-
Immunity Aug 2020Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally...
Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1 hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.
Topics: Animals; Clostridiales; Colitis, Ulcerative; Crohn Disease; Female; Gastrointestinal Microbiome; Goblet Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Muramidase; Paneth Cells; STAT6 Transcription Factor
PubMed: 32814028
DOI: 10.1016/j.immuni.2020.07.010 -
Gastroenterology Oct 2021Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS,...
BACKGROUND & AIMS
Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism.
METHODS
The presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning-based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays.
RESULTS
Biofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea.
CONCLUSIONS
The presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease.
Topics: Austria; Bacteria; Biofilms; Case-Control Studies; Colitis, Ulcerative; Colon; Colonoscopy; Deep Learning; Gastrointestinal Microbiome; Germany; Humans; Image Interpretation, Computer-Assisted; Intestinal Mucosa; Irritable Bowel Syndrome; Metabolomics; Microscopy, Confocal; Microscopy, Electron, Scanning; Predictive Value of Tests; Ribotyping
PubMed: 34146566
DOI: 10.1053/j.gastro.2021.06.024 -
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 -
The American Journal of Clinical... May 2022Mechanisms linking a proinflammatory diet to obesity remain under investigation. The ability of diet to influence the gut microbiome (GM) in creating chronic low-grade...
Associations of the Dietary Inflammatory Index with total adiposity and ectopic fat through the gut microbiota, LPS, and C-reactive protein in the Multiethnic Cohort-Adiposity Phenotype Study.
BACKGROUND
Mechanisms linking a proinflammatory diet to obesity remain under investigation. The ability of diet to influence the gut microbiome (GM) in creating chronic low-grade systemic inflammation provides a plausible connection to adiposity.
OBJECTIVES
Assess whether any associations seen between the Energy-Adjusted Dietary Inflammatory Index (E-DII score), total fat mass, visceral adipose tissue (VAT), or liver fat (percentage volume) operated through the GM or microbial related inflammatory factors, in a multiethnic cross-sectional study.
METHODS
In the Multiethnic Cohort-Adiposity Phenotype Study (812 men, 843 women, aged 60-77 y) we tested whether associations between the E-DII and total adiposity, VAT, and liver fat function through the GM, LPS, and high-sensitivity C-reactive protein (hs-CRP). DXA-derived total fat mass, MRI-measured VAT, and MRI-based liver fat were measured. Participants provided stool and fasting blood samples and completed an FFQ. Stool bacterial DNA was amplified and the 16S rRNA gene was sequenced at the V1-V3 region. E-DII score was computed from FFQ data, with a higher E-DII representing a more proinflammatory diet. The associations between E-DII score, GM (10 phyla, 28 genera, α diversity), and adiposity phenotypes were examined using linear regression and mediation analyses, adjusting for confounders.
RESULTS
There were positive total effects (c) between E-DII and total fat mass (c = 0.68; 95% CI: 0.47, 0.90), VAT (c = 4.61; 95% CI: 2.95, 6.27), and liver fat (c = 0.40; 95% CI: 0.27, 0.53). The association between E-DII score and total fat mass was mediated by LPS, Flavonifractor, [Ruminococcus] gnavus group, and Tyzzerella. The association between E-DII score and ectopic fat occurred indirectly through Fusobacteria, Christensenellaceae R-7 group, Coprococcus 2, Escherichia-Shigella, [Eubacterium] xylanophilum group, Flavonifractor, Lachnoclostridium, [Ruminococcus] gnavus group, Tyzzerella, [Ruminococcus] gnavus group (VAT only), and α diversity (liver fat only). There was no significant association between E-DII score and adiposity phenotype through hs-CRP.
CONCLUSIONS
Associations found between E-DII and adiposity phenotypes occurred through the GM and LPS.
Topics: Adiposity; C-Reactive Protein; Cross-Sectional Studies; Diet; Female; Gastrointestinal Microbiome; Humans; Inflammation; Lipopolysaccharides; Male; Obesity; Phenotype; RNA, Ribosomal, 16S
PubMed: 34871345
DOI: 10.1093/ajcn/nqab398 -
Nature Communications Oct 2021Understanding the functional potential of the gut microbiome is of primary importance for the design of innovative strategies for allergy treatment and prevention. Here... (Clinical Trial)
Clinical Trial
Understanding the functional potential of the gut microbiome is of primary importance for the design of innovative strategies for allergy treatment and prevention. Here we report the gut microbiome features of 90 children affected by food (FA) or respiratory (RA) allergies and 30 age-matched, healthy controls (CT). We identify specific microbial signatures in the gut microbiome of allergic children, such as higher abundance of Ruminococcus gnavus and Faecalibacterium prausnitzii, and a depletion of Bifidobacterium longum, Bacteroides dorei, B. vulgatus and fiber-degrading taxa. The metagenome of allergic children shows a pro-inflammatory potential, with an enrichment of genes involved in the production of bacterial lipo-polysaccharides and urease. We demonstrate that specific gut microbiome signatures at baseline can be predictable of immune tolerance acquisition. Finally, a strain-level selection occurring in the gut microbiome of allergic subjects is identified. R. gnavus strains enriched in FA and RA showed lower ability to degrade fiber, and genes involved in the production of a pro-inflammatory polysaccharide. We demonstrate that a gut microbiome dysbiosis occurs in allergic children, with R. gnavus emerging as a main player in pediatric allergy. These findings may open new strategies in the development of innovative preventive and therapeutic approaches. Trial: NCT04750980.
Topics: Allergens; Animals; Bacteroides; Bifidobacterium longum; Case-Control Studies; Child; Child, Preschool; Clostridiales; Dander; Eggs; Faecalibacterium prausnitzii; Female; Food Hypersensitivity; Gastrointestinal Microbiome; Humans; Immune Tolerance; Lipopolysaccharides; Male; Milk; Nuts; Pollen; Prunus persica; Pyroglyphidae; Respiratory Hypersensitivity; Urease
PubMed: 34645820
DOI: 10.1038/s41467-021-26266-z -
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 -
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