Microbial and genetic-based framework identifies drug targets in inflammatory bowel disease

Abstract

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.

Effect of Extracellular Vesicles Derived From Lactobacillus plantarum Q7 on Gut Microbiota and Ulcerative Colitis in Mice

“…Currently, the pathogenesis of IBD remains incompletely understood. The use of IBD drugs is severely limited by low efficacy, side effects and intolerance (2). It was reported that probiotics could alleviate IBD by maintaining normal gut microbiota, enhancing mucosal barrier function, and inhibiting exposure to inflammatory signals, which are expected to be a new treatment for IBD (3)(4)(5).…”

Cyclic GMP‐AMP synthase contributes to epithelial homeostasis in intestinal inflammation via Beclin‐1‐mediated autophagy

“…One study reported data similar to ours, demonstrating that cGAS deficiency leads to increased intestinal inflammation and increased colitis‐associated tumorigenesis 22 . Another study that utilized a longer model of DSS colitis along with a higher percentage of DSS reported cGAS deficiency to be protective during the reparative phase of murine colitis 21 . The reasons for this discrepancy are unclear; however, differences in model design and/or facility microbiome profiles may play key roles 48 …”

“…22 Another study that utilized a longer model of DSS colitis along with a higher percentage of DSS reported cGAS deficiency to be protective during the reparative phase of murine colitis. 21 The reasons for this discrepancy are unclear; however, differences in model design and/or facility microbiome profiles may play key roles. 48 Understanding the effects of the host microbiome on IBD pathogenesis is crucial to gaining insight into the pathogenesis of disease.…”

“…Inflammatory signaling within the intestinal epithelium can contribute to epithelial ulceration, progression of inflammation through the intestinal cell, fistulization, stricture formation, and loss of barrier integrity allowing for a progression of disease 43 . cGAS has been demonstrated to be upregulated in patients with IBD 21 . However, the role that increased cGAS plays in human IBD remains unknown.…”

“…Limited data exist on the role of cGAS in intestinal epithelial inflammation. One study demonstrated cGAS to be upregulated during human IBD and cGAS deficiency to be associated with diminished severity of murine colitis 21 . Another study looked at the role of cGAS in colitis‐associated cancer and found that cGAS deficiency was associated with increased colitis‐associated tumorigenesis 22 .…”