Could gut microbial metabolism be linked to remission after anti-TNF treatment?

Details

Altered interactions between the mucosal immune system and intestinal microbiota contribute to the development of inflammatory bowel diseases (IBD). How cytokine inhibitors such as tumor necrosis factor antagonists (anti-TNF agents) affect the intestinal microbiome is unclear. Researchers investigated anti-TNF effects on gut microbial community structure and function in a longitudinal, two-step study of patients with IBD. They related their findings to treatment outcomes and examined fecal metabolite patterns before and after anti-TNF therapy.

In a prospective study of two cohorts in Germany, the discovery cohort included 12 patients with IBD, 17 patients with rheumatic disease, and 19 healthy controls. Fecal samples were collected at baseline and 2, 6, and 30 weeks after anti-TNF therapy was started. The validation cohort included 23 patients with IBD treated with anti-TNF or vedolizumab (anti-α4β7 integrin) and 99 healthy controls; fecal samples were collected at baseline and weeks 2, 6, and 14.

Fecal microbiota were analyzed using V3–V4 16S ribosomal RNA gene amplicon sequencing. Clinical response and remission were determined using clinical disease activity scores. Researchers used the AGORA (Assembly of Gut Organisms through Reconstruction and Analysis) resource to reconstruct metabolic networks and infer associated fecal metabolite levels in silico. They also performed metabolomic analyses on fecal samples from a subset of patients to validate metabolites associated with treatment outcomes.

Anti-TNF therapy shifted fecal microbiota diversity toward that of controls in patients with IBD, but not in patients with rheumatic disease. Across timepoints, diversity indices did not differ significantly between patients with IBD who did and did not achieve clinical remission after therapy. In contrast, in silico modeling of metabolic interactions between gut microbes found that metabolite exchange was significantly reduced at baseline in fecal samples from patients with IBD and was associated with later clinical remission. Predicted levels of butyrate and substrates involved in its synthesis, ethanol or acetaldehyde, were significantly associated with clinical remission following anti-TNF therapy; fecal metabolomic analyses verified these associations.

The researchers concluded that metabolic network reconstruction and assessment of fecal metabolic profiles might help identify patients with IBD likely to achieve clinical remission after anti-TNF therapy and improve understanding of the heterogeneity of IBD.