Abstract
Abstract Background The advent of biologic therapy has revolutionized the treatment paradigm in IBD. In developing countries including India, where affordability and accessibility drive the treatment choice, it is important to understand the mechanisms behind biologic therapy and pave way to the future to predict response rates. This prospective study examines the impact of biologic therapy on the gut microbiome in moderate-to severe CD patients in India. Methods Fecal samples were collected from healthy controls(n=36) and 39 CD patients at baseline and after completing induction doze [Infliximab (n=16), Vedolizumab (n=6), and Ustekinumab (n=17)]. Individuals on recent antibiotics(<8weeks)/probiotics/NSAIDs were excluded. Clinical response was assessed at 6-weeks, with follow-up at 6 months to classify responders (CDAI<150) and non-responders(CDAI>150). DNA was isolated from 114 fecal samples and subjected to whole-genome shotgun metagenomics to generate a minimum of 6GB data per sample. After removal of human DNA read contamination, taxonomy and functional annotation was assigned using Kraken2, Bracken, and Human3 tools and statistical significance by using Wilcoxon Test (R-Studio). Results The gut microbiome in CD at baseline exhibited reduced diversity, lower SCFA-producing bacteria and increased pro-inflammatory bacteria like Collinsella and Escherichia compared to healthy cohort. The human DNA content in fecal samples was significantly higher in CD compared to healthy cohort with mean of 19.2% and 0.06% respectively. Post biologic therapy, there was significant restoration of the gut microbiome with increase in bacterial diversity, increased abundance of SCFA-producing Firmicutes and Phascolaractobacterium , probiotic Bifidobacterium species and reduction in pathogenic bacteria Enterococcus gallinarium. The average human DNA content also decreased to 9.6%. On sub-analysis, between responders (n=31) and non-responders; pathogenic Klebsiella pneumonia, Fusobacterium and Corynebacterium were found to be higher in non-responders compared to responders (Fig2A). Further, 19 metabolic pathways significantly differed between responders and non-responders, which included those pathways responsible for degradation of carbohydrates and generation of precursor metabolites and energy higher in the former (Fig2B). Conclusion There is increased gut dysbiosis in CD relative to healthy cohort which appears to get restored upon biologic therapy. The findings suggest the biologic therapy may play a role in restoring the compromised intestinal barrier in CD. A microbiome-based signature to predict response rates on biologic therapy can be seen in future.
Published Version
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