Alvarado, David M.

Ciorba, Matthew A.

Cushing, Kelly

Clinical and Translational Gastroenterology

English

PubMed

Kelly Cushing

David M Alvarado

Matthew A Ciorba

Crossref

Butyrate and Mucosal Inflammation: New Scientific Evidence Supports Clinical Observation

Digital Commons@Becker

Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2015Butyrate and mucosal inflammation: New scientificevidence supports clinical observationKelly CushingDavid M. AlvaradoMatthew A. CiorbaFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsTRANSLATIONAL MEDICINE: BENCH TO BEDSIDEButyrate and Mucosal Inflammation: New ScientificEvidence Supports Clinical ObservationKelly Cushing, MD1, David M. Alvarado, PhD1 and Matthew A. Ciorba, MD1Clinical and Translational Gastroenterology (2015) 6, e108; doi:10.1038/ctg.2015.34; published online 27 August 2015Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are bacterial metabolites generated via thefermentation of dietary fibers. Luminal SCFAs are recognized as a preferred energy substrate for the colonic epithelium. As earlyas the 1980s, SCFAs were observed to offer therapeutic benefit in some forms of colitis.1 Since then, clinical trials have producedvariable results in confirming the efficacy of SCFAs for diversion colitis or for inflammatory bowel disease (IBD)-associated colitis.Putative mechanistic explanations for these clinical effects have been put forth along the way, particularly regarding butyrate.2Now, more than two decades after the initial clinical description, research is illuminating the basic mechanisms by which SCFAsinfluence gut immune responses to promote homeostasis. These findings have stimulated a resurgence of interest in the topic.This Translational Medicine: From Bench to Bedside mini-review focuses on recently published papers evaluating the basicimmunologic effects of butyrate on mucosal inflammation and integrity.Butyrate limits intestinal inflammation by promoting the formation of the regulatory T cells (Tregs), a population of adaptiveimmune cells that suppress inflammatory responses.3,4 Furusawa et al. sought to identify the mechanism by which commensalmicrobiota induce Tregs.3 They found that “germ-free” mice have lower numbers of Tregs than conventionally raised mice, whichhave an intact gut microbiome. They also observed that a high-fiber diet led to greater Treg numbers than a low-fiber diet.Metabolomic analysis identified an increase in SCFA production in mice fed the high-fiber diet. Using dietary supplementation toincrease cecal concentrations of acetate, propionate, and butyrate, the authors found the most significant increase in Tregsoccurred in animals receiving butyrate. In a related study, Arpaia et al. illustrate the importance of resident microbe metabolites(SCFAs) in extrathymic Treg generation.4 Tregs were induced by fecal extracts from conventionally raised mice, but not by fecalextracts from germ-free mice or mice treated with antibiotics. This group further showed that supplementation with butyrate indrinking water, was sufficient to induce Tregs in mice. In both studies, the increase in Tregs was attributed to the inhibition ofhistone H3 deacetylases (HDACs, a class of regulatory proteins that function as inhibitors of gene expression). Treatment withbutyrate relieved HDAC inhibition of FoxP3, a protein important for formation of Tregs.Butyrate alsomodulates the function of innate immune cells. Chang et al. observed a reduction in pro-inflammatory cytokines inmacrophages treated with butyrate in vitro and in macrophages isolated from mice given butyrate in their drinking water.5 Theimplicated mechanism was again related to butyrate’s ability to inhibit HDACs, and thus the inflammatory cascade. This finding isinteresting as it demonstrates that microbes produce metabolites that suppress “first-line” innate immune cells from mounting aninflammatory response against these microbes.Singh et al. proposed another mechanism of action for butyrate in the innate immune system. They found that this SCFAactivates a receptor for niacin in the colon called Gpr109a.6 Genetic ablation of this receptor resulted in an increased susceptibilityto colitis. Dendritic cells and macrophages isolated from Gpr109a knockout mice showed reduced capacity to promote T-celldifferentiation into Tregs even in the presence of butyrate. Furthermore, the authors linked their findings to colon carcinogenesisby showing Gpr109a-deficient mice had increased susceptibility to both colitis-associated and genetically driven (Apc) coloncancers. Finally, the authors also demonstrated that butyrate signaling throughGpr109a on epithelial cells promoted expression ofthe pro-homeostatic cytokine IL-18. Taken together, the authors concluded butyrate is important in promoting an immune tolerantcolon mucosa, which is resistant to neoplasia.The effect of butyrate is not limited to immune cells. Kelly et al. demonstrated that butyrate increases colonic epithelial celloxygen consumption, leading to a phenomenon known as “physiological hypoxia”.7 Physiologic hypoxia is a good thing as itsupports normal intestinal barrier function through the activity of hypoxia-inducible factor (HIF). Disruption of the gut microbiotawith antibiotics reduces luminal SCFAs and epithelial aerobicmetabolism. These changes lead to HIF destabilization and reducedbarrier function. Thus, butyrate also has a role in maintaining healthy colon barrier function, which prevents the flux of potentiallypathogenic microbes across the epithelium.Together these studies paint a remarkably positive picture for SCFAs, and butyrate in particular, in promoting and maintainingmucosal homeostasis. However, a few caveats should be considered before we move to offering SCFA or butyrate enemas to all1Department of Gastroenterology, Washington University, St Louis, Missouri, USACorrespondence: Kelly Cushing, MD, Department of Gastroenterology, Washington University, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.E-mail: kcushing@dom.wustl.eduCitation: Clinical and Translational Gastroenterology (2015) 6, e108; doi:10.1038/ctg.2015.34& 2015 the American College of Gastroenterology All rights reserved 2155-384X/15www.nature.com/ctgour colitis patients. As previously noted, butyrate’s efficacy in human colitis trials conducted to date has been inconsistent. Thisdiscrepancywas also present in themousemodels of colitis.Where butyrate reduced inflammation in a T-cell-drivenmousemodelof colitis,3 it did not lessen colitis severity in a model initiated by disruption of the epithelial barrier.5 The pathophysiology of humanIBD is complex, but generally involves both immune cell activation and epithelial barrier dysfunction. Perhaps a missing link inunderstanding the inconsistent clinical trial results lies in how butyrate or other SCFAs affect the growth and differentiation state ofnormal epithelial cells. These functions are critical to wound healing that is required to achieve mucosal healing in IBD. To date,in vitro studies evaluating butyrate’s effects on the colon epithelium have been done exclusively in colon cancer cell lines that donot accurately reflect the normal epithelium. Fortunately, new methodologies now exist that allow the culture of normal(non-cancer) human epithelial cells8 and can be tailored to address these critical unanswered questions.In summary, these recent studies provide new mechanistic insight as to how bacterial derived metabolites (SCFAs) impact themucosal immune system and suppress inflammatory signaling. Butyrate appears to have the most powerful effects on innateimmune cells, adaptive immune cells, and epithelial barrier function. These exciting findings strongly indicate that butyrate or othermicrobial metabolites deserve rigorous evaluation as therapeutic targets for IBD and colon cancer. Additional mechanistic studieswill hopefully guide us in how these can be most effectively applied and overcome the limitations of efficacy observed in clinicaltrials over the last two decades.CONFLICT OF INTERESTGuarantor of the article: Matthew A. Ciorba, MD.Specific author contributions: Kelly Cushing, David Alvarado and Matthew Ciorba were involved in review of the literature,preparation of the manuscript, and final editing of the manuscript.Financial support: Support provided by W. M. Keck Fellowship (D.M.A.), grants T32DK007130 (K.C.), and DK100737 (M.A.C.).Potential competing interests: None.1. Harig JM, Soergel KH, Komorowski RA et al. Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 1989; 320: 23–28.2. Thibault R, Blachier F, Darcy-Vrillon B et al. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis 2010; 16: 684–695.3. Furusawa Y, Obata Y, Fukuda S et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504: 446–450.4. Arpaia N, Campbell C, Fan X et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504: 451–455.5. Chang PV, Hao L, Offermanns S et al. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA 2014; 111: 2247–2252.6. Singh N, Gurav A, Sivaprakasam S et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 2014; 40:128–139.7. Kelly CJ, Zheng L, Campbell EL et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 2015; 17: 662–671.8. VanDussen KL, Marinshaw JM, Shaikh N et al. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 2014; 64: 911–920.Clinical and Translational Gastroenterology is an open-access journal published by Nature Publishing Group. This work is licensedunder aCreativeCommonsAttribution-NonCommercial-ShareAlike 4.0 International License. The imagesorother third partymaterial inthis article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if thematerial is not included under theCreative Commons license, users will need to obtain permission from the license holder to reproduce thematerial. To view a copy of this license, visithttp://creativecommons.org/licenses/by-nc-sa/4.0/Translational Medicine: Bench to Bedside2Clinical and Translational Gastroenterology

Butyrate and mucosal inflammation: New scientific evidence supports clinical observation

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Butyrate and mucosal inflammation: New scientific evidence supports clinical observation

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