Compositional and functional alteration of gut microbiota profiles in response to anti-TNF-α therapy in inflammatory bowel disease: A Pilot study

Abstract

Background and aim: Inflammatory bowel disease (IBD) is a chronic and relapsing disorder that is strongly linked to intestinal microbiota alteration (dysbiosis). Anti-tumor necrosis factor-alpha (anti-TNF-α) therapies have revolutionized IBD treatment over the last two decades. Clinical response to anti-TNF-α treatment generally involves alteration of the gut microbiota composition, although change in the microbiome following therapy has generated some contradictory theories. We examine the composition and function of the intestinal microbiota following treatment with TNF-α inhibitors and examine this relationship in the context of clinical and endoscopic response in a cohort of IBD patients in Saudi Arabia. Method: An analysis of fecal-derived microbiota in 20 human samples was performed using 16S rRNA gene-based microbiota profiling and next generation sequencing, utilizing Illumina MiSeq. Ten samples were collected at baseline prior to treatment with TNF-α antagonists and ten samples were collected following treatment. Inter- and intra-species variation was tested using ɑ-diversity and β-diversity metrics along with appropriate statistical analysis. An examination of functional metagenomic profile variation was performed following biologics exposure. Results: A total of 5 087 721 clean-paired sequence reads were generated across subjects before and after biologics treatment and assigned to 401 different operational taxonomic units (OTUs). The two taxonomic microbial groups (before and after treatment) demonstrated no clear separation. Anti-TNF-α treatments induced more specific variation, rather than involving a global impact on the gastrointestinal (GI) microbiota profiles, with a statistically significant increase in the Firmicutes (P = 0.01) and a statistically significant decrease in Proteobacteria (P = 0.04). This was accompanied by a remarkable increase in protective taxa, responsible for short-chain fatty acids production, such as the Lachnospiraceae family, which belongs to the Clostridiales order (P = 0.005). A notable increase in F. prausnitzii and a decrease in the relative abundance of E. coli were observed. At the functional level, an up-regulation in the carbohydrate metabolism pathway was shown in addition to a down-regulation in cellular process and signaling pathways (P = 0.04, P = 0.006, respectively). Conclusion: TNF-α antagonists reduced GI microbiota with pro-inflammatory capacity enabling protective bacteria to thrive. The biologics caused specific compositional and functional variation rather than a global alteration of the gut microbiota profile in biologic-responsive IBD patients, leading to an improvement in treatment efficacy.

Keywords

• GI microbiota
• Anti-TNF-α therapy
• Crohn's disease
• Ulcerative colitis