Dataset Information

Host Genetic and Gut Microbial Signatures in Familial Inflammatory Bowel Disease.

ABSTRACT: INTRODUCTION:The family history of inflammatory bowel disease (IBD) has been strongly associated with risk of developing IBD. This study aimed to identify the host genetic and gut microbial signatures in familial IBD. METHODS:Genetic analyses using genome-wide single nucleotide polymorphism genotyping and whole exome sequencing were performed to calculate weighted genetic risk scores from known IBD-associated common variants and to identify rare deleterious protein-altering variants specific to patients with familial IBD in 8 Korean families that each included more than 2 affected first-degree relatives (FDRs) and their unaffected FDR(s). In parallel, gut microbial community was analyzed by 16S rRNA sequencing of stools from the sample individuals. RESULTS:The risk of familial IBD was not well explained by the genetic burden from common IBD-risk variants, suggesting the presence of family-shared genetic and environmental disease-risk factors. We identified 17 genes (AC113554.1, ACE, AKAP17A, AKAP9, ANK2, ASB16, ASIC3, DNPH1, DUS3L, FAM200A, FZD10, LAMA5, NUTM2F, PKN1, PRR26, WDR66, and ZC3H4) that each contained rare, potentially deleterious variants transmitted to the affected FDRs in multiple families. In addition, metagenomic analyses revealed significantly different diversity of gut microbiota and identified a number of differentially abundant taxa in affected FDRs, highlighting 22 novel familial disease-associated taxa with large abundance changes and the previously reported gut dysbiosis including low alpha diversity in IBD and 16 known IBD-specific taxa. DISCUSSION:This study identified familial IBD-associated rare deleterious variants and gut microbial dysbiosis in familial IBD.

SUBMITTER: Park YM

PROVIDER: S-EPMC7386341 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Host Genetic and Gut Microbial Signatures in Familial Inflammatory Bowel Disease.

Park Yoo Min YM Ha Eunji E Gu Ki-Nam KN Shin Ga Young GY Lee Chang Kyun CK Kim Kwangwoo K Kim Hyo Jong HJ

Clinical and translational gastroenterology 20200701 7

<h4>Introduction</h4>The family history of inflammatory bowel disease (IBD) has been strongly associated with risk of developing IBD. This study aimed to identify the host genetic and gut microbial signatures in familial IBD.<h4>Methods</h4>Genetic analyses using genome-wide single nucleotide polymorphism genotyping and whole exome sequencing were performed to calculate weighted genetic risk scores from known IBD-associated common variants and to identify rare deleterious protein-altering varian ...[more]

PMID: 32764209

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Project description:Rationale: With increasing incidence and prevalence of inflammatory bowel disease (IBD), it has become one of the major public health threats, and there is an urgent need to develop new therapeutic agents. Although the pathogenesis of IBD is still unclear, previous research has provided evidence for complex interplays between genetic, immune, microbial, and environmental factors. Here, we constructed a gene-microbiota interaction-based framework to discover IBD biomarkers and therapeutics. Methods: We identified candidate biomarkers for IBD by analyzing the publicly available transcriptomic and microbiome data from IBD cohorts. Animal models of IBD and diarrhea were established. The inflammation-correlated microbial and genetic variants in gene knockout mice were identified by 16S rRNA sequences and PCR array. We performed bioinformatic analysis of microbiome functional prediction and drug repurposing. Our validation experiments with cells and animals confirmed anti-inflammatory properties of a drug candidate. Results: We identified the DNA-sensing enzyme cyclic GMP-AMP synthase (cGAS) as a potential biomarker for IBD in both patients and murine models. cGAS knockout mice were less susceptible to DSS-induced colitis. cGAS-associated gut microbiota and host genetic factors relating to IBD pathogenesis were also identified. Using a computational drug repurposing approach, we predicted 43 candidate drugs with high potency to reverse colitis-associated gene expression and validated that brefeldin-a mitigates inflammatory response in colitis mouse model and colon cancer cell lines. Conclusions: By integrating computational screening, microbiota interference, gene knockout techniques, and in vitro and in vivo validation, we built a framework for predicting biomarkers and host-microbe interaction targets and identifying repurposing drugs for IBD, which may be tested further for clinical application. This approach may also be a tool for repurposing drugs for treating other diseases.

Dataset Information

Host Genetic and Gut Microbial Signatures in Familial Inflammatory Bowel Disease.

Publications

Host Genetic and Gut Microbial Signatures in Familial Inflammatory Bowel Disease.

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