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Aim: Saliva can reflect an individual's physiological status or susceptibility to systemic disease. However, little attention has been given to salivary analysis in children with idiopathic nephrotic syndrome (INS). We aimed to perform a comprehensive analysis of saliva from INS children., Methods: A total of 18 children (9 children with INS and 9 normal controls) were recruited. Saliva was collected from each INS patient in the acute and remission phases. 16S rRNA gene sequencing, widely targeted metabolomics, and 4D-DIA proteomics were performed., Results: Actinobacteria and Firmicutes were significantly enriched in the pretreatment group compared with the normal control group, while Bacteroidota and Proteobacteria were significantly decreased. A total of 146 metabolites were identified as significantly different between INS children before treatment and normal controls, which covers 17 of 23 categories. KEGG enrichment analysis revealed three significantly enriched pathways, including ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and terpenoid backbone biosynthesis (P < 0.05). A total of 389 differentially expressed proteins were selected between INS children before treatment and normal controls. According to the KEGG and GO enrichment analyses of the KOGs, abnormal ribosome structure and function and humoral immune disorders were the most prominent differences between INS patients and normal controls in the proteomic analysis., Conclusion: Oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders"., (© 2024 Asian Pacific Society of Nephrology.)

The prevalence of the world's second leading neurodegenerative disorder Parkinson's disease (PD) is well known while its pathogenesis is still a topical issue to explore. Clinical and experimental reports suggest the prevalence of disturbed gut microflora in PD subjects, with an abundance of especially Gram-negative bacteria. The endotoxin lipopolysaccharide (LPS) released from the outer cell layer of these bacteria interacts with the toll-like receptor 4 (TLR4) present on the macrophages and it stimulates the downstream inflammatory cascade in both the gut and brain. Recent research also suggests a positive correlation between LPS, alpha-synuclein, and TLR4 levels, which indicates the contribution of a parallel LPS-alpha-synuclein-TLR4 axis in stimulating inflammation and neurodegeneration in the gut and brain, establishing a body-first type of PD. However, owing to the novelty of this paradigm, further investigation is mandatory. Modulating LPS biosynthesis and LPS-TLR4 interaction can ameliorate gut dysbiosis and PD. Several synthetic LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase; LPS-synthesizing enzyme) inhibitors and TLR4 antagonists are reported to show beneficial effects including neuroprotection in PD models, however, are not devoid of side effects. Plant-derived compounds have been long documented for their benefits as nutraceuticals and thus to search for effective, safer, and multitarget therapeutics, the present study focused on summarizing the evidence reporting the potential of phyto-compounds as LpxC inhibitors and TLR4 antagonists. Studies demonstrating the dual potential of phyto-compounds as the modulators of LpxC and TLR4 have not yet been reported. Also, very few preliminary studies have reported LpxC inhibition by phyto-compounds. Nevertheless, remarkable neuroprotection along with TLR4 antagonism has been shown by curcumin and juglanin in PD models. The present review thus provides a wide look at the research progressed to date in discovering phyto-compounds that can serve as LpxC inhibitors and TLR4 antagonists. The study further recommends the need for expanding the search for potential candidates that can render dual protection by inhibiting both the biosynthesis and TLR4 interaction of LPS. Such multitarget therapeutic intervention is believed to bring fruitful yields in countering gut dysbiosis, neuroinflammation, and dopaminergic neuron damage in PD patients through a single treatment paradigm., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The microbiome-gut-brain axis is related to schizophrenia (SCZ). The role of intestinal mycobiota in SCZ has been under investigated. We present a half-year follow-up study involving 109 chronic SCZ patients and 77 healthy controls. Intestinal mycobiota was tested by internal transcribed spacer (ITS). Untargeted liquid chromatography-mass spectrometry (LC-MS) was used to measure fecal metabolites. Symptom severity was assessed using the Positive and Negative Syndrome Scale. Enterotype analysis showed that Candida-type patients exhibited severer positive symptoms and depression factors than Saccharomyces-type patients. Candida and its top species and operational taxonomic units (OTUs) were positively correlated with depression factors (all p=0.001). Fecal metabolites analysis showed that upregulated metabolites were associated with chronic inflammation (NF-κB pathway and T helper cell differentiation), downregulated metabolites were associated with glutamate metabolism, serotonergic and dopaminergic synapse. Procrustes analysis revealed significant correlation between intestinal mycobiota and fecal metabolites (M2=0.937, p<0.001). Metabolic module analysis showed that the top module, MEturquoise (associated with Th1 and Th2 cell differentiation), was negatively correlated with SCZ (r=-0.783, p<0.0001), positively correlated with Candida, Aspergillus, Trichosporon and Talaromyces (decreased in SCZ) and negatively correlated with Saccharomyces (increased in SCZ). We also found impairments of intestinal barrier in SCZ, characterized by increased in blood D-lactate (mucosa impairment marker) and decreased in blood mucin 2 (mucosal barrier protective protein). Serum levels of TNF-α was increased and showed stable high levels during treatment. This study suggests that mycobiota dysbiosis-related chronic inflammation and an impaired intestinal mucosal barrier are associated with chronic SCZ., (Copyright © 2024. Published by Elsevier B.V.)

Patients with glycogen storage disease type Ib (GSD-Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD-Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo-polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single-cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper-activation of the CCL4L2-VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD-Ib. Collectively, the microbiota-driven pathomechanism of IBD is demonstrated in GSD-Ib and revealed the active role of the CCL4L2-VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2-VISR axis may represent a potential therapy for GSD-associated IBD., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Aims: The prevalence of gestational diabetes mellitus (GDM) has spurred investigations into various interconnected factors, among which gut dysbiosis is notably prominent. Although gut dysbiosis is strongly associated with GDM, the specific role of the gut microbiome in the pathogenesis of GDM remains unknown. This study aims to explore the pathogenesis of GDM from gut microbiota., Materials and Methods: In our study, we constructed two GDM mice models: one induced by a high-fat diet (HFD) and the other through fecal microbiota transplantation (FMT) from GDM patients. In vitro, we used a co-culture system of RAW264.7 and 3T3-L1 adipocytes., Key Findings: We induced a GDM-like state in pregnant mice by FMT from GDM patients, which was consistent with the HFD model. A potential mechanism identified involves the diminished abundance of SCFA-producing microbiota, which reduces SCFAs, particularly propionic acid and butyric acid. In vitro, butyric and propionic acids were observed to alleviate LPS-induced TLR4-NF-κB activation, thereby reducing inflammation levels and inhibiting adipose insulin resistance via the PI3K/AKT signaling pathway. This reduction appears to trigger the polarization of adipose tissue macrophages toward M1 and promote insulin resistance in adipose tissue., Significance: Our study fills this knowledge gap by finding that alterations in gut microbiota have an independent impact on hyperglycemia and insulin resistance in the GDM state. In vivo and in vitro, gut dysbiosis is linked to adipose tissue inflammation and insulin resistance via the bacterial product SCFAs in the GDM state, providing new insights into the pathogenesis of GDM., Competing Interests: Declaration of competing interest The authors declare no competing financial interest. Data availability. The data that support the findings of this study are available from the corresponding author upon reasonable request. The following are the supplementary data related to this article. Supplementary data to this article can be found online at https://doi.org/10.1016/j.lfs.2024.122744., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Colistin is renowned as a last-resort antibiotic due to the emergence of multidrug-resistant pathogens. However, its potential toxicity significantly hampers its clinical utilization. Melatonin, chemically known as N-acetyl-5-hydroxytryptamine, is an endogenous hormone produced by the pineal gland and possesses diverse biological functions. However, the protective role of melatonin in alleviating antibiotic-induced intestinal inflammation remains unknown. Herein, we reveal that colistin stimulation markedly elevates intestinal inflammatory levels and compromises the gut barrier. In contrast, pretreatment with melatonin safeguards mice against intestinal inflammation and mucosal damage. Microbial diversity analysis indicates that melatonin supplementation prevents a reduction in the abundance of Erysipelotrichales and Bifidobacteriales, as well as an increase in Desulfovibrionales abundance, following colistin exposure. Remarkably, short-chain fatty acids (SCFAs) analysis shows that propanoic acid contributes to the protective effect of melatonin on colistin-induced intestinal inflammation. Furthermore, the protection effects of melatonin and propanoic acid on LPS-induced cellular inflammation in RAW 264.7 cells are confirmed. Mechanistic investigations suggest that intervention with melatonin and propanoic acid can repress the activation of the TLR4 signal and its downstream NF-κB and MAPK signaling pathways, thereby mitigating the toxic effects of colistin. Our work highlights the unappreciated role of melatonin in preventing the potential detrimental effects of colistin on intestinal health and suggests a combined therapeutic strategy to effectively manage intestinal infectious diseases., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N 6 -methyladenosine (m 6 A), the most abundant mammalian mRNA modification. However, which and how gut microbiota-derived metabolites reprogram host transcriptome and m 6 A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota-derived metabolites impact host transcriptome and m 6 A epitranscriptome using multiple mouse models and multi-omics approaches. Various antibiotics-induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ-free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid-producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m 6 A epitranscriptome in multiple tissues. Mechanistically, the expression of m 6 A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m 6 A biology. Collectively, these results demonstrate that antibiotic-induced gut dysbiosis regulates the landscape of host transcriptome and m 6 A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Postpartum depression (PPD) is a severe mental disorder that affects approximately 10---20% of women after childbirth. The precise mechanism underlying PPD pathogenesis remains elusive, thus limiting the development of therapeutics. Gut microbiota dysbiosis is considered to contribute to major depressive disorder. However, the associations between gut microbiota and PPD remain unanswered. Here, we established a mouse PPD model by sudden ovarian steroid withdrawal after hormone-simulated pseudopregnancy-human (HSP-H) in ovariectomy (OVX) mouse. Ovarian hormone withdrawal induced depression-like and anxiety-like behaviors and an altered gut microbiota composition. Fecal microbiota transplantation (FMT) from PPD mice to antibiotic cocktail-treated mice induced depression-like and anxiety-like behaviors and neuropathological changes in the hippocampus of the recipient mice. FMT from healthy mice to PPD mice attenuated the depression-like and anxiety-like behaviors as well as the inflammation mediated by the NOD-like receptor protein (NLRP)-3/caspase-1 signaling pathway both in the gut and the hippocampus, increased fecal short-chain fatty acids (SCFAs) levels and alleviated gut dysbiosis with increased SCFA-producing bacteria and reduced Akkermansia in the PPD mice. Also, downregulation of NLRP3 in the hippocampus mitigated depression-like behaviors in PPD mice and overexpression of NLRP3 in the hippocampal dentate gyrus induced depression-like behaviors in naïve female mice. Intriguingly, FMT from healthy mice failed to alleviate depression-like behaviors in PPD mice with NLRP3 overexpression in the hippocampus. Our results highlighted the NLRP3 inflammasome as a key component within the microbiota-gut-brain axis, suggesting that targeting the gut microbiota may be a therapeutic strategy for PPD., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in microbiome composition are associated with disease pathology. Stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes in the context of stress. Using a model of chronic stress, we show that the glycocalyx protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a novel regulator of mucin 13 expression., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.A.M. is an inventor on a Stanford patent related to the use of mucinases as research tools; she is also a consultant for InterVenn Biosciences. A.G. is a consultant for Novoron Bioscience., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic pain is a heavily debilitating condition and a huge socio-economic burden, with no efficient treatment. Over the past decade, the gut microbiota has emerged as an important regulator of nervous system's health and disease states. Yet, its contribution to the pathogenesis of chronic somatic pain remains poorly documented. Here, we report that male but not female mice lacking Myosin1a (KO) raised under single genotype housing conditions (KO-SGH) are predisposed to develop chronic pain in response to a peripheral tissue injury. We further underscore the potential of MYO1A loss-of-function to alter the composition of the gut microbiota and uncover a functional connection between the vulnerability to chronic pain and the dysbiotic gut microbiota of KO-SGH males. As such, parental antibiotic treatment modifies gut microbiota composition and completely rescues the injury-induced pain chronicity in male KO-SGH offspring. Furthermore, in KO-SGH males, this dysbiosis is accompanied by a transcriptomic activation signature in the dorsal root ganglia (DRG) macrophage compartment, in response to tissue injury. We identify CD206 + CD163 - and CD206 + CD163 + as the main subsets of DRG resident macrophages and show that both are long-lived and self-maintained and exhibit the capacity to monitor the vasculature. Consistently, in vivo depletion of DRG macrophages rescues KO-SGH males from injury-induced chronic pain underscoring a deleterious role for DRG macrophages in a Myo1a-loss-of function context. Together, our findings reveal gene-sex-microbiota interactions in determining the predisposition to injury-induced chronic pain and point-out DRG macrophages as potential effector cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: APOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear., Methods: C57BL/6 WT and ApoH -/- mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed., Results: ApoH -/- mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH -/- mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH -/- mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism., Conclusion: APOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice., Competing Interests: Declaration of competing interest Yaming Liu has patent issued to Yaming Liu. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale: Currently, there are occasional reports of health problems caused by sleep deprivation (SD). However, to date, there remains a lack of in-depth research regarding the effects of SD on the growth and development of oocytes in females. The present work aimed to investigate whether SD influences ovarian folliculogenesis in adolescent female mice. Methods: Using a dedicated device, SD conditions were established in 3-week old female mice (a critical stage of follicular development) for 6 weeks and gut microbiota and systemic metabolomics were analyzed. Analyses were related to parameters of folliculogenesis and reproductive performance of SD females. Results: We found that the gut microbiota and systemic metabolomics were severely altered in SD females and that these were associated with parameters of premature ovarian insufficiency (POI). These included increased granulosa cell apoptosis, reduced numbers of primordial follicles (PmFs), correlation with decreased AMH, E2, and increased LH in blood serum, and a parallel increased number of growing follicles and changes in protein expression compatible with PmF activation. SD also reduced oocyte maturation and reproductive performance. Notably, fecal microbial transplantation from SD females into normal females induced POI parameters in the latter while niacinamide (NAM) supplementation alleviated such symptoms in SD females. Conclusion: Gut microbiota and alterations in systemic metabolomics caused by SD induced POI features in juvenile females that could be counteracted with NAM supplementation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diseases like obesity and intestinal inflammation diseases are accompanied by dysbiosis of the gut microbiota (DSGM), which leads to various complications, including systemic metabolic disorders. DSGM reportedly impairs the fertility of male mice; however, the regulatory mechanism is unclear. Exosomes are molecular mediators of intercellular communication, but the regulation of spermatogenesis by non-reproductive tissue-originated exosomes remains unknown. The present study shows that DSGM altered the miRNA expression profile of mouse circulating exosomes and impaired spermatogenesis. Moreover, the single-cell sequencing results indicate that circulating exosomes from mice with DSGM impaired spermatogenesis, while circulating exosomes from wild mice improved spermatogenesis by promoting meiosis. Further study demonstrates that DSGM leads to abnormal upregulation of miR-211-5p in gut-derived circulating exosomes, which inhibited the expression of meiosis-specific with coiled-coil domain (Meioc) in the testes and impaired spermatogenesis by disturbing meiosis process. In summary, this study defines the important role of gut-derived exosomes in connecting the "gut-testis" axis., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Context: Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear., Objective: The objective of this work is to examine the alteration of gut microbiota in patients with CS., Methods: We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS., Results: We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae&#95;bacterium&#95;6&#95;1&#95;45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro., Conclusion: This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Captivity is an important and efficient technique for rescuing endangered species. However, it induces infertility, and the underlying mechanism remains obscure. This study used the plateau pika ( Ochotona curzoniae ) as a model to integrate physiological, metagenomic, metabolomic, and transcriptome analyses and explore whether dysbiosis of the gut microbiota induced by artificial food exacerbates infertility in captive wild animals. Results revealed that captivity significantly decreased testosterone levels and the testicle weight/body weight ratio. RNA sequencing revealed abnormal gene expression profiles in the testicles of captive animals. The microbial α-diversity and Firmicutes/Bacteroidetes ratio were drastically decreased in the captivity group. Bacteroidetes and Muribaculaceae abundance notably increased in captive pikas. Metagenomic analysis revealed that the alteration of flora increased the capacity for carbohydrate degradation in captivity. The levels of microbe metabolites' short-chain fatty acids (SCFAs) were significantly high in the captive group. Increasing SCFAs influenced the immune response of captivity plateau pikas; pro-inflammatory cytokines were upregulated in captivity. The inflammation ultimately contributed to male infertility. In addition, a positive correlation was observed between Gastranaerophilales family abundance and testosterone concentration. Our results provide evidence for the interactions between artificial food, the gut microbiota, and male infertility in pikas and benefit the application of gut microbiota interference in threatened and endangered species.

The gut microbiota is associated with memory; however, the relationship between dysbiosis-induced memory deficits and hippocampal glutamatergic neurons remains unclear. In our study, a mouse dysbiosis model showed impaired memory-related behavior in the passive avoidance test; decreased expression levels of glutaminase, excitatory amino acid transporter (EAAT)1, EAAT2, vesicular glutamate transporter 2, synaptophysin, brain-derived neurotrophic factor, doublecortin, neuronal nuclear protein, glial fibrillary acidic protein, and S100β; and decreased phosphorylation of N-methyl-D-aspartate receptor subunit 1, calmodulin-dependent protein kinase II, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1, and cAMP response element-binding protein in the hippocampus. This suggests that dysbiosis-induced memory dysfunction is associated with the hippocampal glutamatergic nervous system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Gut microbiome dysbiosis has been widely implicated in cognitive impairment, but the identity of the specific bacterial taxa and mechanisms are not fully elucidated. Brain glucose hypometabolism coincides with the cognitive decline. This study explored the link among cognition, gut microbiota and glucose uptake based on the fecal microbiota transplantation from mild cognitive impairment individuals (MCI-FMT) and investigated whether similar mechanisms were involved in 27-hydroxycholesterol (27-OHC)-induced cognitive decline. Our results showed that the MCI-FMT mice exhibited learning and memory decline and morphological lesions in the brain and colon tissues. There were reduced 18 F-fluorodeoxyglucose uptake, downregulated expression of glucose transporters (GLUT1,3,4) and upregulated negative regulator of glucose uptake (TXNIP) in the brain. MCI-FMT altered the bacterial composition and diversity of the recipient mice, and the microbial signatures highlighted by the increased abundance of Bacteroides recapitulated the negative effects of MCI bacterial colonization. However, inhibiting Bacteroidetes or TXNIP increased the expression of GLUT1 and GLUT4, significantly improving brain glucose uptake and cognitive performance in 27-OHC-treated mice. Our study verified that cognitive decline and abnormal cerebral glucose uptake were associated with gut microbiota dysbiosis; we also revealed the involvement of Bacteroidetes and molecular mechanisms of TXNIP-related glucose uptake in cognitive deficits caused by 27-OHC.

Gastrointestinal (GI) cancer is a major health concern due to its prevalence, impact on well-being, high mortality rate, economic burden, and potential for prevention and early detection. GI cancer research has made remarkable strides in understanding biology, risk factors, and treatment options. An emerging area of research is the gut microbiome's role in GI cancer development and treatment response. The gut microbiome, vital for digestion, metabolism, and immune function, is increasingly linked to GI cancers. Dysbiosis and alterations in gut microbe composition may contribute to cancer development. Scientists study how specific bacteria or microbial metabolites influence cancer progression and treatment response. Modulating the gut microbiota shows promise in enhancing treatment efficacy and preventing GI cancers. Gut microbiota dysbiosis can impact GI cancer through inflammation, metabolite production, genotoxicity, and immune modulation. Microbes produce metabolites like short-chain fatty acids, bile acids, and secondary metabolites. These affect host cells, influencing processes like cell proliferation, apoptosis, DNA damage, and immune regulation, all implicated in cancer development. This review explores the latest research on gut microbiota metabolites and their molecular mechanisms in GI cancers. The hope is that this attempt will help in conducting other relevant research to unravel the precise mechanism involved, identify microbial signatures associated with GI cancer, and develop targets., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The human gut microbiota is a complex and dynamic community of microorganisms, that influence metabolic, neurodevelopmental, and immune pathways. Microbial dysbiosis, characterized by changes in microbial diversity and relative abundances, is implicated in the development of various chronic neurological and neurodegenerative disorders. These disorders are marked by the accumulation of pathological protein aggregates, leading to the progressive loss of neurons and behavioural functions. Dysregulations in protein-protein interaction networks and signalling complexes, critical for normal brain function, are common in neurological disorders but challenging to unravel, particularly at the neuron and synapse-specific levels. To advance therapeutic strategies, a deeper understanding of neuropathogenesis, especially during the progressive disease phase, is needed. Biomarkers play a crucial role in identifying disease pathophysiology and monitoring disease progression. Proteomics, a powerful technology, shows promise in accelerating biomarker discovery and aiding in the development of novel treatments. In this chapter, we provide an in-depth overview of how proteomic techniques, utilizing various biofluid samples from patients with neurological conditions and diverse animal models, have contributed valuable insights into the pathogenesis of numerous neurological disorders. We also discuss the current state of research, potential challenges, and future directions in proteomic approaches to unravel neuro-pathological conditions., (Copyright © 2024. Published by Elsevier Inc.)

Background: Obesity is closely associated with lipid accumulation and intestinal microbiota dysbiosis. It has been proved that probiotics supplement contributes to alleviate obesity. The objective of this study was to investigate the mechanism by which Lactobacillus plantarum HF02 (LP-HF02) alleviated lipid accumulation and intestinal microbiota dysbiosis in high-fat diet-induced obese mice., Results: Our results showed that LP-HF02 ameliorated body weight, dyslipidemia, liver lipid accumulation, and liver injury in obese mice. As expected, LP-HF02 inhibited pancreatic lipase activity in small intestinal contents and increased fecal triglyceride levels, thereby reducing dietary fat hydrolysis and absorption. Moreover, LP-HF02 ameliorated the intestinal microbiota composition, as evidenced by the enhanced ratio of Bacteroides to Firmicutes, the decreased abundance of pathogenic bacteria (including Bacteroides, Alistipes, Blautia, and Colidextribacter) and the increased abundance of beneficial bacteria (including Muribaculaceae, Akkermansia, Faecalibaculum, and Rikenellaceae&#95;RC9&#95;gut&#95;group). LP-HF02 also increased fecal short-chain fatty acids (SCFAs) levels and colonic mucosal thickness, and subsequently decreased serum lipopolysaccharide (LPS), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in obese mice. Additionally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot results demonstrated that LP-HF02 ameliorated hepatic lipid accumulation via activating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway., Conclusion: Therefore, our results indicated that LP-HF02 could be considered as a probiotic preparation for preventing obesity. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

While dysbiosis in the gut is implicated in the impaired induction of oral tolerance generated in mesenteric lymph nodes (MesLNs), how dysbiosis affects this process remains unclear. Here, we describe that antibiotic-driven gut dysbiosis causes the dysfunction of CD11c + CD103 + conventional dendritic cells (cDCs) in MesLNs, preventing the establishment of oral tolerance. Deficiency of CD11c + CD103 + cDCs abrogates the generation of regulatory T cells in MesLNs to establish oral tolerance. Antibiotic treatment triggers the intestinal dysbiosis linked to the impaired generation of colony-stimulating factor 2 (Csf2)-producing group 3 innate lymphoid cells (ILC3s) for regulating the tolerogenesis of CD11c + CD103 + cDCs and the reduced expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) on CD11c + CD103 + cDCs for generating Csf2-producing ILC3s. Thus, antibiotic-driven intestinal dysbiosis leads to the breakdown of crosstalk between CD11c + CD103 + cDCs and ILC3s for maintaining the tolerogenesis of CD11c + CD103 + cDCs in MesLNs, responsible for the failed establishment of oral tolerance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Evidence on the effect of gut microbiota on the number of metabolic syndrome (MetS) risk factors among children is scarce. We aimed to examine the alterations of gut microbiota with different numbers of MetS risk factors among children., Methods: Data were collected from a nested case-control study at the baseline of the Huantai Childhood Cardiovascular Health Cohort Study in Zibo, China. We compared the differences in gut microbiota based on 16S rRNA gene sequencing among 72 children with different numbers of MetS risk factors matched by age and sex (i.e., none, one, and two-or-more MetS risk factors; 24 children for each group)., Results: The community richness (i.e., the total number of species in the community) and diversity (i.e., the richness and evenness of species in the community) of gut microbiota decreased with an increased number of MetS risk factors in children (P for trend < 0.05). Among genera with a relative abundance greater than 0.01%, the relative abundance of Lachnoclostridium (P FDR  = 0.009) increased in the MetS risk groups, whereas Alistipes (P FDR  < 0.001) and Lachnospiraceae&#95;NK4A136&#95;group (P FDR  = 0.043) decreased in the MetS risk groups compared to the non-risk group. The genus Christensenellaceae&#95;R-7&#95;group excelled at distinguishing one and two-or-more risk groups from the non-risk group (area under the ROC curve [AUC]: 0.84 - 0.92), while the genera Family&#95;XIII&#95;AD3011&#95;group (AUC: 0.73 - 0.91) and Lachnoclostridium (AUC: 0.77 - 0.80) performed moderate abilities in identifying none, one, and two-or-more MetS risk factors in children., Conclusions: Based on the nested case-control study and the 16S rRNA gene sequencing technology, we found that dysbiosis of gut microbiota, particularly for the genera Christensenellaceae&#95;R-7&#95;group, Family&#95;XIII&#95;AD3011&#95;group, and Lachnoclostridium may contribute to the early detection and the accumulation of MetS risk factors in childhood., (© 2023. The Author(s).)

Obesity is characterized by systemic low-grade inflammation associated with disturbances of intestinal homeostasis and microbiota dysbiosis. Mitochondrial metabolism sustains epithelial homeostasis by providing energy to colonic epithelial cells (CEC) but can be altered by dietary modulations of the luminal environment. Our study aimed at evaluating whether the consumption of an obesogenic diet alters the mitochondrial function of CEC in mice. Mice were fed for 22 weeks with a 58% kcal fat diet (diet-induced obesity [DIO] group) or a 10% kcal fat diet (control diet, CTRL). Colonic crypts were isolated to assess mitochondrial function while colonic content was collected to characterize microbiota and metabolites. DIO mice developed obesity, intestinal hyperpermeability, and increased endotoxemia. Analysis of isolated colonic crypt bioenergetics revealed a mitochondrial dysfunction marked by decreased basal and maximal respirations and lower respiration linked to ATP production in DIO mice. Yet, CEC gene expression of mitochondrial respiration chain complexes and mitochondrial dynamics were not altered in DIO mice. In parallel, DIO mice displayed increased colonic bile acid concentrations, associated with higher abundance of Desulfovibrionaceae. Sulfide concentration was markedly increased in the colon content of DIO mice. Hence, chronic treatment of CTRL mouse colon organoids with sodium sulfide provoked mitochondrial dysfunction similar to that observed in vivo in DIO mice while acute exposure of isolated mitochondria from CEC of CTRL mice to sodium sulfide diminished complex IV activity. Our study provides new insights into colon mitochondrial dysfunction in obesity by revealing that increased sulfide production by DIO-induced dysbiosis impairs complex IV activity in mouse CEC., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Anxiety-like behavior and social withdrawal induced by obesity and oxidative stress are significant health concerns in contemporary society. Our previously study found that Bacillus amyloliquefaciens SC06 (SC06) decreased the body weight of high-fat diet (HFD)-fed male mice and protected porcine intestinal epithelial cells against oxidative stress. The present study further investigated the effect of SC06 on HFD-induced obesity, anxiety-like behavior and social withdrawal of male mice and explored its mechanism. Results showed that SC06 significantly decreased HFD-induced obesity as evidenced by the decreased body weight, weight of liver and epididymal fat. Meanwhile, SC06 attenuated the anxiety-like behavior of HFD-fed male mice as illustrated by the more exploration time in both the open arms of elevated plus maze and the central area of open field and the reversed their social withdrawal tested in the three-chamber social choice task. SC06 also reduced reactive oxygen species (ROS) concentration and normalized the mitochondrial morphology in the hippocampus. SC06 reduced the systemic inflammation and increased the expression of intestinal tight junctions (ZO-1 and Claudin1). Furthermore, SC06 also altered the microbial diversity and composition, and decreased Firmicutes to Bacteroidetes ratio of HFD-fed male mice. These findings suggest SC06 attenuate HFD-induced anxiety-like behavior and social withdrawal of male mice by attenuating hippocampal oxidation stress, systemic inflammation, dysbiosis and improving intestinal barrier function., Competing Interests: Conflict of interest The author declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Gut microbiota dysbiosis is already a global problem after antibiotic overuse. This study was to investigate the therapeutic effect of lentinan and the mechanism of recovery of intestinal inflammation on broad-spectrum antibiotic-driven gut microbial dysbiosis in mice. Gut microbiota was elucidated by the Illumina MiSeq platform. Gas chromatography/mass spectrometry was used to investigate short-chain fatty acid content. Colon histology, expression of tight-junction associated proteins and pro-inflammatory cytokines levels were evaluated. The results showed that the gut microbiota of diversity and richness were reduced and various taxonomic levels of the gut microbiota were perturbed after antibiotics gavage. The abundance of Firmicutes and Bacteroidetes shifted to Proteobacteria and increased the relative abundance of harmful microbiota (Parabacteroides and Klebsiella) post-antibiotics, whereas lentinan administration reversed the dysbiosis and increased beneficial microbiota, including S24-7, Lactobacillus, Oscillospira, Ruminococcus and Allobaculum. The concentrations of propionic acid and butyric acid were significantly increased by treatment with lentinan. And lentinan improved colon tissue morphology and reduced pro-inflammatory cytokines via altering NF-κB signaling pathway in antibiotic-driven gut microbial dysbiosis mice. Taken together, the results proved that lentinan can be used as a prebiotic and the result provided a theoretical basis for improving the clinical treatment of broad-spectrum antibiotics side effects., (© 2022. The Author(s).)

Background: Systemic low-grade inflammation observed in diet-induced obesity has been associated with dysbiosis and disturbance of intestinal homeostasis. This latter relies on an efficient epithelial barrier and coordinated intestinal epithelial cell (IEC) renewal that are supported by their mitochondrial function. However, IEC mitochondrial function might be impaired by high fat diet (HFD) consumption, notably through gut-derived metabolite production and fatty acids, that may act as metabolic perturbators of IEC., Scope of Review: This review presents the current general knowledge on mitochondria, before focusing on IEC mitochondrial function and its role in the control of intestinal homeostasis, and featuring the known effects of nutrients and metabolites, originating from the diet or gut bacterial metabolism, on IEC mitochondrial function. It then summarizes the impact of HFD on mitochondrial function in IEC of both small intestine and colon and discusses the possible link between mitochondrial dysfunction and altered intestinal homeostasis in diet-induced obesity., Major Conclusions: HFD consumption provokes a metabolic shift toward fatty acid β-oxidation in the small intestine epithelial cells and impairs colonocyte mitochondrial function, possibly through downstream consequences of excessive fatty acid β-oxidation and/or the presence of deleterious metabolites produced by the gut microbiota. Decreased levels of ATP and concomitant O 2 leaks into the intestinal lumen could explain the alterations of intestinal epithelium dynamics, barrier disruption and dysbiosis that contribute to the loss of epithelial homeostasis in diet-induced obesity. However, the effect of HFD on IEC mitochondrial function in the small intestine remains unknown and the precise mechanisms by which HFD induces mitochondrial dysfunction in the colon have not been elucidated so far., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Obesity is a combination of genetic, environmental factors, and systemic inflammation of adipose tissue. In the last decade, more and more evidence suggests that intestinal microbiota is an environmental factor that plays a crucial role in obesity and associated metabolic disorders. Here, we review the association between intestinal microbiota and obesity based on the literature data available to us. The intestinal flora, in the equilibrium state of conventional bacteria, protects the health of the host and helps the development of the immune system. The genome, diet, lifestyle, and epigenetic changes of the host can pathologically alter the composition of the microbiota. In dysbiosis, the development of the gut-associated lymphoid tissue (GALT) associated with the intestinal tract is impaired and the integrity of the intestinal barrier is impaired. Due to the consequent intestinal hyperpermeability, components of pathogenic pathogens such as lipopolysaccharides enter the bloodstream. These components bind to receptors on adipose tissue immune cells as ligands for molecular samples with pathogenic properties and induce adipose tissue dysfunction. The secretion of inflammatory cytokines in adipose tissue is increased. This induces persistent low chronic inflammation, which is responsible for the development of obesity. The damage to health caused by the hyperpermeability of the intestinal barrier can be reduced by interventions, or restored early in the process. Knowing the relationships will help prevent and treat obesity.

Background: Chronic abdominal pain is the most common cause for gastroenterology consultation and is frequently associated with functional gastrointestinal disorders including irritable bowel syndrome and inflammatory bowel disease. These disorders present similar brain/gut/microbiota trialogue alterations, associated with abnormal intestinal permeability, intestinal dysbiosis and colonic hypersensitivity (CHS). Intestinal dysbiosis can alter colon homeostasis leading to abnormal activation of the innate immunity that promotes CHS, perhaps involving the toll-like receptors (TLRs), which play a central role in innate immunity., Aim: To understand the mechanisms between early life event paradigm on intestinal permeability, fecal microbiota composition and CHS development in mice with TLRs expression in colonocytes., Methods: Maternal separation model (NMS) CHS model, which mimics deleterious events in childhood that can induce a wide range of chronic disorders during adulthood were used. Colonic sensitivity of NMS mice was evaluated by colorectal distension (CRD) coupled with intracolonic pressure variation (IPV) measurement. Fecal microbiota composition was analyzed by 16S rRNA sequencing from weaning to CRD periods. TLR mRNA expression was evaluated in colonocytes. Additionally, the effect of acute intrarectal instillation of the TLR5 agonist flagellin (FliC) on CHS in adult naive wildtype mice was analyzed., Results: Around 50% of NMS mice exhibited increased intestinal permeability and CHS associated with intestinal dysbiosis, characterized by a significant decrease of species richness, an alteration of the core fecal microbiota and a specific increased relative abundance of flagellated bacteria. Only TLR5 mRNA expression was increased in colonocytes of NMS mice with CHS. Acute intrarectal instillation of FliC induced transient increase of IPV, reflecting transient CHS appearance., Conclusion: Altogether, these data suggest a pathophysiological continuum between intestinal dysbiosis and CHS, with a role for TLR5., Competing Interests: Conflict-of-interest statement: All authors have nothing to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IκBζ in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating inflammatory diseases. Mechanistically, the IκBζ deficiency results in decrease in the number of Paneth cells and impairment in expression of IL-17-inducible genes involved in IgA production. The decrease in Paneth cells is caused by aberrant activation of IFN-γ signaling and a failure of IL-17-dependent recovery from IFN-γ-induced damage. Thus, the IL-17R-IκBζ axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop between the gut microbiota and immune cells., (© 2022. The Author(s).)

Interleukin-6 (IL-6) in mucosal immune cells is involved in post-injury intestinal regeneration, inflammation responses, and gastric homeostasis. However, the interaction between IL-6 and the dynamic balance of gut microbiota (GM) remains unexplored. Intestinal pathology was assessed by hematoxylin and eosin and periodic acid-Schiff staining in wild-type (WT) and IL-6 gene knockout (KO) C57BL/6J mice. GM profiles were established via high-throughput sequencing of the fecal bacterial 16S rRNA gene. Intestinal α- and β-defensins were measured by quantitative real-time PCR; further, flow cytometry was performed to analyze isolated intraepithelial lymphocytes (IELs). Compared with the WT, IL-6 KO did not obviously change gut structures, but significantly reduced GM diversity, resulting in reduced metabolic pathways with decreased gram-positive but elevated gram-negative bacteria. More taxa alterations included differences at the phyla (e.g., increased Verrucomicrobia and decreased Firmicutes) and genera (e.g., increased Akkermansia and decreased Lactobacillus) levels. Absence of IL-6 also significantly increased intestinal expression of defensins α3 and α4 (Defa3 and Defa4) and the percentage of natural TCRγδ + IELs, providing a molecular basis for triggering mucosal immune response. Therefore, IL-6 loss remodels GM composition and alters IEL maintenance, identifying IL-6 as a crucial cytokine for GM dysbiosis and mucosal immunity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Scope: Inflammatory bowel disease is an inflammatory gastrointestinal disorder associated with intestinal barrier damage, cell proliferation disorder, and dysbiosis of the intestinal microbiota. It remains unknown whether alpha-ketoglutarate (α-KG) can alleviate colitis in mice., Methods and Results: Six-week-old male C57BL/6 mice supplemented with or without 0.5% α-KG (delivered in the form of sodium salt) are subjected to drinking water or 2.5% DSS to induce colitis. The results show that α-KG administration is attenuated the severity of colitis, as is indicated by reduced body-weight loss, colon shortening and colonic hyperplasia, and repressed proinflammatory cytokine secretion in DSS-challenged mice. Additionally, DSS-induced increases in malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2 ), and decreases in glutathione (GSH) levels are attenuated by α-KG administration. Further study shows that the protective effect of α-KG is associated with restoring gut barrier integrity by enhancing the expression of tight junction proteins, increasing Lactobacillus levels, and regulating gut hyperplasia by the Wnt-Hippo signaling pathway in DSS-induced colitis., Conclusion: Collectively, the data provided herein demonstrate that α-KG administration is attenuated mucosal inflammation, barrier dysfunction, and gut microflora dysbiosis. This beneficial effect is associated with increased Lactobacillus levels and regulated colon hyperplasia by the Wnt-Hippo signaling pathway., (© 2022 Wiley-VCH GmbH.)

Obesity is a global health issue associated with increased prevalence of disease and mortality. Molokhia (Corchorus olitorius L.) leaves, used as vegetables in Asia and Africa, comprise abundant water-soluble mucilage polysaccharides. The present study aimed to evaluate the effects of molokhia leaf polysaccharide fraction (MPF) on high-fat diet (HFD)-induced obesity and gut dysbiosis in mice. A significant decrease was observed in the body weight, adipocyte size, triglyceride serum, and low-density lipoprotein cholesterol levels, as well as in the expression of lipid synthesis-related proteins in mice treated with 4 mg/kg of MPF (MPF4). Moreover, the expression of the tight junction protein increased significantly; however, gut permeability and related inflammatory marker levels decreased in the MPF4 group. Furthermore, MPF ameliorated gut dysbiosis, whereas the MPF4 group presented a decreased Firmicutes to Bacteroidetes ratios and an increased abundance of Akkermansia during exposure to HFD. Our findings reveal that rhamnogalacturonan-Ⅰ rich MPF attenuates obesity in mice subjected to HFD by modulating the gut microbiota., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The profile of the human small intestinal microbiota remains to be uncovered primarily due to sampling difficulties. Ileostomy provides the intestinal luminal contents as ileostomy effluents (IE) that offer opportunity for performing extensive analyses of nutrients, gastrointestinal fluids, metabolites, and microbiome. In the present study, we evaluated changes in the microbiome, pH, and bacterial short-chain fatty acids (SCFAs) in IE obtained from patients who had undergone ileostomy following surgical resection of colon cancer and inflammatory bowel disease (IBD). We enrolled 11 patients who varied in the duration of ileostomy from 3 days to >5 years after surgery and had no inflammation in the small intestine. The analyses suggested that IE from patients previously having IBD had less diversity and greater intraday and interday fluctuations, and increased pH and decreased levels of propionic acid and acetic acid than those in IE from patients previously having cancer. Furthermore, correlation analysis suggested a possible effect of the intestinal microbiome on luminal pH, presumably via SCFA production. The present study suggested that inflammation in the colon may induce long-term dysbiosis in the small intestine even after removal of diseased parts of the colon. Moreover, pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) was found to have beneficial effects on postoperative bowel dysfunction and the human small intestinal microbiota. Taken together, these results suggest the necessity of a direct remedy for dysbiosis and the treatment of gastrointestinal lesions to achieve favorable outcomes for chronic gastrointestinal disorders., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable impairment of cognitive function and interpersonal relationships. Furthermore, some individuals with ASD have gastrointestinal disorders that have been correlated with impairments in intestinal microbiota. Gut microbiota are important not only for intestinal health, but also for many other functions including food digestion, energy production, immune system regulation, and, according to current data, behavior. Disruption of the indigenous microbiota, microbial dysbiosis (imbalance between microorganisms present in the gut), overgrowth of potentially pathogenic microorganisms, a less diverse microbiome, or lower levels of beneficial bacteria in children with ASD can affect behavior. Metabolome analysis in children with ASD has identified perturbations in multiple metabolic pathways that might be associated with cognitive functions. Recent studies have shown that the intestinal microbiome provides environmental signals that can modify host response to stimuli by modifying the host epigenome, which affects DNA methylation, histone modification, and non-coding RNAs. The most studied microbiota-produced epigenetic modifiers are short-chain fatty acids, although other products of intestinal microbiota might also cause epigenetic modifications in the host's DNA. Here we review evidence suggesting that epigenetic alterations caused by modification of gene expression play an important role in understanding ASD., (© 2021 Mac Keith Press.)

The metabolic syndrome (MetS) has become a global public health burden due to its link to cardiovascular disease and diabetes mellitus. The present study was designed to characterize the metabolic and cardiovascular disturbances, as well as changes in gut microbiota associated with high-fructose high-fat diet (HFFD)-induced MetS in Watanabe heritable hyperlipidemic (WHHL) rabbits. Twenty-one Watanabe rabbits were assigned to a control (n = 9) and HFFD (n = 12) groups, receiving a chow diet and a HFFD, respectively. During a 12-weeks protocol, morphological parameters were monitored; plasma fasting levels of lipids, glucose and insulin were measured and a glucose tolerance test (GTT) was performed. HOMA-IR was calculated. Cardiac function and vascular reactivity were evaluated using the Langendorff isolated heart and isolated carotid arteries methods, respectively. 16S rRNA sequencing of stool samples was used to determine gut microbial composition and abundance. HFFD-fed Watanabe rabbits exhibited increased fasting insulin (p < 0.03, 12th week vs. Baseline), HOMA-IR (p < 0.03 vs. Control), area under the curve of the GTT (p < 0.02 vs. Control), triglycerides (p < 0.05, 12th week vs. Baseline), TC (p < 0.01 vs. Control), LDL-C (p < 0.001 vs. Control). The HFFD group also displayed a significant decrease in intestinal microbial richness, evenness and diversity (FDR < 0.001, FDR < 0.0001, FDR < 0.01, respectively vs. Control group) and an increase in its Firmicutes/Bacteroidetes ratio (R = 3.39 in control vs. R = 28.24 in the HFFD group) indicating a shift in intestinal microbial composition and diversity. Our results suggest that HFFD induces insulin resistance and gut microbiota dysbiosis and accentuates dyslipidemia; and that, when subjected to HFFD, Watanabe rabbits might become a potential diet-induced MetS animal models with two main features, dyslipidemia and insulin resistance., Competing Interests: The authors have declared that no competing interests exist.

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout (KO) mice. While young GHS-R KO mice showed marginal changes in Bacteroidetes and Firmicutes, aged GHS-R KO mice exhibited reduced Bacteroidetes and increased Firmicutes, featuring a disease-susceptible microbiome profile. To further study the role of GHS-R in intestinal inflammation in aging, we induced acute colitis in young and aged GHS-R KO mice using dextran sulfate sodium (DSS). The GHS-R KO mice showed more severe disease activity scores, higher proinflammatory cytokine expression, and decreased expression of tight junction markers. These results suggest that GHS-R plays an important role in microbiome homeostasis and gut inflammation during aging; GHS-R suppression exacerbates intestinal inflammation in aging and increases vulnerability to colitis. Collectively, our finding reveals for the first time that GHS-R is an important regulator of intestinal health in aging; targeting GHS-R may present a novel therapeutic strategy for prevention/treatment of aging leaky gut and inflammatory bowel disease.

Background & Aims: Microbiota composition and mechanisms of host-microbiota interactions in the esophagus are unclear. We aimed to uncover fundamental information about the esophageal microbiome and its potential significance to eosinophilic esophagitis (EoE)., Methods: Microbiota composition, transplantation potential, and antibiotic responsiveness in the esophagus were established via 16S ribosomal RNA sequencing. Functional outcomes of microbiota colonization were assessed by RNA sequencing analysis of mouse esophageal epithelium and compared with the human EoE transcriptome. The impact of dysbiosis was assessed using a preclinical model of EoE., Results: We found that the murine esophagus is colonized with diverse microbial communities within the first month of life. The esophageal microbiota is distinct, dominated by Lactobacillales, and demonstrates spatial heterogeneity as the proximal and distal esophagus are enriched in Bifidobacteriales and Lactobacillales, respectively. Fecal matter transplantation restores the esophageal microbiota, demonstrating that the local environment drives diversity. Microbiota colonization modifies esophageal tissue morphology and gene expression that is enriched in pathways associated with epithelial barrier function and overlapping with genes involved in EoE, including POSTN, KLK5, and HIF1A. Finally, neonatal antibiotic treatment reduces the abundance of Lactobacillales and exaggerates type 2 inflammation in the esophagus. Clinical data substantiated loss of esophageal Lactobacillales in EoE compared with controls., Conclusions: The esophagus has a unique microbiome with notable differences between its proximal and distal regions. Fecal matter transplantation restores the esophageal microbiome. Antibiotic-induced dysbiosis exacerbates disease in a murine model of EoE. Collectively, these data establish the composition, transplantation potential, antibiotic responsiveness, and host-microbiota interaction in the esophagus and have implications for gastrointestinal health and disease., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Skeletal muscle mass plays a critical role in a healthy lifespan by helping to regulate glucose homeostasis. As seen in sarcopenia, decreased skeletal muscle mass impairs glucose homeostasis, but it may also be caused by glucose dysregulation. Gut microbiota modulates lipopolysaccharide (LPS) production, short-chain fatty acids (SCFA), and various metabolites that affect the host metabolism, including skeletal muscle tissues, and may have a role in the sarcopenia etiology. Here, we aimed to review the relationship between skeletal muscle mass, glucose homeostasis, and gut microbiota, and the effect of consuming probiotics and prebiotics on the development and pathological consequences of sarcopenia in the aging human population. This review includes discussions about the effects of glucose metabolism and gut microbiota on skeletal muscle mass and sarcopenia and the interaction of dietary intake, physical activity, and gut microbiome to influence sarcopenia through modulating the gut-muscle axis. Emerging evidence suggests that the microbiome can regulate both skeletal muscle mass and function, in part through modulating the metabolisms of short-chain fatty acids and branch-chain amino acids that might act directly on muscle in humans or indirectly through the brain and liver. Dietary factors such as fats, proteins, and indigestible carbohydrates and lifestyle interventions such as exercise, smoking, and alcohol intake can both help and hinder the putative gut-muscle axis. The evidence presented in this review suggests that loss of muscle mass and function are not an inevitable consequence of the aging process, and that dietary and lifestyle interventions may prevent or delay sarcopenia.

Pneumococcal pneumonia is a leading cause of morbidity and mortality worldwide. An increased susceptibility is due, in part, to compromised immune function. Zinc is required for proper immune function, and an insufficient dietary intake increases the risk of pneumonia. Our group was the first to reveal that the Zn transporter, ZIP8, is required for host defense. Furthermore, the gut microbiota that is essential for lung immunity is adversely impacted by a commonly occurring defective ZIP8 allele in humans. Taken together, we hypothesized that loss of the ZIP8 function would lead to intestinal dysbiosis and impaired host defense against pneumonia. To test this, we utilized a novel myeloid-specific Zip8 KO mouse model in our studies. The comparison of the cecal microbial composition of wild-type and Zip8 KO mice revealed significant differences in microbial community structure. Most strikingly, upon a S. pneumoniae lung infection, mice recolonized with Zip8 KO-derived microbiota exhibited an increase in weight loss, bacterial dissemination, and lung inflammation compared to mice recolonized with WT microbiota. For the first time, we reveal the critical role of myeloid-specific ZIP8 on the maintenance of the gut microbiome structure, and that loss of ZIP8 leads to intestinal dysbiosis and impaired host defense in the lung. Given the high incidence of dietary Zn deficiency and the ZIP8 variant allele in the human population, additional investigation is warranted to improve surveillance and treatment strategies.

Aims: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI)., Methods: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin., Key Findings: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces., Significance: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Genetic defects in SLC26A3 (DRA), an intestinal Cl - /HCO 3 - exchanger, result in congenital chloride diarrhea (CLD), marked by lifelong acidic diarrhea and a high risk of inflammatory bowel disease. Slc26a3 -/- mice serve as a model to understand the pathophysiology of CLD and search for treatment options. This study investigates the microbiota changes in slc26a3 -/- colon, the genotype-related causes for the observed microbiota alterations, its inflammatory potential, as well as the corresponding host responses. The luminal and the mucosa-adherent cecal and colonic microbiota of cohoused slc26a3 -/- and wt littermates were analyzed by 16S rRNA gene sequencing. Fecal microbiota transfer from cohoused slc26a3 -/- and wt littermates to germ-free wt mice was performed to analyze the stability and the inflammatory potential of the communities.The cecal and colonic luminal and mucosa-adherent microbiota of slc26a3 -/- mice was abnormal from an early age, with a loss of diversity, of short-chain fatty acid producers, and an increase of pathobionts. The transfer of slc26a3 -/- microbiota did not result in intestinal inflammation and the microbial diversity in the recipient mice normalized over time. A strong increase in the expression of Il22, Reg3β/γ, Relmβ , and other proteins with antimicrobial functions was observed in slc26a3 -/- colon from juvenile age, while the mucosal and systemic inflammatory signature was surprisingly mild. The dysbiotic microbiota, low mucosal pH, and mucus barrier defect in slc26a3 -/- colon are accompanied by a stark upregulation of the expression of a panel of antimicrobial proteins. This may explain the low inflammatory burden in the gut of these mice.

This study aims to elucidate the relationships between gut microbiota, bile acid metabolism, and psychological comorbidity in Crohn's disease (CD). We profiled the fecal microbiota composition and quantified the bile acid pool of 39 CD patients and 14 healthy controls using 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. Significant reductions in the secondary bile acids, LCA and DCA, were found in both the feces and serum samples of CD patients, while the concentration of 7-DHCA was particularly higher in the serum of CD patients with psychological disorders. The fecal levels of HDCA and 12-DHCA of the CD patients were inversely correlated with their Self-Rated Depression Scale (SDS) scores, whereas the serum level of 7-DHCA was positively correlated with the SDS scores. In addition, the fecal levels of TDCA, TLCA, and TβMCA showed a positive correlation with the Self-Rated Anxiety Scale (SAS) scores. The fecal microbiota biodiversity was particularly declined in CD patients with psychological disorders. An enrichment of Ruminococcus gnavus in CD patients may cause psychological disorders by affecting the microbiota-gut-brain axis via its ability to degrade the gut barrier, regulate the tryptophan-kynurenine metabolism, and modulate bile acid metabolism. In addition, the overabundant Enterobacteriaceae and Lachnospiraceae in CD patients may contribute to psychological comorbidity via dysregulating their bile acids metabolism. Taken together, changes in the gut microbiota composition may cooperate with alterations in the bile acid metabolism that are involved in the development of psychological disorders in CD., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Loss of Paneth cell (PC) function is implicated in intestinal dysbiosis, mucosal inflammation, and numerous intestinal disorders, including necrotizing enterocolitis (NEC). Studies in mouse models show that zinc transporter ZnT2 ( SLC30A2 ) is critical for PC function, playing a role in granule formation, secretion, and antimicrobial activity; however, no studies have investigated whether loss of ZnT2 function is associated with dysbiosis, mucosal inflammation, or intestinal dysfunction in humans. SLC30A2 was sequenced in healthy preterm infants (26-37 wks; n = 75), and structural analysis and functional assays determined the impact of mutations. In human stool samples, 16S rRNA sequencing and RNAseq of bacterial and human transcripts were performed. Three ZnT2 variants were common (>5%) in this population: H 346 Q, f = 19%; L 293 R, f = 7%; and a previously identified compound substitution in Exon7, f = 16%). H 346 Q had no effect on ZnT2 function or beta-diversity. Exon7 impaired zinc transport and was associated with a fractured gut microbiome. Analysis of microbial pathways suggested diverse effects on nutrient metabolism, glycan biosynthesis and metabolism, and drug resistance, which were associated with increased expression of host genes involved in tissue remodeling. L 293 R caused profound ZnT2 dysfunction and was associated with overt gut dysbiosis. Microbial pathway analysis suggested effects on nucleotide, amino acid and vitamin metabolism, which were associated with the increased expression of host genes involved in inflammation and immune response. In addition, L 293 R was associated with reduced weight gain in the early postnatal period. This implicates ZnT2 as a novel modulator of mucosal homeostasis in humans and suggests that genetic variants in ZnT2 may affect the risk of mucosal inflammation and intestinal disease.

Aims: Previous studies have demonstrated that chronic periodontitis (CP) is closely associated with the occurrence and development of a variety of systemic diseases. In this study, we successfully constructed a rat CP model through dental silk ligation, and the corresponding inflammatory reactions and fatty lesions were observed in the liver., Main Methods: Sprague-Dawley rats (n = 6) underwent tooth ligation at the bilateral first molars with silk thread to induce CP and were sacrificed 8 weeks later and compared to non-ligated rats (n = 6). RNA sequencing and 16S rRNA analysis were performed to determine the molecular mechanisms of CP involved in inducing liver disease. Alveolar bone loss, liver enzymes, mandible and liver histopathology, and inflammatory responses were compared between groups., Key Findings: RNA sequencing of liver tissue showed that the expression of SCD1 increased significantly in CP rats compared to controls. KEGG enrichment analysis showed that the AMPK signalling pathway may be involved in liver steatosis. The intestinal flora of faecal samples of rats were analysed by 16S rRNA sequencing, and the results indicated that the intestinal flora of the CP group was evidently imbalanced. The expression levels of tight junction proteins (ZO-1, occludin, and claudin-1) were significantly reduced in CP rats. Meanwhile, increases in serum IL-1β and lipopolysaccharide in CP rats reflected a systemic inflammatory response., Significance: CP may be involved in the occurrence and development of hepatic injury and liver steatosis, and its mechanism may be related to the oral-gut-liver axis and SCD1/AMPK signal activation in the liver., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Antibiotics are widely applied for the treatment of bacterial infections, but their long-term use may lead to gut flora dysbiosis and detrimental effects on brain physiology, behavior as well as cognitive performance. Still, a striking lack of knowledge exists concerning electrophysiological correlates of antibiotic-induced changes in gut microbiota and behavior. Here, we investigated changes in the synaptic transmission and plasticity together with behaviorally-relevant network activities from the hippocampus of antibiotic-treated mice. Prolonged antibiotic treatment led to a reduction of myeloid cell pools in bone marrow, circulation and those surveilling the brain. Circulating Ly6C hi inflammatory monocytes adopted a proinflammatory phenotype with increased expression of CD40 and MHC II. In the central nervous system, microglia displayed a subtle activated phenotype with elevated CD40 and MHC II expression, increased IL-6 and TNF production as well as with an increased number of Iba1 + cells in the hippocampal CA3 and CA1 subregions. Concomitantly, we detected a substantial reduction in the synaptic transmission in the hippocampal CA1 after antibiotic treatment. In line, carbachol-induced cholinergic gamma oscillation were reduced upon antibiotic treatment while the incidence of hippocampal sharp waves was elevated. These alterations were associated with the global changes in the expression of neurotrophin nerve growth factor and inducible nitric oxide synthase, both of which have been shown to influence cholinergic system in the hippocampus. Overall, our study demonstrates that antibiotic-induced dysbiosis of the gut microbiome and subsequent alteration of the immune cell function are associated with reduced synaptic transmission and gamma oscillations in the hippocampus, a brain region that is critically involved in mediation of innate and cognitive behavior., (Copyright © 2021 Elsevier Inc. All rights reserved.)