Butyrate in Inflammatory Bowel Disease Therapy

Abstract

We have recently read with great interest the manuscript titled “Metabolic functions of gut microbes associate with efficacy of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel diseases” published in a recent issue of Gastroenterology.1Aden K. et al.Gastroenterology. 2019; 157: 1279-1292Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar The authors reported that the level of butyrate was associated with anti-TNF treatment efficacy in inflammatory bowel disease (IBD), which is a very interesting and important outcome for further studies toward a therapy cure for IBD. We posit that butyrate exerts extensive anti-inflammatory effects and as such exhibits a more pronounced and important role in IBD than an individual anti-cytokine agent, which has only a limited anti-inflammatory effect. Long-lasting inflammation and ulceration of the colon are predominantly the main characteristics of IBD, which are features of Crohn’s disease and ulcerative colitis. Crohn’s disease is characterized by transmural inflammation involving all layers of the intestinal wall, whereas ulcerative colitis only affects the superficial mucosal layer. Thus, anti-inflammatory therapies are an appropriate treatment approach. In the 1990s, anti-TNF was found to have sufficient effects in controlling inflammation in IBD with a high response rate. Although anti-TNF therapy is effective for some patients with IBD, the treatment effectiveness for IBD is still considered suboptimal given that overall 30% of patients are intractable and 20% of responsive patients lose treatment response each year.2Wong U. Cross R.K. Expert Opin Drug Metab Toxicol. 2017; 13: 1039-1046Crossref PubMed Scopus (35) Google Scholar,3Gaujoux R. et al.Gut. 2019; 68: 604-614Crossref PubMed Scopus (76) Google Scholar Therefore, other anti-cytokine approaches have also been explored such as treatments with anti–IL-6 and anti–IL-1β. These antibodies have produced good response outcomes. Antibodies against the IL-23/IL-17 axis, including MEDI2070 and risankizumab, have also shown good mixed response rates of the order of 20%–50%. In addition, IL-13 blocking has also been investigated. With the exception of anti-cytokines, integrin-mediated immune cell trafficking has also been studied.4Zeissig S. et al.Gut. 2019; 68: 25-39Crossref PubMed Scopus (78) Google Scholar However, there is currently no therapeutic treatment that leads to a cure for IBD. The clinical outcomes with these approaches fashions a treatment regime for IBD with increased complexity. We contemplate that all of these treatment approaches may not be clinically efficacious to persistently and indelibly control the proinflammatory responses, given that they target a part of the inflammatory process phenomenon and not the cause. One of the major mechanisms of the pathogenesis of IBD is intestinal dysbiosis. The correction of gut dysbiosis may be an important and plausible approach to successfully reequilibrate inflammatory responses in IBD. The finding of the authors certainly supports the important causal role of decreased levels of butyrate in the pathogenesis of IBD. IBD treatment approaches that correct gut microbial dysbiosis that earmark increasing gut luminal levels of butyrate can promote and exert a significant anti-inflammatory effect. However, gut luminal dysbiosis may be difficult to correct, because a metabolically complex cohort of bacterial interactions predominate in the gut. Butyrate is produced in collaboration by many commensal bacteria in the colon. A number of bacteria have been identified that have the capacity to synthesize butyrate while other bacteria could facilitate the growth of butyrate-producing bacteria or produce short chain fatty acid precursors used for the synthesis of butyrate. Notwithstanding, intestinal luminal bacterial dysbiosis remains a difficult outcome to correct. Supplementation with butyrate may be a practical approach. High levels of butyrate could exert significant anti-inflammatory effects through numerous metabolic pathways, which may normalize proinflammatory cytokines. Butyrate can act on regulatory T cells to decrease both TNF-alpha and IL-6 production. Butyrate also increases the levels of other anti-inflammatory immune cells such as M2 macrophages and inhibits pro-inflammatory immune cells such as M1 macrophages and neutrophils. Zhai et al5Zhai S. et al.FEMS Microbiol Lett. 2019; : 366Google Scholar have shown that butyrate decreases proinflammatory cytokines including IL-6, IL-1β, MCP1/CCL2, and TLR4. Moreover, butyrate also inhibits multiple proinflammatory signaling pathways through histone deacetylase inhibitors-dependent and -independent mechanisms.6Chen J. et al.Nutrients. 2019; 11: E1026Crossref PubMed Scopus (45) Google Scholar Therefore, we anticipate that butyrate could not only facilitate anti-TNF treatments, but also improve treatment efficacy with other anti-inflammatory cytokines. Importantly, the short chain fatty acid butyrate may be further developed for the treatment of IBD individually or in combination with other treatment modalities. Metabolic Functions of Gut Microbes Associate With Efficacy of Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel DiseasesGastroenterologyVol. 157Issue 5PreviewAltered interactions between the mucosal immune system and intestinal microbiota contribute to pathogenesis of inflammatory bowel diseases (IBD). It is not clear how inhibitors of cytokines, such as antagonists of tumor necrosis factor (anti-TNF), affect the intestinal microbiome. We investigated the effects of anti-TNF agents on gut microbe community structure and function in a longitudinal 2-step study of patients with IBD. We correlated our findings with outcomes of treatment and investigated patterns of metabolites in fecal samples before and after anti-TNF therapy. Full-Text PDF Open AccessReplyGastroenterologyVol. 158Issue 5PreviewWe thank our colleagues Chiba et al and Chen et al, who expand our observations on the metabolic functions of the gut microbiota in inflammatory bowel disease (IBD) and their association with response to anti-tumor necrosis factor (TNF) treatment.1 Both comments suggest that intestinal butyrate levels as a therapeutic target in IBD, either as a primary therapy or as a companion principle for optimizing efficacy of TNF antagonists. Chiba et al report on the potential clinical effects of a plant-based, fiber-rich diet known to elevate short chain fatty acids (SCFA) levels, including butyrate. Full-Text PDF