Critical Role Of Gut Microbiota Research Articles

Persistent organic pollutants in foods, their interplay with gut microbiota and resultant toxicity

Persistent Organic Pollutants (POPs) have become immensely prevalent in the environment as a result of their unique chemical properties (persistent, semi-volatile and bioaccumulative nature). Their occurrence in the soil, water and subsequently in food has become a matter of concern. With food being one of the major sources of exposure, the detrimental impact of these chemicals on the gut microbiome is inevitable. The gut microbiome is considered as an important integrant for human health. It participates in various physiological, biochemical and immunological activities; thus, affects the metabolism and physiology of the host. A myriad of studies have corroborated an association between POP-induced gut microbial dysbiosis and prevalence of disorders. For instance, ingestion of polychlorinated biphenyls, polybrominated diphenyl ethers or organochlorine pesticides influenced bile acid metabolism via alteration of bile salt hydrolase activity of Lactobacillus, Clostridium or Bacteroides genus. At the same time, some chemicals such as DDE have the potential to elevate Proteobacteria and Firmicutes/Bacteriodetes ratio influencing their metabolic activity leading to enhanced short-chain fatty acid synthesis, ensuing obesity or a pre-diabetic state. This review highlights the impact of POPs exposure on the gut microbiota composition and metabolic activity, along with an account of its corresponding consequences on the host physiology. The critical role of gut microbiota in impeding the POPs excretion out of the body resulting in their prolonged exposure and consequently, enhanced degree of toxicity is also emphasized.

Inflammation: The Straw That Broke the NAFLD Liver!

Inflammation: The Straw That Broke the NAFLD Liver!

Critical Role of Gut Microbiota and Epigenetic Factors in the Pathogenesis of Behçet's Disease.

Behçet’s disease (BD) is a chronic refractory multisystem autoinflammatory disease, characterized by typical clinical features of non-specific vasculitis, oral and genital ulcers, uveitis, as well as skin lesions. The exact etiopathogenesis of BD remains unknown, existing studies have indicated that genetics and environmental factors contribute to the increased development of BD. Recently, several studies have shown that external environmental factors can affect the process of epigenetic modification, and abnormalities of epigenetic factors have been confirmed to be involved in the occurrence of BD. At the same time, abnormalities of gut microbiota (GM) in the body, have also been confirmed to participate in the pathogenesis of BD by regulating the balance of Th17/Tregs. This article reviews the pathogenesis of BD and summarizes numerous clinical studies, focusing on the mechanism of GM and epigenetic factors impacting on BD, and providing new ideas for further elucidating the pathogenesis of BD.

Mining the Gut Microbiota for Microbial-Based Therapeutic Strategies in Cancer Immunotherapy.

The past two decades witnessed a revolution in our understanding of host–microbiota interactions that led to the concept of the super-organism consisting of a eukaryotic part and a prokaryotic part. Owing to the critical role of gut microbiota in modulating the host immune system, it is not beyond all expectations that more and more evidence indicated that the shift of gut microbiota influenced responses to numerous forms of cancer immunotherapy. Therapy targeting gut microbiota is becoming a promising strategy to improve cancer immunotherapy. In this review, we discuss the role of the gut microbiota in response to cancer immunotherapy, the mechanisms that the gut microbiota influences cancer immunotherapy, and therapeutic strategies targeting gut microbiota to improve cancer immunotherapy.

Early-life polyphenol intake promotes Akkermansia growth and increase of host goblet cells in association with the potential synergistic effect of Lactobacillus

Mounting evidence suggests a critical role of gut microbiota in human colon health. Early life is a key developmental growth period, especially for building up gut microbiota and strengthening the colonic barrier. The connection between host colon and gut microbiota especially during early life is an area of increasing interest to researchers, also polyphenols improve host health through modulating this complex relationship. Postweaning (three-week-old) and adult (six-week-old) mice kept under specific pathogen-free conditions were used to investigate how early-life grape polyphenols supplementation influence the association between host colon and gut microbiota. Before grape polyphenols supplementation, postweaning mice had a higher original absolute abundance of Lactobacillus compared to adult mice. A 2-week grape polyphenols supplementation significantly boosted the abundance of Akkermansia and Lactobacillus and increased Lactobacillus-secreted lactate in postweaning mice. Early-life grape polyphenols supplementation also promoted the bloom of goblet cells and mucin 2, which benefitted both Akkermansia growth and colonic barrier. Moreover, the grape polyphenols-modulated bone morphogenetic protein (BMP), Notch and Wnt3 pathways triggered the bloom of goblet cells in GPs-administrated postweaning mice, and the increase in lactate could modulate those pathways. Meanwhile, adult mice were not affected by grape polyphenols supplementation. These results suggested that early-life polyphenol supplementation promoted Akkermansia growth and colonic barrier, which was in association with the sufficient abundance of Lactobacillus during early life. This study also indicated that Lactobacillus interact with Akkermansia through changing the physiology of host colonic goblet cells.

Probiotics ameliorate alveolar bone loss by regulating gut microbiota.

ObjectivesOestrogen deficiency is an aetiological factor of postmenopausal osteoporosis (PMO), which not only decreases bone density in vertebrae and long bone but also aggravates inflammatory alveolar bone loss. Recent evidence has suggested the critical role of gut microbiota in osteoimmunology and its influence on bone metabolisms. The present study aimed to evaluate the therapeutic effects of probiotics on alveolar bone loss under oestrogen‐deficient condition.Materials and MethodsInflammatory alveolar bone loss was established in ovariectomized (OVX) rats, and rats were daily intragastrically administered with probiotics until sacrifice. Gut microbiota composition, intestinal permeability, systemic immune status and alveolar bone loss were assessed to reveal the underlying correlation between gut microbiota and bone metabolisms.ResultsWe found administration of probiotics significantly prevented inflammatory alveolar bone resorption in OVX rats. By enriching butyrate‐producing genera and enhancing gut butyrate production, probiotics improved intestinal barrier and decreased gut permeability in the OVX rats. Furthermore, the oestrogen deprivation‐induced inflammatory responses were suppressed in probiotics‐treated OVX rats, as reflected by reduced serum levels of inflammatory cytokines and a balanced distribution of CD4+IL‐17A+ Th17 cells and CD4+CD25+Foxp3+ Treg cells in the bone marrow.ConclusionsThis study demonstrated that probiotics can effectively attenuate alveolar bone loss by modulating gut microbiota and further regulating osteoimmune response and thus represent a promising adjuvant in the treatment of alveolar bone loss under oestrogen deficiency.

Abstract P150: Concerted Diurnal Rhythms Of Gut Microbiota With Salt-sensitive Hypertension And Renal Damage

Circadian, diurnal rhythm is a vital physiological feature of life forms, which enables holobionts to adapt to the day and night cycles. Evidence suggests that both factions of the holobiont, i.e, the host and its microbiota demonstrate physiological circadian rhythms. Blood pressure is a good example of a host physiological feature with a well-defined diurnal rhythm. In a healthy human, blood pressure (BP) rises to its peak during awakening morning hours and declines to the lowest level during night. In salt-sensitive hypertension, aberrant diurnal rhythms of BP and gut dysbiosis have been demonstrated. Given the critical role of gut microbiota in BP regulation, our current objective was to investigate whether there are synchronous rhythms of holobiont in rodents on low salt and high salt diets and if inflammation pattern also changes diurnally. We examined Dahl Salt-Sensitive (S) rats on low (0.3%) and high (2%) salt diets and BP and inflammation pattern was checked. As hypothesized, both microbiota and kidney inflammation showed diurnal rhythm in response to low salt and high salt diet. Major shifts in diurnal patterns of specific groups of microbiota were observed between the dark (active) and light (rest) phases, which correlated with the diurnal rhythmicity of BP. Diurnal rhythms of Firmicutes, Bacteroidetes and Actinobacteria were independently associated with BP. Discrete bacterial taxa were observed to correlate independently or interactively with one or more of the following 3 factors- 1) BP rhythm, 2) dietary salt, 3) amplitude of BP. PICRUSt analysis revealed diurnal rhythmicity of microbial pathways, characterized by microbiota upregulated biosynthetic processes during active phase and upregulated degradation pathways of metabolites in resting phase. These diurnal changes in microbiota, their functional pathways and BP amplitude were associated with concerted rhythmicity of renal Lipocalin 2 and Kim1 expression and circulating β-hydroxybutyrate in high salt S rats. Such concerted rhythmicity of holobiont with peak of changes at active phase of salt hypertension suggests that targeting this timepoint to reshape microbiota and/or intervene with medication could efficiently benefit the hypertensives

Gut microbiome alterations and its link to corticosteroid resistance in immune thrombocytopenia

Quantitative metagenomic studies have linked the gut microbiota to autoimmune disorders. Here, we performed deep shotgun metagenomic sequencing of fecal samples from 99 immune thrombocytopenia (ITP) patients and 52 healthy controls. Dysbiosis in the gut microbiome of ITP was detected phylogenetically and functionally, and classifier based on species markers distinguished individuals with ITP from healthy controls. In particular, the abundance of Ruminococcus gnavus, Bifidobacterium longum and Akkermansia muciniphila was markedly increased in treatment-naïve ITP patients, and the alterations of microbial species were correlated with clinical indices. Functionally, the secondary bile acid biosynthesis and flagellar assembly were depleted in the gut microbiota of ITP, which may contribute to the onset of ITP by affecting the immune system. Furthermore, we found that corticosteroid treatment affected the gut microbiome of ITP. Compared with corticosteroid-sensitive ITP patients, we identified that the corticosteroid-resistant ITP patients displayed a distinct gut microbiome, which was different from that of the treatment-naïve ITP patients. Together, we provided support for the critical role of gut microbiota in the development of ITP and established a foundation for further research characterizing gut microbiota in relation to corticosteroid resistance of ITP.

1751. The Impact of Prophylactic Systemic Antibiotics (PSA) on Cytomegalovirus (CMV) Infection: A Post-hoc Analysis of a Randomized Controlled Trial (RCT) in Hematopoietic Cell Transplantation (HCT) Recipients

BackgroundProphylactic systemic antibiotics (PSA) during conditioning regimen-induced neutropenia after hematopoietic cell transplantation (HCT) reduce bacteremia but may disrupt the gut microbiota, potentially affecting viral immunity and risk for viral infections. Prior studies suggest a critical role of gut microbiota in the reconstitution of CMV-specific CD8+ T cells and in protection from respiratory viral infections after HCT (J Immunol 2007; 178: 5209; Blood 2018; 131:2978). To identify whether PSA is associated with differences in CMV infection outcomes after HCT, we conducted a post-hoc analysis of CMV infection in the only RCT of PSA exclusively performed in HCT recipients (Infection 1986; 14:115). In that trial, HCT patients received either PSA (ticarcillin/tobramycin/vancomycin or mezlocillin/ceftizoxime) or no systemic antibiotics during neutropenia (absolute neutrophil count <500/mm3).MethodsA post-hoc analysis was performed of a previously conducted RCT in the pre-antiviral era (1984–1986) at the Fred Hutch. Patients received unscreened blood products and were tested weekly by CMV culture in throat, and disease was evaluated by tissue biopsy or bronchoalveolar lavage. CMV disease was confirmed by chart review. We compared the cumulative incidence of CMV at any site, CMV throat shedding, and CMV disease between randomization groups by day 100 post-transplant, treating death as a competing risk. Overall survival was also compared using Kaplan–Meier method.Results119 and 125 allograft recipients were randomized to PSA and no prophylaxis, respectively. Baseline characteristics in both groups were balanced. CMV infection at any site and CMV throat shedding were greater in the PSA group (Figures 1 and 2); CMV disease was numerically reduced in the no PSA group (Figure 3). Overall survival by day 100 was not different between the groups (Figure 4).ConclusionCMV infection risk appeared to be increased in recipients of PSA with a significant anaerobic spectrum. While current PSA regimens have narrower spectrum activity, these results provide the rationale to study if changes in gut microbiota play a role in CMV reactivation and adaptive immunity after HCT. Disclosures All authors: No reported disclosures.

Microbiota Metabolite Short-Chain Fatty Acids Facilitate Mucosal Adjuvant Activity of Cholera Toxin through GPR43.

The gut microbiota has been shown critical for mucosal adjuvant activity of cholera toxin (CT), a potent mucosal adjuvant. However, the mechanisms involved remain largely unknown. In this study, we report that depletion of gut bacteria significantly decreased mucosal and systemic Ab responses in mice orally immunized with OVA and CT. Feeding mice short-chain fatty acids (SCFAs) promoted Ab responses elicited by CT, and, more importantly, rescued Ab responses in antibiotic-treated mice. In addition, mice deficient in GPR43, a receptor for SCFAs, showed impaired adjuvant activity of CT. Administering CT did not promote SCFA production in the intestines; thus, SCFAs facilitated but did not directly mediate the adjuvant activity of CT. SCFAs promoted B cell Ab production by promoting dendritic cell production of BAFF and ALDH1a2, which induced B cell expression of IFN regulatory factor 4, Blimp1, and XBP1, the plasma B cell differentiation-related genes. Furthermore, when infected with Citrobacter rodentium, GPR43-/- mice exhibited decreased Ab responses and were more susceptible to infection, whereas the administration of SCFAs promoted intestinal Ab responses in wild-type mice. Our study thereby demonstrated a critical role of gut microbiota and their metabolite SCFAs in promoting mucosal adjuvant activity of CT through GPR43.

Intermittent Fasting Alleviates Diabetes-induced Cognitive Decline via Gut Microbiota-metabolites-brain Axis (OR32-04-19)

ObjectivesCognitive decline is one of severe type 2 diabetes complications. Intermittent fasting (IF) is a promising dietary intervention for T2D risk reduction, but its protective effect and mechanism on diabetic cognitive dysfunction remain elusive. Gut microbiota plays a vital role interphasing diet and host physiology and pathology and highly affected by the dietary composition and patterns. It has been reported that the microbiota homeostasis is essential for maintenance of gut health and for modulating cognitive function. We hypothesized that gut microbiota might play a pivotal role in mediating protective effects of IF on diabetes-induced cognitive decline. MethodsAfter a 28-day IF regimen treatment, cognitive behavioral tests and brain insulin signaling were assessed on db/db mice. The microbiota-metabolites-brain axis alterations were detected by multiple-omics analysis (transciptomics, 16S rRNA sequencing and metabolomics). A intergrade multi-omics analysis was performed to analyze the correlation among gut microbiota, plasma metabolites, and hippocampal gene expression. ResultsHere we found that a 28-day Intermittent fasting (IF) regimen improved cognitive deficits in db/db mice via a microbiota-metabolites-brain axis assessed by behavioral tests and multiple-omics analysis: IF activated AMPK/PGC1α signaling, enhanced mitochondrial biogenesis in hippocampus and elevated genes enriched in hippocampal metabolic function. Moreover, IF re-structured gut microbiota and improved plasma microbial metabolites in relation to diabetes and cognitive function, e.g., serotonin, 3-Indolepropionic acid, and bile acids. Integration of multi-omics data demonstrated strong links between IF-related genes, gut microbiome and metabolites. Furthermore, removal of gut microbiota with antibiotics partly abolished the observed benefits of IF on cognition and hippocampal metabolic function. ConclusionsTaken together, the present study suggests a critical role of gut microbiota in connecting peripheral metabolism with brain function, which could lead to novel interventions against metabolism-implicated neurodegenerative pathophysiologies. Funding SourcesThis work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China.

Dietary Polysaccharide from Enteromorpha Clathrata Modulates Gut Microbiota and Promotes the Growth of Akkermansia muciniphila, Bifidobacterium spp. and Lactobacillus spp.

Recently, accumulating evidence has suggested that Enteromorpha clathrata polysaccharide (ECP) could contribute to the treatment of diseases. However, as a promising candidate for marine drug development, although ECP has been extensively studied, less consideration has been given to exploring its effect on gut microbiota. In this light, given the critical role of gut microbiota in health and disease, we investigated here the effect of ECP on gut microbiota using 16S rRNA high-throughput sequencing. As revealed by bioinformatic analyses, ECP considerably changed the structure of the gut microbiota and significantly promoted the growth of probiotic bacteria in C57BL/6J mice. However, interestingly, ECP exerted different effects on male and female microbiota. In females, ECP increased the abundances of Bifidobacterium spp. and Akkermansia muciniphila, a next-generation probiotic bacterium, whereas in males, ECP increased the population of Lactobacillus spp. Moreover, by shaping a more balanced structure of the microbiota, ECP remarkably reduced the antigen load from the gut in females. Altogether, our study demonstrates for the first time a prebiotic effect of ECP on gut microbiota and forms the basis for the development of ECP as a novel gut microbiota modulator for health promotion and disease management.

Cholera toxin requires microbiota metabolites short-chain fatty acids for its mucosal adjuvant activity

Abstract Cholera toxin (CT) is a potent mucosal adjuvant, however, the mechanisms by which CT induces both mucosal and systemic immune responses are still not completely understood. It has been shown recently that gut microbiota is critical in inducing immune response by CT, however, the mechanisms involved remain largely unknown. We demonstrated in this study that gut microbiota metabolites short-chain fatty acids (SCFA), which are solely metabolic products of gut microbiota from dietary fiber, are required for CT in inducing antigen-specific IgG and IgA responses after oral immunization. Depleting of gut bacteria by antibiotics significantly decreased mucosal and systemic IgG and IgA responses in mice orally immunized with ovalbumin (OVA) and CT. Feeding SCFA acetate and butyrate rescued antibody responses in antibiotics-treated WT mice. Furthermore, deficiency of GPR43, a SCFA binding receptor, impaired CT’s adjuvant activity. Acetate and butyrate did not directly act on B cells to promote IgG production, but promoted B cell IgG production and plasma B cell differentiation related genes in the presence of WT but not GPR43−/− DC. Furthermore, SCFA increased IgG production by both WT and GPR43−/− B cells when cultured with WT DC, indicating a crucial role for DC expression of GPR43 in SCFA induction of B cell IgG production. Mechanistically, SCFA promoted DC expressions of BAFF, a B cell activating factor, and Aldh1a2, an enzyme promoting production of retinoic acid (RA) from Vitamin A. Blockade either RA or BAFF signaling significantly inhibited SCFA induced B-cell IgG production. Therefore, our study indicated a critical role of gut microbiota and their metabolites SCFA in promoting the mucosal adjuvant activity of CT through partially GPR43.

Interindividual Variability in Metabolism of [6]-Shogaol by Gut Microbiota.

[6]-Shogaol (6S), one of the major bioactive components in dry ginger, is attracting considerable attention because of its wide spectrum of biological activities, but its metabolic fate is still not fully understood. In the present study, the microbial metabolism of 6S was examined for the first time in in vitro batch fecal fermentation system and in mice. Two major microbial metabolites were detected and identified as 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9) and 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11). Our results indicated that reductions of the double bond and the ketone group are the major metabolic pathways of 6S by the human gut microbiota. We also observed the interindividual variability in the metabolism of M11 to M9 by human gut microbiota. In addition, we demonstrated that the glucuronidated form of 6S and its metabolites could be rapidly deconjugated by human gut microbiota and in mice, which can be regarded as a reactive process taking place in the intestinal tract. To our knowledge, this is the first report involving the identification of the microbial metabolites of 6S in an in vitro fermentation system, and the first demonstration of the critical role of gut microbiota in producing the bioactive free form of 6S and its metabolites in the intestinal tract in mice.

24 The Critical Role of Gut Microbiota in Determining Behavioral Changes and Susceptibility to Inflammation in a Model of Depression

24 The Critical Role of Gut Microbiota in Determining Behavioral Changes and Susceptibility to Inflammation in a Model of Depression

Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice

There is increasing interest in the bidirectional communication between the mammalian host and prokaryotic cells. Catecholamines (CA), candidate molecules for such communication, are presumed to play an important role in the gut lumen; however, available evidence is limited because of the lack of actual data about luminal CA. This study evaluated luminal CA levels in the gastrointestinal tract and elucidated the involvement of gut microbiota in the generation of luminal CA by comparing the findings among specific pathogen-free mice (SPF-M), germ-free mice (GF-M), and gnotobiotic mice. Substantial levels of free dopamine and norepinephrine were identified in the gut lumen of SPF-M. The free CA levels in the gut lumen were lower in GF-M than in SPF-M. The majority of CA was a biologically active, free form in SPF-M, whereas it was a biologically inactive, conjugated form in GF-M. The association of GF-M with either Clostridium species or SPF fecal flora, both of which have abundant β-glucuronidase activity, resulted in the drastic elevation of free CA. The inoculation of E. coli strain into GF-M induced a substantial amount of free CA, but the inoculation of its mutant strain deficient in the β-glucuronidase gene did not. The intraluminal administration of DA increased colonic water absorption in an in vivo ligated loop model of SPF-M, thus suggesting that luminal DA plays a role as a proabsorptive modulator of water transport in the colon. These results indicate that gut microbiota play a critical role in the generation of free CA in the gut lumen.

MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease

BackgroundThe bacterial microflora aggravates graft-versus-host-disease (GvHD) after allogeneic stem cell transplantation, but the underlying mechanisms of manifestations of intestinal GvHD (iGvHD) in the gut remain poorly understood.AimTo analyse the gut...

The Key Importance of Soy Isoflavone Bioavailability to Understanding Health Benefits

Research over the past two decades has provided significant epidemiological and other evidence for the health benefits of the consumption of soy-based foods. A large number of dietary intervention studies have examined the effects of soy isoflavones on risk factors for cardiovascular disease and hormone-dependent cancers. However, these report large variability in outcome measures, very limited reproducibility between studies, and in some cases, controversy between the results of clinical trials using dietary soy or soy protein and isoflavone supplementation. This highlights a major gap in our understanding of soy isoflavone uptake, metabolism, distribution, and overall bioavailability. There are many potential factors that may influence bioavailability and a better knowledge is necessary to rationalize the inconsistencies in the intervention and clinical studies. This review focuses attention on our current state of knowledge in this area and highlights the importance of metabolism of the parent soy isoflavones and the critical role of gut microbiota on the bioavailability of these compounds and their metabolites.