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We 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.1Aden K. et al.Gastroenterology. 2019; 157: 1279-1292Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar 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. The diet was administered in a standardized fashion during the induction phase of infliximab therapy. Although this study was a single-center, uncontrolled trial encompassing 46 patients, the efficacy rates of 96% clinical remission at week 6 underscores the idea that nutrition-based interventions acting on gut microbial homeostasis might be a potential approach for optimizing the anti-inflammatory efficacy of TNF antagonists. In the second letter, Chen et al reason that all targeted single-factor therapies like TNF antagonists or integrin blockers only target 1 selected inflammatory effector principle, but not the root cause of the disease. Thus, they may be a priori limited in their clinical efficacy. They argue that the intestinal microbiota via butyrate levels control a large network of cytokines in the gut mucosa. As such, butyrate could represent an etiologic master regulator, which might be used for optimizing efficacies of a broader spectrum of immunomodulators or could even be used as a monotherapy. We would like to recall that the link of butyrate levels, bacteria, and inflammatory responses in IBD is not novel. In 1980, a landmark article by Roediger2Roediger W.E.W. Lancet. 1980; 316: 712-715Abstract Scopus (562) Google Scholar for the first time put forward the—at the time rather absurd—hypothesis that ulcerative colitis could in fact be an energy deficiency syndrome of intestinal epithelial cells (IECs). Using meticulous biochemical methods, the article showed that butyrate oxidation was impaired, whereas aerobic glycolysis was partially switched on in IECs of UC patients. It concluded that SCFA of anaerobic bacteria are a major physiologic source of energy in IECs, the lack of which cannot be properly compensated by a switch to aerobic glucose metabolism, rendering the barrier vulnerable to chronic inflammation. Follow-up work showed that inhibiting epithelial fatty acid oxidation leads to an IBD-like syndrome in rats.3Roediger W.E. Nance S. Br J Exp Pathol. 1986; 67: 773-782PubMed Google Scholar The findings prompted a series of clinical trials, which aimed at investigating the clinical effects of local application of butyrate in IBD.4Scheppach W. et al.Gastroenterology. 1992; 103: 51-56Abstract Full Text PDF PubMed Google Scholar,5Steinhart A.H. et al.Aliment Pharmacol Ther. 1996; 10: 729-736Crossref PubMed Scopus (175) Google Scholar Trial results were mixed with regard to clinical efficacy, but the high therapeutic failure rate was clearly associated with compliance problems caused by local irritation, an inability to hold SCFA-containing enema fluid, and the disturbing odor of the compound. Stratifying for individuals who had a higher compliance rates clearly increased the efficacy signal. Probably owing to this low usefulness and the patent profile, application of SCFAs was mostly abandoned as a therapeutic principle for decades. Laboratory studies over the years expanded the initial observation in the epithelium and showed the additional impact of butyrate on different immune cell types, via direct energy-dependent processes, as a chemoattractant 6or via its effects on chromatin structure via histone deacetylases.6Sina C. et al.J Immunol. 2009; 183: 7514-7522Crossref PubMed Scopus (274) Google Scholar, 7Schulthess J. et al.Immunity. 2019; 50: 432-445.e7Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar However, it is the emerging knowledge on the role of intestinal microbiota in IBD that is currently the main driver of bringing SCFAs back to life as a potential therapeutic principle.8Lloyd-Price J. et al.Nature. 2019; 569: 655-662Crossref PubMed Scopus (948) Google Scholar The intestinal microbiome is no longer considered to be an immunologically passive bystander, but is thought to actively contribute or even cause the deregulation of the mucosal immune system. As a consequence, the intestinal microbiome must be considered as an actionable target for IBD therapy. Given the complexity of the metabolic functions of the intestinal microbiota, which we are just beginning to understand, it is in our view unlikely that SCFAs will be the magical master regulators, neither as a companion to biologicals nor as a monotherapy. Yet, we agree with our colleagues that the manipulation of microbial metabolic networks, by nutrition or by application of microbial metabolites could be a disruptive approach toward precision therapy in IBD. Among other examples, microbial metabolites of the tryptophan pathway, which are known to play a role in the energy metabolism of IECs and to influence immune homeostasis via the AhR/IL22 pathway,9Hashimoto T. et al.Nature. 2012; 487: 477-481Crossref PubMed Scopus (812) Google Scholar, 10Lamas B. et al.Nat Med. 2016; 22: 598-605Crossref PubMed Scopus (733) Google Scholar, 11Nikolaus S. et al.Gastroenterology. 2017; 153: 1504-1516.e2Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar represent a promising path of translational exploration. Longitudinal studies comparing microbial metabolic signatures in association with therapeutic response across approved therapies as well as a thorough mechanistic understanding of intestinal metabolic networks in large IBD patient cohorts are warranted to not only listen to molecular tales of the host–microbe interaction, but also to finally use this metabolic language in clinical practice. Butyrate in Inflammatory Bowel Disease TherapyGastroenterologyVol. 158Issue 5PreviewWe 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.1 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. Full-Text PDF How to Optimize Effects of Infliximab in Inflammatory Bowel Disease: Incorporation of a Plant-Based DietGastroenterologyVol. 158Issue 5PreviewSince the advent of biologics such as infliximab and adalimumab for inflammatory bowel disease (IBD), primary nonresponders (PNRs) to biologics have been reported to be around 30% of patients with either Crohn’s disease (CD) or ulcerative colitis. Many studies have been conducted in an attempt to identify the underlying mechanisms of and predicting factors for nonresponse, but few studies have investigated the potential role of changes in the intestinal microbiome. Aden et al1 studied this topic. Full-Text PDF