Consistent compositional shifts in the gut microbiota are observed in IBD and other chronic intestinal disorders and may contribute to pathogenesis. The identities of microbial biomolecular ...mechanisms and metabolic products responsible for disease phenotypes remain to be determined, as do the means by which such microbial functions may be therapeutically modified.
The composition of the microbiota and metabolites in gut microbiome samples in 47 subjects were determined. Samples were obtained by endoscopic mucosal lavage from the cecum and sigmoid colon regions, and each sample was sequenced using the 16S rRNA gene V4 region (Illumina-HiSeq 2000 platform) and assessed by UPLC mass spectroscopy. Spearman correlations were used to identify widespread, statistically significant microbial-metabolite relationships. Metagenomes for identified microbial OTUs were imputed using PICRUSt, and KEGG metabolic pathway modules for imputed genes were assigned using HUMAnN. The resulting metabolic pathway abundances were mostly concordant with metabolite data. Analysis of the metabolome-driven distribution of OTU phylogeny and function revealed clusters of clades that were both metabolically and metagenomically similar.
The results suggest that microbes are syntropic with mucosal metabolome composition and therefore may be the source of and/or dependent upon gut epithelial metabolites. The consistent relationship between inferred metagenomic function and assayed metabolites suggests that metagenomic composition is predictive to a reasonable degree of microbial community metabolite pools. The finding that certain metabolites strongly correlate with microbial community structure raises the possibility of targeting metabolites for monitoring and/or therapeutically manipulating microbial community function in IBD and other chronic diseases.
AIM To study the type and frequency of adverse events associated with anti-tumor necrosis factor(TNF)therapy and evaluate for any serologic and genetic associations.METHODS This study was a ...retrospective review of patients attending the inflammatory bowel disease(IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer’s protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure.RESULTS Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients(21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the antiTNF agent. In total: n = 66(5%) infusion reactions; n = 49(4%) allergic/serum sickness reactions; n = 19(1.5%) lupus-like reactions, n = 52(4%) rash, n = 18(1.4%) infections. In Crohn’s disease, Ig A ASCA(P = 0.04) and Ig G-ASCA(P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions(P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT(Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic, and pathways associations.
Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale ...functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt+ Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1−/− mice. The proportions of Th17 and RORγt+ Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1−/− colitis model. Thus, an impact on intestinal Th17 and RORγt+ Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.
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•Fecal microbiotas from humans with IBD alter gut CD4+ T cell homeostasis in mice•Microbiotas from individuals with IBD induce more Th2 and Th17 cells•Microbiotas from healthy individuals induce more RORgt+ Treg cells•In a model of colitis, mice colonized with IBD microbiotas get more severe disease
Britton et al. examine 30 human microbiotas from healthy individuals and individuals afflicted with inflammatory bowel disease (IBD). Their findings define an impact on intestinal Th17 and RORγt+ regulatory T cell compartments as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.
Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. ...The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (Tregs) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.
Advances in genomic technologies have led to increasing reports of monogenic inflammatory bowel disease (IBD). Here, we systematically review the literature to determine the clinical features, ...genetic profile, and previously used treatment strategies in monogenic IBD.
A systematic review of MEDLINE articles published between January 2000 and December 2020 was conducted. A total of 750 individual monogenic IBD cases were identified from 303 eligible articles.
The most frequently reported monogenic IBD genes were IL10RA/B, XIAP, CYBB, LRBA, and TTC7A. In total, 63.4% of patients developed IBD before 6 years of age, 17.4% developed IBD between ages 10 and 17.9 years, and 10.9% developed IBD after age 18. There was a substantial difference between these age groups and the underlying monogenic disorders. Only 31.7% had any history of extraintestinal comorbidity (EIC) before IBD onset, but 76.0% developed at least 1 EIC during their clinical course. The most common EICs were atypical infection (44.7%), dermatologic abnormality (38.4%), and autoimmunity (21.9%). Bowel surgery, biologic therapy, and hematopoietic stem cell transplantation were performed in 27.1%, 32.9%, and 23.1% of patients, respectively.
Monogenic IBD cases, although rare, have varied extraintestinal comorbidities and limited treatment options including surgery and transplant. Early identification and improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is important for effective management.
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Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not ...only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn’s disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn’s disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.
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•M. restricta is associated with the colonic mucosa in Crohn’s disease (CD) patients•M. restricta exacerbates colitis in wild-type and gnotobiotic mice•M. restricta is found in CD patients with a disease-linked polymorphism in CARD9•Malassezia-exacerbated colitis in mice requires signaling via CARD9
Limon et al. surveyed intestinal wall-associated fungi in patients with Crohn’s disease (CD) and healthy controls and found a common commensal skin yeast called Malassezia, preferentially in CD patients. Malassezia exacerbates colitis in mouse models through mechanisms requiring CARD9, a signaling protein involved in anti-fungal immunity.
The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community ...that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the "mycobiome") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
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