Volkova, A.A.; Butuzov, A.V.; Novikova, M.R.; Kvichansky, A.A.; Moiseeva, Y.V.; Onufriev, M.V.; et al. Neuroinflammatory Cytokine Response, Neuronal Death and Microglial Proliferation in the Hippocampus of Rats during the Early Period after Lateral Fluid-Percussion-Induced Traumatic Injury of the Neocortex. *Mol. Neurobiol.* **2022**, *59*, 1151–1167. [CrossRef]

88. Deleemans, J.M.; Chleilat, F.; Reimer, R.A.; Henning, J.W.; Baydoun, M.; Piedalue, K.A.; McLennan, A.; Carlson, L.E. The chemo-gut study: Investigating the long-term effects of chemotherapy on gut microbiota, metabolic, immune, psychological and cognitive parameters in young adult Cancer survivors; study protocol. *BMC Cancer* **2019**, *19*, 1243. [CrossRef]

89. Tetel, M.J.; de Vries, G.J.; Melcangi, R.C.; Panzica, G.; O'Mahony, S.M. Steroids, stress and the gut microbiome-brain axis. *J. Neuroendocrinol.* **2018**, *30*, e12548. [CrossRef]
66. Choi, J.-S.; Kim, S.-Y.; Cha, J.-H.; Choi, Y.-S.; Sung, K.-W.; Oh, S.T.; Kim, O.N.; Chung, J.-W.; Chun, M.-H.; Lee, S.B.; et al. Upregulation of gp130 and STAT3 activation in the rat hippocampus following transient forebrain ischemia. *Glia* **2003**, *41*, 237–246. [CrossRef]

67. Joly, F.; Lange, M.; Dos Santos, M.; Vaz-Luis, I.; Di Meglio, A. Long-Term Fatigue and Cognitive Disorders in Breast Cancer Survivors. *Cancers* **2019**, *11*, 1896. [CrossRef]

68. Abrahams, H.J.G.; Gielissen, M.F.M.; Schmits, I.C.; Verhagen, C.A.H.H.V.M.; Rovers, M.M.; Knoop, H. Risk factors, prevalence, and course of severe fatigue after breast cancer treatment: A meta-analysis involving 12 327 breast cancer survivors. *Ann. Oncol.* **2016**, *27*, 965–974. [CrossRef]

69. Wolff, B.S.; Raheem, S.A.; Saligan, L.N. Comparing passive measures of fatigue-like behavior in mice. *Sci. Rep.* **2018**, *8*, 14238. [CrossRef]

70. Sánchez-Lara, K.; Ugalde-Morales, E.; Motola-Kuba, D.; Green, D. Gastrointestinal symptoms and weight loss in cancer patients receiving chemotherapy. *Br. J. Nutr.* **2013**, *109*, 894–897. [CrossRef]

71. Guindon, J.; Deng, L.; Fan, B.; Wager-Miller, J.; Hohmann, A.G. Optimization of a cisplatin model of chemotherapy-induced peripheral neuropathy in mice: Use of vitamin C and sodium bicarbonate pretreatments to reduce nephrotoxicity and improve animal health status. *Mol. Pain* **2014**, *10*, 56. [CrossRef]

72. Du, X.F.; Jiang, C.Z.; Wu, C.F.; Won, E.K.; Choung, S.Y. Synergistic immunostimulating activity of pidotimod and red ginseng acidic polysaccharide against cyclophosphamide-induced immunosuppression. *Arch. Pharmacal Res.* **2008**, *31*, 1153–1159. [CrossRef] [PubMed]

73. Zhang, S.; Liu, Y.; Xiang, D.; Yang, J.; Liu, D.; Ren, X.; Zhang, C. Assessment of dose-response relationship of 5-fluorouracil to murine intestinal injury. *Biomed. Pharmacother.* **2018**, *106*, 910–916. [CrossRef] [PubMed]

74. Dougherty, J.P.; Springer, D.A.; Cullen, M.J.; Gershengorn, M.C. Evaluation of the effects of chemotherapy-induced fatigue and pharmacological interventions in multiple mouse behavioral assays. *Behav. Brain Res.* **2019**, *360*, 255–261. [CrossRef] [PubMed]

75. Hsu, T.-H.; Hung, S.-W.; Wu, C.-Y.; Chiu, C.-C.; Hong, H.-T.; Lee, G.-C.; Chen, C.-C.; Lin, J.-S.; Wu, C.-P. Supplementation of beef extract improves chemotherapy-induced fatigue and toxic effects in mice. *J. Funct. Foods* **2020**, *75*, 104232. [CrossRef]

76. Arantes-Rodrigues, R.; Henriques, A.; Pinto-Leite, R.; Faustino-Rocha, A.; Pinho-Oliveira, J.; Teixeira-Guedes, C.; Seixas, F.; Gama, A.; Colaço, B.; Colaço, A.; et al. The effects of repeated oral gavage on the health of male CD-1 mice. *Lab. Anim.* **2012**, *41*, 129–134. [CrossRef] [PubMed]

77. Jones, C.P.; Boyd, K.L.; Wallace, J.M. Evaluation of Mice Undergoing Serial Oral Gavage While Awake or Anesthetized. *J. Am. Assoc. Lab. Anim. Sci.* **JAALAS** **2016**, *55*, 805–810.

78. Wu, Y.; Qin, C.; Lu, X.; Marchiori, J.; Feng, Q. North American ginseng inhibits myocardial NOX2-ERK1/2 signaling and tumor necrosis factor-α expression in endotoxemia. *Pharmacol. Res.* **2016**, *111*, 217–225. [CrossRef]

79. Chanana, P.; Kumar, A. GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety Like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation. *Front. Neurosci.* **2016**, *10*, 84. [CrossRef]

80. Gulyaeva, N.V. Functional Neurochemistry of the Ventral and Dorsal Hippocampus: Stress, Depression, Dementia and Remote Hippocampal Damage. *Neurochem. Res.* **2019**, *44*, 1306–1322. [CrossRef]

81. Akazawa, K.-h.; Cui, Y.; Tanaka, M.; Kataoka, Y.; Yoneda, Y.; Watanabe, Y. Mapping of regional brain activation in response to fatigue-load and recovery in rats with c-Fos immunohistochemistry. *Neurosci. Res.* **2010**, *66*, 372–379. [CrossRef]

82. Anacker, C.; Luna, V.M.; Stevens, G.S.; Millette, A.; Shores, R.; Jimenez, J.C.; Chen, B.; Hen, R. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. *Nature* **2018**, *559*, 98–102. [CrossRef]

83. John, J.; Kinra, M.; Mudgal, J.; Viswanatha, G.L.; Nandakumar, K. Animal models of chemotherapy-induced cognitive decline in preclinical drug development. *Psychopharmacology* **2021**, *238*, 3025–3053. [CrossRef]

84. Groves, T.R.; Farris, R.; Anderson, J.E.; Alexander, T.C.; Kiffer, F.; Carter, G.; Wang, J.; Boerma, M.; Allen, A.R. 5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice. *Behav. Brain Res.* **2017**, *316*, 215–224. [CrossRef]

85. Snyder, J.S.; Ferrante, S.C.; Cameron, H.A. Late maturation of adult-born neurons in the temporal dentate gyrus. *PLoS ONE* **2012**, *7*, e48757. [CrossRef]

86. Onufriev, M.V.; Uzakov, S.S.; Freiman, S.V.; Stepanichev, M.Y.; Moiseeva, Y.V.; Lazareva, N.A.; Markevich, V.A.; Gulyaeva, N.V. The Dorsal and Ventral Hippocampus Have Different Reactivities to Proinflammatory Stress: Corticosterone Levels, Cytokine Expression, and Synaptic Plasticity. *Neurosci. Behav. Physiol.* **2018**, *48*, 1024–1031. [CrossRef]

87. Komoltsev, I.G.; Tretyakova, L.V.; Frankevich, S.O.; Shirobokova, N.I.; Volkova, A.A.; Butuzov, A.V.; Novikova, M.R.; Kvichansky, A.A.; Moiseeva, Y.V.; Onufriev, M.V.; et al. Neuroinflammatory Cytokine Response, Neuronal Death and Microglial Proliferation in the Hippocampus of Rats during the Early Period after Lateral Fluid-Percussion-Induced Traumatic Injury of the Neocortex. *Mol. Neurobiol.* **2022**, *59*, 1151–1167. [CrossRef]

88. Deleemans, J.M.; Chleilat, F.; Reimer, R.A.; Henning, J.W.; Baydoun, M.; Piedalue, K.A.; McLennan, A.; Carlson, L.E. The chemo-gut study: Investigating the long-term effects of chemotherapy on gut microbiota, metabolic, immune, psychological and cognitive parameters in young adult Cancer survivors; study protocol. *BMC Cancer* **2019**, *19*, 1243. [CrossRef]

89. Tetel, M.J.; de Vries, G.J.; Melcangi, R.C.; Panzica, G.; O'Mahony, S.M. Steroids, stress and the gut microbiome-brain axis. *J. Neuroendocrinol.* **2018**, *30*, e12548. [CrossRef]
90. Fung, T.C.; Olson, C.A.; Hsiao, E.Y. Interactions between the microbiota, immune and nervous systems in health and disease. *Nat. Neurosci.* **2017**, *20*, 145–155. [CrossRef]

91. Song, M.-Y.; Kim, B.-S.; Kim, H. Influence of *Panax ginseng* on obesity and gut microbiota in obese middle-aged Korean women. *J. Ginseng Res.* **2014**, *38*, 106–115. [CrossRef]

92. Zhou, R.; He, D.; Xie, J.; Zhou, Q.; Zeng, H.; Li, H.; Huang, L. The Synergistic Effects of Polysaccharides and Ginsenosides from American Ginseng (*Panax quinquefolius* L.) Ameliorating Cyclophosphamide-Induced Intestinal Immune Disorders and Gut Barrier Dysfunctions Based on Microbiome-Metabolomics Analysis. *Front. Immunol.* **2021**, *12*, 665901. [CrossRef]

93. Wang, W.; Chen, L.; Zhou, R.; Wang, X.; Song, L.; Huang, S.; Wang, G.; Xia, B. Increased proportions of *Bifidobacterium* and the *Lactobacillus* group and loss of butyrate-producing bacteria in inflammatory bowel disease. *J. Clin. Microbiol.* **2014**, *52*, 398–406. [CrossRef]

94. Juan, Z.; Chen, J.; Ding, B.; Yongping, L.; Liu, K.; Wang, L.; Le, Y.; Liao, Q.; Shi, J.; Huang, J.; et al. Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: A randomised, double-blind, and placebo-controlled trial. *Eur. J. Cancer* **2022**, *161*, 10–22. [CrossRef]

95. Million, M.; Maraninchi, M.; Henry, M.; Armougom, F.; Richet, H.; Carrieri, P.; Valero, R.; Raccah, D.; Vialettes, B.; Raoult, D. Obesity-associated gut microbiota is enriched in *Lactobacillus reuteri* and depleted in *Bifidobacterium animalis* and *Methanobrevibacter smithii*. *Int J. Obes.* **2012**, *36*, 817–825. [CrossRef]

96. Breton, J.; Tirelle, P.; Hasanat, S.; Pernot, A.; L'Huillier, C.; do Rego, J.C.; Déchelotte, P.; Coëffier, M.; Bindels, L.B.; Ribet, D. Gut microbiota alteration in a mouse model of Anorexia Nervosa. *Clin. Nutr.* **2021**, *40*, 181–189. [CrossRef]

97. Dempsey, E.; Corr, S.C. *Lactobacillus* spp. for Gastrointestinal Health: Current and Future Perspectives. *Front. Immunol.* **2022**, *13*, 840245. [CrossRef]

98. Hoffmann, M.; Rath, E.; Hölzlwimmer, G.; Quintanilla-Martinez, L.; Loach, D.; Tannock, G.; Haller, D. *Lactobacillus reuteri* 100-23 transiently activates intestinal epithelial cells of mice that have a complex microbiota during early stages of colonization. *J. Nutr.* **2008**, *138*, 1684–1691. [CrossRef]

99. Jones, R.M.; Luo, L.; Ardita, C.S.; Richardson, A.N.; Kwon, Y.M.; Mercante, J.W.; Alam, A.; Gates, C.L.; Wu, H.; Swanson, P.A.; et al. Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. *EMBO J.* **2013**, *32*, 3017–3028. [CrossRef]

100. Akao, T.; Kanaoka, M.; Kobashi, K. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration-measurement of compound K by enzyme immunoassay. *Biol. Pharm. Bull.* **1998**, *21*, 245–249. [CrossRef]

101. Sun, J.; Wu, W.; Guo, Y.; Qin, Q.; Liu, S. Pharmacokinetic study of ginsenoside Rc and simultaneous determination of its metabolites in rats using RRLC-Q-TOF-MS. *J. Pharm. Biomed. Anal.* **2014**, *88*, 16–21. [CrossRef] [PubMed]

102. Chae, S.; Kang, K.A.; Youn, U.; Park, J.S.; Hyun, J.W. A Comparative Study of the Potential Antioxidant Activities of Ginsenosides. *J. Food Biochem.* **2010**, *34*, 31–43. [CrossRef]

103. Al-Asmari, A.K.; Khan, A.Q.; Al-Qasim, A.M.; Al-Yousef, Y. Ascorbic acid attenuates antineoplastic drug 5-fluorouracil induced gastrointestinal toxicity in rats by modulating the expression of inflammatory mediators. *Toxicol. Rep.* **2015**, *2*, 908–916. [CrossRef] [PubMed]

104. Moreira Lopes, T.C.; Mosser, D.M.; Gonçalves, R. Macrophage polarization in intestinal inflammation and gut homeostasis. *Inflamm. Res.* **2020**, *69*, 1163–1172. [CrossRef] [PubMed]

105. Al-Sadi, R.; Ye, D.; Boivin, M.; Guo, S.; Hashimi, M.; Ereifej, L.; Ma, T.Y. Interleukin-6 Modulation of Intestinal Epithelial Tight Junction Permeability Is Mediated by JNK Pathway Activation of Claudin-2 Gene. *PLoS ONE* **2014**, *9*, e85345. [CrossRef]

106. Thevaranjan, N.; Puchta, A.; Schulz, C.; Naidoo, A.; Szamosi, J.C.; Verschoor, C.P.; Loukov, D.; Schenck, L.P.; Jury, J.; Foley, K.P.; et al. Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction. *Cell Host Microbe* **2017**, *21*, 455–466.e4. [CrossRef]

107. Jeon, H.-J.; Yeom, Y.; Kim, Y.-S.; Kim, E.; Shin, J.-H.; Seok, P.R.; Woo, M.J.; Kim, Y. Effect of vitamin C on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated early colon cancer in mice. *Nutr. Res. Pract.* **2018**, *12*, 101–109. [CrossRef]

108. Han, S.-K.; Joo, M.-K.; Kim, J.-K.; Jeung, W.; Kang, H.; Kim, D.-H. Bifidobacteria-Fermented Red Ginseng and Its Constituents Ginsenoside Rd and Protopanaxatriol Alleviate Anxiety/Depression in Mice by the Amelioration of Gut Dysbiosis. *Nutrients* **2020**, *12*, 901. [CrossRef]

109. Pan, W.; Stone, K.P.; Hsuchou, H.; Manda, V.K.; Zhang, Y.; Kastin, A.J. Cytokine Signaling Modulates Blood-Brain Barrier Function. *Curr. Pharm. Des.* **2011**, *17*, 3729–3740. [CrossRef]

110. Roberts, A.J.; Khom, S.; Bajo, M.; Vlkolinsky, R.; Polis, I.; Cates-Gatto, C.; Roberto, M.; Gruol, D.L. Increased IL-6 expression in astrocytes is associated with emotionality, alterations in central amygdala GABAergic transmission, and excitability during alcohol withdrawal. *Brain Behav. Immun.* **2019**, *82*, 188–202. [CrossRef]

111. Haroon, F.; Drögemüller, K.; Händel, U.; Brunn, A.; Reinhold, D.; Nishanth, G.; Mueller, W.; Trautwein, C.; Ernst, M.; Deckert, M.; et al. Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation. *J. Immunol.* **2011**, *186*, 6521–6531. [CrossRef]

112. Vallières, L.; Campbell, I.L.; Gage, F.H.; Sawchenko, P.E. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. *J. Neurosci. Off. J. Soc. Neurosci.* **2002**, *22*, 486–492. [CrossRef]
90. Fung, T.C.; Olson, C.A.; Hsiao, E.Y. Interactions between the microbiota, immune and nervous systems in health and disease. *Nat. Neurosci.* **2017**, *20*, 145–155. [CrossRef]

91. Song, M.-Y.; Kim, B.-S.; Kim, H. Influence of *Panax ginseng* on obesity and gut microbiota in obese middle-aged Korean women. *J. Ginseng Res.* **2014**, *38*, 106–115. [CrossRef]

92. Zhou, R.; He, D.; Xie, J.; Zhou, Q.; Zeng, H.; Li, H.; Huang, L. The Synergistic Effects of Polysaccharides and Ginsenosides from American Ginseng (*Panax quinquefolius* L.) Ameliorating Cyclophosphamide-Induced Intestinal Immune Disorders and Gut Barrier Dysfunctions Based on Microbiome-Metabolomics Analysis. *Front. Immunol.* **2021**, *12*, 665901. [CrossRef]

93. Wang, W.; Chen, L.; Zhou, R.; Wang, X.; Song, L.; Huang, S.; Wang, G.; Xia, B. Increased proportions of *Bifidobacterium* and the *Lactobacillus* group and loss of butyrate-producing bacteria in inflammatory bowel disease. *J. Clin. Microbiol.* **2014**, *52*, 398–406. [CrossRef]

94. Juan, Z.; Chen, J.; Ding, B.; Yongping, L.; Liu, K.; Wang, L.; Le, Y.; Liao, Q.; Shi, J.; Huang, J.; et al. Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: A randomised, double-blind, and placebo-controlled trial. *Eur. J. Cancer* **2022**, *161*, 10–22. [CrossRef]

95. Million, M.; Maraninchi, M.; Henry, M.; Armougom, F.; Richet, H.; Carrieri, P.; Valero, R.; Raccah, D.; Vialettes, B.; Raoult, D. Obesity-associated gut microbiota is enriched in *Lactobacillus reuteri* and depleted in *Bifidobacterium animalis* and *Methanobrevibacter smithii*. *Int J. Obes.* **2012**, *36*, 817–825. [CrossRef]

96. Breton, J.; Tirelle, P.; Hasanat, S.; Pernot, A.; L'Huillier, C.; do Rego, J.C.; Déchelotte, P.; Coëffier, M.; Bindels, L.B.; Ribet, D. Gut microbiota alteration in a mouse model of Anorexia Nervosa. *Clin. Nutr.* **2021**, *40*, 181–189. [CrossRef]

97. Dempsey, E.; Corr, S.C. *Lactobacillus* spp. for Gastrointestinal Health: Current and Future Perspectives. *Front. Immunol.* **2022**, *13*, 840245. [CrossRef]

98. Hoffmann, M.; Rath, E.; Hölzlwimmer, G.; Quintanilla-Martinez, L.; Loach, D.; Tannock, G.; Haller, D. *Lactobacillus reuteri* 100-23 transiently activates intestinal epithelial cells of mice that have a complex microbiota during early stages of colonization. *J. Nutr.* **2008**, *138*, 1684–1691. [CrossRef]

99. Jones, R.M.; Luo, L.; Ardita, C.S.; Richardson, A.N.; Kwon, Y.M.; Mercante, J.W.; Alam, A.; Gates, C.L.; Wu, H.; Swanson, P.A.; et al. Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. *EMBO J.* **2013**, *32*, 3017–3028. [CrossRef]

100. Akao, T.; Kanaoka, M.; Kobashi, K. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration-measurement of compound K by enzyme immunoassay. *Biol. Pharm. Bull.* **1998**, *21*, 245–249. [CrossRef]

101. Sun, J.; Wu, W.; Guo, Y.; Qin, Q.; Liu, S. Pharmacokinetic study of ginsenoside Rc and simultaneous determination of its metabolites in rats using RRLC-Q-TOF-MS. *J. Pharm. Biomed. Anal.* **2014**, *88*, 16–21. [CrossRef] [PubMed]

102. Chae, S.; Kang, K.A.; Youn, U.; Park, J.S.; Hyun, J.W. A Comparative Study of the Potential Antioxidant Activities of Ginsenosides. *J. Food Biochem.* **2010**, *34*, 31–43. [CrossRef]

103. Al-Asmari, A.K.; Khan, A.Q.; Al-Qasim, A.M.; Al-Yousef, Y. Ascorbic acid attenuates antineoplastic drug 5-fluorouracil induced gastrointestinal toxicity in rats by modulating the expression of inflammatory mediators. *Toxicol. Rep.* **2015**, *2*, 908–916. [CrossRef] [PubMed]

104. Moreira Lopes, T.C.; Mosser, D.M.; Gonçalves, R. Macrophage polarization in intestinal inflammation and gut homeostasis. *Inflamm. Res.* **2020**, *69*, 1163–1172. [CrossRef] [PubMed]

105. Al-Sadi, R.; Ye, D.; Boivin, M.; Guo, S.; Hashimi, M.; Ereifej, L.; Ma, T.Y. Interleukin-6 Modulation of Intestinal Epithelial Tight Junction Permeability Is Mediated by JNK Pathway Activation of Claudin-2 Gene. *PLoS ONE* **2014**, *9*, e85345. [CrossRef]

106. Thevaranjan, N.; Puchta, A.; Schulz, C.; Naidoo, A.; Szamosi, J.C.; Verschoor, C.P.; Loukov, D.; Schenck, L.P.; Jury, J.; Foley, K.P.; et al. Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction. *Cell Host Microbe* **2017**, *21*, 455–466.e4. [CrossRef]

107. Jeon, H.-J.; Yeom, Y.; Kim, Y.-S.; Kim, E.; Shin, J.-H.; Seok, P.R.; Woo, M.J.; Kim, Y. Effect of vitamin C on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated early colon cancer in mice. *Nutr. Res. Pract.* **2018**, *12*, 101–109. [CrossRef]

108. Han, S.-K.; Joo, M.-K.; Kim, J.-K.; Jeung, W.; Kang, H.; Kim, D.-H. Bifidobacteria-Fermented Red Ginseng and Its Constituents Ginsenoside Rd and Protopanaxatriol Alleviate Anxiety/Depression in Mice by the Amelioration of Gut Dysbiosis. *Nutrients* **2020**, *12*, 901. [CrossRef]

109. Pan, W.; Stone, K.P.; Hsuchou, H.; Manda, V.K.; Zhang, Y.; Kastin, A.J. Cytokine Signaling Modulates Blood-Brain Barrier Function. *Curr. Pharm. Des.* **2011**, *17*, 3729–3740. [CrossRef]

110. Roberts, A.J.; Khom, S.; Bajo, M.; Vlkolinsky, R.; Polis, I.; Cates-Gatto, C.; Roberto, M.; Gruol, D.L. Increased IL-6 expression in astrocytes is associated with emotionality, alterations in central amygdala GABAergic transmission, and excitability during alcohol withdrawal. *Brain Behav. Immun.* **2019**, *82*, 188–202. [CrossRef]

111. Haroon, F.; Drögemüller, K.; Händel, U.; Brunn, A.; Reinhold, D.; Nishanth, G.; Mueller, W.; Trautwein, C.; Ernst, M.; Deckert, M.; et al. Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation. *J. Immunol.* **2011**, *186*, 6521–6531. [CrossRef]

112. Vallières, L.; Campbell, I.L.; Gage, F.H.; Sawchenko, P.E. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. *J. Neurosci. Off. J. Soc. Neurosci.* **2002**, *22*, 486–492. [CrossRef]
113. Berger, A.M.; Mitchell, S.A.; Jacobsen, P.B.; Pirl, W.F. Screening, evaluation, and management of cancer-related fatigue: Ready for implementation to practice? *CA Cancer J. Clin.* **2015**, *65*, 190–211. [CrossRef]

114. Miller, A.H.; Jones, J.F.; Drake, D.F.; Tian, H.; Unger, E.R.; Pagnoni, G. Decreased basal ganglia activation in subjects with chronic fatigue syndrome: Association with symptoms of fatigue. *PLoS ONE* **2014**, *9*, e98156. [CrossRef]

115. Karshikoff, B.; Sundelin, T.; Lasselin, J. Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms. *Front. Immunol.* **2017**, *8*, 21. [CrossRef]

116. Dougherty, J.P.; Wolff, B.S.; Cullen, M.J.; Saligan, L.N.; Gershengorn, M.C. Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue. *Pharm. Res.* **2017**, *124*, 1–8. [CrossRef]

117. Zombeck, J.A.; Fey, E.G.; Lyng, G.D.; Sonis, S.T. A clinically translatable mouse model for chemotherapy-related fatigue. *Comp. Med.* **2013**, *63*, 491–497.

118. Renner, M.; Feng, R.; Springer, D.; Chen, M.K.; Ntamack, A.; Espina, A.; Saligan, L.N. A murine model of peripheral irradiation-induced fatigue. *Behav. Brain Res.* **2016**, *307*, 218–226. [CrossRef]

119. Perals, D. Revisiting the open-field test: What does it really tell us about animal personality? *Anim. Behav.* **2017**, *123*, 69–79. [CrossRef]

120. Wang, C.; Zhang, Y.; Shao, S.; Cui, S.; Wan, Y.; Yi, M. Ventral Hippocampus Modulates Anxiety-Like Behavior in Male but Not Female C57BL/6J Mice. *Neuroscience* **2019**, *418*, 50–58. [CrossRef]

121. Konsman, J.P.; Laaker, C.J.; Lloyd, K.R.; Hiltz, A.; Smith, B.L.; Smail, M.A.; Reyes, T.M. Translationally relevant mouse model of early life cancer and chemotherapy exposure results in brain and small intestine cytokine responses: A potential link to cognitive deficits. *Brain Behav. Immun.* **2022**, *99*, 192–202. [CrossRef]

122. Kok, A. Cognitive control, motivation and fatigue: A cognitive neuroscience perspective. *Brain Cogn.* **2022**, *160*, 105880. [CrossRef]
113. Berger, A.M.; Mitchell, S.A.; Jacobsen, P.B.; Pirl, W.F. Screening, evaluation, and management of cancer-related fatigue: Ready for implementation to practice? *CA Cancer J. Clin.* **2015**, *65*, 190–211. [CrossRef]

114. Miller, A.H.; Jones, J.F.; Drake, D.F.; Tian, H.; Unger, E.R.; Pagnoni, G. Decreased basal ganglia activation in subjects with chronic fatigue syndrome: Association with symptoms of fatigue. *PLoS ONE* **2014**, *9*, e98156. [CrossRef]

115. Karshikoff, B.; Sundelin, T.; Lasselin, J. Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms. *Front. Immunol.* **2017**, *8*, 21. [CrossRef]

116. Dougherty, J.P.; Wolff, B.S.; Cullen, M.J.; Saligan, L.N.; Gershengorn, M.C. Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue. *Pharm. Res.* **2017**, *124*, 1–8. [CrossRef]

117. Zombeck, J.A.; Fey, E.G.; Lyng, G.D.; Sonis, S.T. A clinically translatable mouse model for chemotherapy-related fatigue. *Comp. Med.* **2013**, *63*, 491–497.

118. Renner, M.; Feng, R.; Springer, D.; Chen, M.K.; Ntamack, A.; Espina, A.; Saligan, L.N. A murine model of peripheral irradiation-induced fatigue. *Behav. Brain Res.* **2016**, *307*, 218–226. [CrossRef]

119. Perals, D. Revisiting the open-field test: What does it really tell us about animal personality? *Anim. Behav.* **2017**, *123*, 69–79. [CrossRef]

120. Wang, C.; Zhang, Y.; Shao, S.; Cui, S.; Wan, Y.; Yi, M. Ventral Hippocampus Modulates Anxiety-Like Behavior in Male but Not Female C57BL/6J Mice. *Neuroscience* **2019**, *418*, 50–58. [CrossRef]

121. Konsman, J.P.; Laaker, C.J.; Lloyd, K.R.; Hiltz, A.; Smith, B.L.; Smail, M.A.; Reyes, T.M. Translationally relevant mouse model of early life cancer and chemotherapy exposure results in brain and small intestine cytokine responses: A potential link to cognitive deficits. *Brain Behav. Immun.* **2022**, *99*, 192–202. [CrossRef]

122. Kok, A. Cognitive control, motivation and fatigue: A cognitive neuroscience perspective. *Brain Cogn.* **2022**, *160*, 105880. [CrossRef]