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Gut Aug 2023Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn's disease and ulcerative colitis. By...
OBJECTIVE
Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn's disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD.
DESIGN
We measured 1684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 patients with IBD and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant's lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels.
RESULTS
We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC=0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near strongly associated with coffee metabolism.
CONCLUSION
In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.
Topics: Humans; Genome-Wide Association Study; Inflammatory Bowel Diseases; Colitis, Ulcerative; Metabolome; Feces; Arylamine N-Acetyltransferase
PubMed: 36958817
DOI: 10.1136/gutjnl-2022-328048 -
Science Immunology May 2024The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade....
The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of in the gut microbiota. Gavage of wild-type mice with enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4 T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
Topics: Animals; Receptors, Immunologic; Mice; Gastrointestinal Microbiome; Membrane Glycoproteins; Immunotherapy; Programmed Cell Death 1 Receptor; Macrophages; Mice, Inbred C57BL; Immune Checkpoint Inhibitors; Mice, Knockout; Female; Intestines
PubMed: 38758808
DOI: 10.1126/sciimmunol.adi5374 -
Cell Reports Aug 2023Colorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and...
Colorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and progression. While meta-analyses have provided mechanistic insight into patients with CRC, study heterogeneity has limited causal associations. Using multi-omics studies on genetically controlled cohorts of mice, we identify diet as the major driver of microbial and metabolomic differences, with reductions in α diversity and widespread changes in cecal metabolites seen in high-fat diet (HFD)-fed mice. In addition, non-classic amino acid conjugation of the bile acid cholic acid (AA-CA) increased with HFD. We show that AA-CAs impact intestinal stem cell growth and demonstrate that Ileibacterium valens and Ruminococcus gnavus are able to synthesize these AA-CAs. This multi-omics dataset implicates diet-induced shifts in the microbiome and the metabolome in disease progression and has potential utility in future diagnostic and therapeutic developments.
Topics: Animals; Mice; Bile Acids and Salts; Microbiota; Gastrointestinal Microbiome; Metabolome; Colorectal Neoplasms
PubMed: 37611587
DOI: 10.1016/j.celrep.2023.112997 -
Nature Communications Aug 2023The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota...
The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis.
Topics: Humans; Animals; Mice; Insulin Resistance; Metabolic Syndrome; Irritable Bowel Syndrome; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Dysbiosis; Phenethylamines; Tryptamines
PubMed: 37591886
DOI: 10.1038/s41467-023-40552-y -
Microbiology (Reading, England) Aug 2023is a human gut symbiont, part of the infant and adult gut microbiota and associated with intestinal and extra-intestinal disorders. mechanisms of adaptation to the gut...
is a human gut symbiont, part of the infant and adult gut microbiota and associated with intestinal and extra-intestinal disorders. mechanisms of adaptation to the gut are strain-specific and underpinned by the capacity of strains to utilize mucin and dietary glycans and produce bacteriocins and adhesins. Several potential mediators underpinning the association between strains and diseases have been identified, including the capacity to elicit a pro- or anti-inflammatory host response and modulate host metabolism, secondary bile acids and tryptophan metabolic pathways. Based on increasing evidence from metagenomics studies in humans and functional investigations and in mouse models, is emerging as a main player in influencing health and disease outcomes from infants to the elderly.
Topics: Humans; Ruminococcus; Gastrointestinal Microbiome; Symbiosis
PubMed: 37622435
DOI: 10.1099/mic.0.001383 -
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 -
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 -
BMC Microbiology Apr 2024Obesity is a metabolic disorder closely associated with profound alterations in gut microbial composition. However, the dynamics of species composition and functional... (Meta-Analysis)
Meta-Analysis
Obesity is a metabolic disorder closely associated with profound alterations in gut microbial composition. However, the dynamics of species composition and functional changes in the gut microbiome in obesity remain to be comprehensively investigated. In this study, we conducted a meta-analysis of metagenomic sequencing data from both obese and non-obese individuals across multiple cohorts, totaling 1351 fecal metagenomes. Our results demonstrate a significant decrease in both the richness and diversity of the gut bacteriome and virome in obese patients. We identified 38 bacterial species including Eubacterium sp. CAG:274, Ruminococcus gnavus, Eubacterium eligens and Akkermansia muciniphila, and 1 archaeal species, Methanobrevibacter smithii, that were significantly altered in obesity. Additionally, we observed altered abundance of five viral families: Mesyanzhinovviridae, Chaseviridae, Salasmaviridae, Drexlerviridae, and Casjensviridae. Functional analysis of the gut microbiome indicated distinct signatures associated to obesity and identified Ruminococcus gnavus as the primary driver for function enrichment in obesity, and Methanobrevibacter smithii, Akkermansia muciniphila, Ruminococcus bicirculans, and Eubacterium siraeum as functional drivers in the healthy control group. Additionally, our results suggest that antibiotic resistance genes and bacterial virulence factors may influence the development of obesity. Finally, we demonstrated that gut vOTUs achieved a diagnostic accuracy with an optimal area under the curve of 0.766 for distinguishing obesity from healthy controls. Our findings offer comprehensive and generalizable insights into the gut bacteriome and virome features associated with obesity, with the potential to guide the development of microbiome-based diagnostics.
Topics: Humans; Gastrointestinal Microbiome; Metagenome; Obesity; Bacteria; Feces; Clostridiales; Akkermansia
PubMed: 38580930
DOI: 10.1186/s12866-024-03278-5