The Immunomodulatory Functions of Butyrate

Abstract

The gastrointestinal (GI) system contains many different types of immune cells, making it a key immune organ system in the human body. In the last decade, our knowledge has substantially expanded regarding our understanding of the gut microbiome and its complex interaction with the gut immune system. Short chain fatty acids (SCFA), and specifically butyrate, play an important role in mediating the effects of the gut microbiome on local and systemic immunity. Gut microbial alterations and depletion of luminal butyrate have been well documented in the literature for a number of systemic and GI inflammatory disorders. Although a substantial knowledge gap exists requiring the need for further investigations to determine cause and effect, there is heightened interest in developing immunomodulatory therapies by means of reprogramming of gut microbiome or by supplementing its beneficial metabolites, such as butyrate. In the current review, we discuss the role of endogenous butyrate in the inflammatory response and maintaining immune homeostasis within the intestine. We also present the experimental models and human studies which explore therapeutic potential of butyrate supplementation in inflammatory conditions associated with butyrate depletion.

Keywords: adaptive immunity; butyrate; dysbiosis; epithelial barrier; gut microbiome; gut microbiota; immunity; inflammation; inflammatory bowel disease; innate immunity; short chain fatty acids.

Figure 1

Distribution of gut microbes within human gastrointestinal tract. Microbiota comprised of bacteria, fungi, yeasts, viruses, and protozoa present throughout the gastrointestinal system, with colon containing the highest number and diversity of microbes. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2015. All Rights Reserved.

Figure 2

Key factors influencing the composition and diversity of the gut microbiome. Many factors can influence the gut microbiota composition and diversity beginning with the birthing process and first feeding methods. Other factors such as diet, psychological and physiological stress, pharmaceutical exposure, geographic residence and traveling and exposures, are among several factors which influence the microbiome throughout the lifecycle. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2015. All Rights Reserved.

Figure 3

Interaction of the gut microbiota with components of intestinal innate and adaptive immunity. Intestinal immune cells including dendritic and mast cells, neutrophils, B and T lymphocytes are depicted in representative locations within gastrointestinal mucosa. G-protein coupled receptors in which butyrate serves as a ligand are present on major immune cells and function as key link for butyrate mediated modulation of immune function. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2021. All Rights Reserved.

Figure 4

Overview of butyrate modulatory effects on immune function. Butyrate enhances the intestinal mucosal barrier by directly inducing tight junctional proteins in the epithelium. This effect is further augmented by butyrate’s induction of IL-22 secretion from ILC3 cells. Through interaction with GPCR 43 and 41, butyrate inhibits the proinflammatory cytokine secretion from neutrophils. Butyrate has direct effects on macrophages and dendritic cells via GPCR and modulates T cell function by increasing Foxp3 T cells while inhibiting IFN-ɣ producing T cells. Butyrate increases serotonin production and is also an inhibitor of HDAC. It modulates B cell function through these routes and increases anti-inflammatory cytokine IL-10 while it decreases IL-17. By increasing IgA and IgG antibody response from B cells, butyrate augments specific immunity and inhibits autoimmunity. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2021. All Rights Reserved.