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Food & Function Jun 2023Refractory constipation is the most severe form of constipation, and its etiology remains unknown. The symptoms of constipation occur repeatedly, which brings great pain...
Refractory constipation is the most severe form of constipation, and its etiology remains unknown. The symptoms of constipation occur repeatedly, which brings great pain to the patient's body and psychology. Accumulating studies suggest that constipation patients present a significant dysbiosis of the gut microbiota compared with healthy individuals. In this study, we analyzed the gut microbiota composition of fresh feces and accumulated feces (old feces) of patients with refractory constipation and found that there was a significant difference between them. Through a mouse model of loperamide-induced constipation, it was proved that the old feces of patients with refractory constipation could aggravate the constipation symptoms in mice, while the fresh feces could alleviate the symptoms, which is consistent with the effect of feces from healthy volunteers in a mouse model of loperamide-induced constipation. We identified an indigenous strain (), which is highly enriched in the fresh feces of patients with refractory constipation, and found that oral administration of could effectively improve the constipation symptoms in mice with constipation induced by loperamide and fecal bacteria transplanted from patients with constipation and significantly improve the stress-related behaviors of mice. This result may be related to the regulation of intestinal , , and other gene expression by and the control of somatostatin (SS) and motilin (MTL) production. Our results suggest that gut microbe intervention with indigenous strains such as is a potential and promising alternative for the treatment of constipation, especially for refractory constipation.
Topics: Mice; Animals; Loperamide; Ruminococcus; Constipation; Clostridiales; Feces
PubMed: 37278206
DOI: 10.1039/d2fo03574j -
Pediatric Allergy and Immunology :... Jan 2022Ruminococcus gnavus (R. gnavus) are mucin-degrading gut bacteria that play a key role in the early colonization of the gut by serving as endogenous sources of...
BACKGROUND
Ruminococcus gnavus (R. gnavus) are mucin-degrading gut bacteria that play a key role in the early colonization of the gut by serving as endogenous sources of nutrients. They can also influence immune development. We had previously reported a lower abundance of R. gnavus in infants with atopic dermatitis (AD) compared with that in healthy subjects. However, the underlying mechanisms remain unclear. In this study, we investigated the effect of orally administered R. gnavus on antibiotic treatment-induced gut dysbiosis (and the underlying mechanism) in a mouse model of AD.
METHODS
Four-week-old female BALB/C mice were administered antibiotic cocktails for 2 weeks. R. gnavus was orally administered throughout the study duration. At 6 weeks of age, AD was induced by epidermal sensitization with ovalbumin. AD phenotypes and systemic and gut immune responses were investigated.
RESULTS
Orally administered R. gnavus significantly reduced AD-associated parameters (i.e., transepidermal water loss, clinical score, total serum immunoglobulin (Ig) E level, OVA-specific IgE level, and skin inflammation). R. gnavus treatment also resulted in significant downregulation of T helper 2-related cytokine mRNA and upregulation of interleukin (IL)-10 and Foxp3 in the skin. The population of CD4 FOXP3 T cells in mesenteric- and skin-draining lymph nodes and butyrate levels in the cecum increased in R. gnavus-administered AD mice.
CONCLUSIONS
Immune modulation by orally administered R. gnavus may alleviate AD symptoms through the enhancement of regulatory T-cell counts and short-chain fatty acids production in AD mice.
Topics: Animals; Clostridiales; Dermatitis, Atopic; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred BALB C; T-Lymphocytes, Regulatory
PubMed: 34633714
DOI: 10.1111/pai.13678 -
Frontiers in Immunology 2023COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome...
BACKGROUND
COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators in the human body and could contribute to the immune responses impacting the progression of COVID-19. However, the causal relationship between specific intestinal bacteria, metabolites and severe COVID-19 remains not clear.
METHODS
Based on two-sample Mendelian randomization (MR) framework, the causal effects of 131 intestinal taxa and 452 plasma metabolites on severe COVID-19 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated with the abundance of intestinal taxa and the concentration of plasma metabolites had been utilized as the instrument variables to infer whether they were causal factors of severe COVID-19. In addition, mediation analysis was conducted to find the potential association between the taxon and metabolite, and further colocalization analysis had been performed to validate the causal relationships.
RESULTS
MR analysis identified 13 taxa and 53 metabolites, which were significantly associated with severe COVID-19 as causal factors. Mediation analysis revealed 11 mediated relationships. Myo-inositol, 2-stearoylglycerophosphocholine, and alpha-glutamyltyrosine, potentially contributed to the association of and with severe COVID-19, respectively. and could mediate the association of myo-inositol and N-acetylalanine, respectively. In addition, abundance was colocalized with severe COVID-19 (PP.H4 = 0.77) and the colon expression of permeability related protein RASIP1 (PP.H4 = 0.95).
CONCLUSIONS
Our study highlights the potential causal relationships between gut microbiome, plasma metabolome and severe COVID-19, which potentially serve as clinical biomarkers for risk stratification and prognostication and benefit the mechanism mechanistic investigation of severe COVID-19.
Topics: Humans; Gastrointestinal Microbiome; COVID-19; Mendelian Randomization Analysis; Mediation Analysis; Metabolome
PubMed: 37662924
DOI: 10.3389/fimmu.2023.1211612 -
Frontiers in Immunology 2023Our aim was to investigate the interactive causal effects between gut microbiota and host urate metabolism and explore the underlying mechanism using genetic methods.
OBJECTIVES
Our aim was to investigate the interactive causal effects between gut microbiota and host urate metabolism and explore the underlying mechanism using genetic methods.
METHODS
We extracted summary statistics from the abundance of 211 microbiota taxa from the MiBioGen (N =18,340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N =7738), gout from the Global Biobank Meta-analysis Initiative (N =1,448,128), urate from CKDGen (N =288,649), and replication datasets from the Global Urate Genetics Consortium (N gout =69,374; N urate =110,347). We used linkage disequilibrium score regression and bidirectional Mendelian randomization (MR) to detect genetic causality between microbiota and gout/urate. Mediation MR and colocalization were performed to investigate potential mediators in the association between microbiota and urate metabolism.
RESULTS
Two taxa had a common causal effect on both gout and urate, whereas the family was replicable. Six taxa were commonly affected by both gout and urate, whereas the genus was replicable. Genetic correlation supported significant results in MR. Two microbiota metabolic pathways were commonly affected by gout and urate. Mediation analysis indicated that the order and family had protective effects on urate mediated by increasing docosahexaenoic acid. These two bacteria shared a common causal variant rs182549 with both docosahexaenoic acid and urate, which was located within locus.
CONCLUSIONS
Gut microbiota and host urate metabolism had a bidirectional causal association, implicating the critical role of host-microbiota crosstalk in hyperuricemic patients. Changes in gut microbiota can not only ameliorate host urate metabolism but also become a foreboding indicator of urate metabolic diseases.
Topics: Humans; Docosahexaenoic Acids; Gastrointestinal Microbiome; Gout; Mendelian Randomization Analysis; Uric Acid
PubMed: 37063923
DOI: 10.3389/fimmu.2023.1148591 -
Cellular and Molecular Gastroenterology... 2024A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver...
BACKGROUND & AIMS
A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB.
METHODS
To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed.
RESULTS
Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination.
CONCLUSIONS
R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.
Topics: Animals; Humans; Mice; Akkermansia; Cholesterol; Clostridiales; Hepatitis B e Antigens; Hepatitis B, Chronic; Gastrointestinal Microbiome
PubMed: 38092311
DOI: 10.1016/j.jcmgh.2023.12.003 -
Anaerobe Feb 2024Ruminococcus gnavus is a rare human pathogen, and clinical data on R. gnavus infection are insufficient. This retrospective study aimed to investigate the clinical...
OBJECTIVES
Ruminococcus gnavus is a rare human pathogen, and clinical data on R. gnavus infection are insufficient. This retrospective study aimed to investigate the clinical characteristics of R. gnavus infections.
METHODS
This study included 13 cases of bacteremia and three cases of non-bacteremia infections caused by R. gnavus. We evaluated the patient data, infection source, clinical outcomes, and antimicrobial susceptibility of R. gnavus isolates for these cases.
RESULTS
The median age of patients was 75 years (range 47-95), and eight patients were female. Twelve cases were presumed to have an intra-abdominal infection source, and the remaining four cases had an unknown infection source. The most common underlying conditions were immunosuppression (seven cases), solid tumors (seven cases), and history of gastrointestinal surgery (five cases). Thirteen patients exhibited gastrointestinal problems (dysfunction, bleeding, intra-abdominal infection, or inflammation). Multiple pathogens were observed in six cases, and fatal outcomes were recorded in three cases. Antimicrobial susceptibility data were available for eight isolates, all of which exhibited low minimum inhibitory concentrations to penicillin (≤0.03 μg/mL), ampicillin-sulbactam (≤0.5 μg/mL), piperacillin-tazobactam (≤4 μg/mL), and metronidazole (≤0.5-1 μg/mL).
CONCLUSION
Ruminococcus gnavus is frequently associated with an intra-abdominal infection source, and treatment strategies should consider the possibility of multiple pathogens.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; Ruminococcus; Retrospective Studies; Intraabdominal Infections; Bacteremia; Anti-Infective Agents; Anti-Bacterial Agents; Clostridiales
PubMed: 38211774
DOI: 10.1016/j.anaerobe.2024.102818 -
Microbial Genomics Jul 2023is prevalent in the intestines of humans and animals, and ambiguities have been reported regarding its relations with the development of diseases and host well-being....
is prevalent in the intestines of humans and animals, and ambiguities have been reported regarding its relations with the development of diseases and host well-being. We postulate the ambiguities of its function in different cases may be attributed to strain-level variability of genomic features of . We performed comparative genomic and pathogenicity prediction analysis on 152 filtered high-quality genomes, including 4 genomes of strains isolated from healthy adults in this study. The mean G+C content of genomes of was 42.73±0.33 mol%, and the mean genome size was 3.46±0.34 Mbp. Genome-wide evolutionary analysis revealed genomes were divided into three major phylogenetic clusters. Pan-core genome analysis revealed that there was a total of 28 072 predicted genes, and the core genes, soft-core genes, shell genes and cloud genes accounted for 3.74 % (1051/28 072), 1.75 % (491/28 072), 9.88 % (2774/28 072) and 84.63 % (23 756/28 072) of the total genes, respectively. The small proportion of core genes reflected the wide divergence among strains. We found certain coding sequences with determined health benefits (such as vitamin production and arsenic detoxification), whilst some had an implication of health adversity (such as sulfide dehydrogenase subunits). The functions of the majority of core genes were unknown. The most widespread genes functioning in antibiotic resistance and virulence are (tetracycline-resistance gene, present in 75 strains) and (capsular polysaccharide biosynthesis protein Cps4J encoding gene, detected in 3 genomes), respectively. Our results revealed genomic divergence and the existence of certain safety-relevant factors of . This study provides new insights for understanding the genomic features and health relevance of , and raises concerns regarding predicted prevalent pathogenicity and antibiotic resistance among most of the strains.
Topics: Adult; Animals; Humans; Ruminococcus; Phylogeny; Clostridiales; Genomics
PubMed: 37486746
DOI: 10.1099/mgen.0.001071 -
Gut Microbes 2022is a prevalent member of the human gut microbiota, which is over-represented in inflammatory bowel disease and neurological disorders. We previously showed that the...
is a prevalent member of the human gut microbiota, which is over-represented in inflammatory bowel disease and neurological disorders. We previously showed that the ability of to forage on mucins is strain-dependent and associated with sialic acid metabolism. Here, we showed that mice monocolonized with ATCC 29149 (-mice) display changes in major sialic acid derivatives in their cecum content, blood, and brain, which is accompanied by a significant decrease in the percentage of sialylated residues in intestinal mucins relative to germ-free (GF) mice. Changes in metabolites associated with brain function such as tryptamine, indolacetate, and trimethylamine -oxide were also detected in the cecal content of -mice when compared to GF mice. Next, we investigated the effect of monocolonization on hippocampus cell proliferation and behavior. We observed a significant decrease of PSA-NCAM immunoreactive granule cells in the dentate gyrus (DG) of -mice as compared to GF mice and recruitment of phagocytic microglia in the vicinity. Behavioral assessments suggested an improvement of the spatial working memory in -mice but no change in other cognitive functions. These results were also supported by a significant upregulation of genes involved in proliferation and neuroplasticity. Collectively, these data provide first insights into how metabolites may influence brain regulation and function through modulation of granule cell development and synaptic plasticity in the adult hippocampus. This work has implications for further understanding the mechanisms underpinning the role of in neurological disorders.
Topics: Animals; Brain; Clostridiales; Gastrointestinal Microbiome; Mice; Mucins; N-Acetylneuraminic Acid; Polysaccharides
PubMed: 35579971
DOI: 10.1080/19490976.2022.2073784 -
ImmunoHorizons Mar 2023Epithelium-derived antimicrobial peptides represent an evolutionarily ancient defense mechanism against pathogens. Regenerating islet-derived protein 3 γ (Reg3γ), the...
Epithelium-derived antimicrobial peptides represent an evolutionarily ancient defense mechanism against pathogens. Regenerating islet-derived protein 3 γ (Reg3γ), the archetypal intestinal antimicrobial peptide, is critical for maintaining host-microbe interactions. Expression of Reg3γ is known to be regulated by the microbiota through two different pathways, although it remains unknown whether specific Reg3γ-inducing bacteria act via one or both of these pathways. In recent work, we identified Ruminococcus gnavus and Limosilactobacillus reuteri as commensal bacteria able to induce Reg3g expression. In this study, we show these bacteria require myeloid differentiation primary response protein 88 and group 3 innate lymphoid cells for induction of Reg3γ in mice. Interestingly, we find that R. gnavus and L. reuteri suppress Reg3γ in the absence of either myeloid differentiation primary response protein 88 or group 3 innate lymphoid cells. In addition, we demonstrate that colonization by these bacteria is not required for induction of Reg3γ, which occurs several days after transient exposure to the organisms. Taken together, our findings highlight the complex mechanisms underlying microbial regulation of Reg3γ.
Topics: Animals; Mice; Bacteria; Immunity, Innate; Limosilactobacillus reuteri; Lymphocytes; Proteins; Ruminococcus
PubMed: 36943156
DOI: 10.4049/immunohorizons.2200096 -
Gut Microbes 2023The prevalence and occurrence of mucin-degrading (MD) bacteria, such as and , is highly associated with human health and disease states. However, MD bacterial...
The prevalence and occurrence of mucin-degrading (MD) bacteria, such as and , is highly associated with human health and disease states. However, MD bacterial physiology and metabolism remain elusive. Here, we assessed functional modules of mucin catabolism, through a comprehensive bioinformatics-aided functional annotation, to identify 54 genes and 296 genes. The reconstructed core metabolic pathways coincided with the growth kinetics and fermentation profiles of and grown in the presence of mucin and its constituents. Genome-wide multi-omics analyses validated the nutrient-dependent fermentation profiles of the MD bacteria and identified their distinct mucolytic enzymes. The distinct metabolic features of the two MD bacteria induced differences in the metabolite receptor levels and inflammatory signals of the host immune cells. In addition, experiments and community-scale metabolic modeling demonstrated that different dietary intakes influenced the abundance of MD bacteria, their metabolic fluxes, and gut barrier integrity. Thus, this study provides insights into how diet-induced metabolic differences in MD bacteria determine their distinct physiological roles in the host immune response and the gut ecosystem.
Topics: Humans; Mucins; Multiomics; Ecosystem; Gastrointestinal Microbiome; Bacteria
PubMed: 37305974
DOI: 10.1080/19490976.2023.2221811