SCFAs Control Skin Immune Responses via Increasing Tregs

We are surrounded by billions of microbes, and our immune system is substantially affected by the commensal bacteria on the surface of our body. Schwarz et al. describe the immune-suppressive effect of sodium butyrate, a bacterial metabolite that is categorized as one of the short-chain fatty acids, during skin inflammatory responses. We are surrounded by billions of microbes, and our immune system is substantially affected by the commensal bacteria on the surface of our body. Schwarz et al. describe the immune-suppressive effect of sodium butyrate, a bacterial metabolite that is categorized as one of the short-chain fatty acids, during skin inflammatory responses. Clinical Implications•Topical administration of sodium butyrate suppresses the CHS response.•Sodium butyrate increases the number of skin-resident IL-10–producing Foxp3+ Tregs.•Topical SCFA administration may become a useful inflammatory disease therapeutic strategy. •Topical administration of sodium butyrate suppresses the CHS response.•Sodium butyrate increases the number of skin-resident IL-10–producing Foxp3+ Tregs.•Topical SCFA administration may become a useful inflammatory disease therapeutic strategy. Human skin and mucosal sites are colonized by a large number of microorganisms, referred to as commensal bacteria or microbiota. These bacteria influence the host immune system under both pathogenic and nonpathogenic conditions. Schwarz et al., 2017Schwarz A. Brushs A. Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system.J Invest Dermatol. 2017; 137: 855-864Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar offer new insight into the specific role of bacterial metabolite short-chain fatty acids (SFCAs) on skin regulatory T cells (Tregs). Adult human skin contains about 20 billion T cells, which corresponds to nearly twice the number of blood circulating T cells (Clark et al., 2006Clark R.A. Chong B. Mirchandani N. Brinster N.K. Yamanaka K. Dowgiert R.K. et al.The vast majority of CLA+ T cells are resident in normal skin.J Immunol. 2006; 176: 4431-4439Crossref PubMed Scopus (574) Google Scholar). Most (>95%) skin-resident T cells are CD45RO+CLA+ memory T cells, and among them, up to 20% are Foxp3+ Tregs. The essential role of Tregs in maintaining skin immune homeostasis has been shown in both mice and humans. Scurfy mice have a missense mutation in Foxp3 and therefore lack Tregs; they develop spontaneous skin inflammation and inflammation in the gut and endocrine organs (Brunkow et al., 2001Brunkow M.E. Jeffery E.W. Hjerrild K.A. Paeper B. Clark L.B. Yasayko S.A. et al.Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.Nat Genet. 2001; 27: 68-73Crossref PubMed Scopus (2024) Google Scholar). The human equivalent of mouse scurfy is seen in IPEX (i.e., immune dysregulation, polyendocrinopathy, enteropathy, X-lined) syndrome, in which patients develop atopic dermatitis-like skin inflammation (Ramsdell et al., 2001Ramsdell F. Peake J. Faravelli F. Casanova J.L. Buist N. Levy-Lahad E. et al.X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.Nat Genet. 2001; 27: 18-20Crossref PubMed Scopus (1482) Google Scholar). These phenotypes suggest that the skin suffers from continuous stimuli, even under steady-state conditions, and that Tregs inhibit nonpathogenic stimuli-induced cutaneous inflammation. In Mazmanian et al., 2008Mazmanian S.K. Round J.L. Kasper D.L. A microbial symbiosis factor prevents intestinal inflammatory disease.Nature. 2008; 453: 620-625Crossref PubMed Scopus (1696) Google Scholar. made an important discovery regarding immune-modulating mechanisms in the gut. They reported that dominant colonization by Bacteroides fragilis protects animals from experimental colitis via increased numbers of IL-10 producing Tregs. Smith et al., 2013Smith P.M. Howitt M.R. Panikov N. Michaud M. Gallini C.A. Bohlooly-Y M. et al.The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013; 341: 569-573Crossref PubMed Scopus (3048) Google Scholar further showed that SCFAs, major derivatives of anaerobic bacteria fermentation, regulate the size and function of colonic Tregs. These studies indicated that commensal bacteria contain proregulatory species that influence immunity in the gut. In skin, skin commensal bacteria vary greatly among different body sites and under different skin conditions. Because skin commensal bacteria also contain SCFA-producing strains (Christensen and Brüggemann, 2013Christensen G.J.M. Brüggemann H. Bacterial skin commensals and their role as host guardians.Benef Microbes. 2013; 5: 201-215Crossref Scopus (183) Google Scholar), an immune-regulatory mechanism similar to that in the gut could also exist in skin. However, it had remained uncertain whether SCFAs would influence the size and function of skin-resident Tregs. Schwarz et al., 2017Schwarz A. Brushs A. Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system.J Invest Dermatol. 2017; 137: 855-864Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar examined how SCFAs would influence skin-resident Tregs. They injected sodium butyrate (SB) subcutaneously or applied it topically, as a representative SCFA, to mouse ear skin 24 hours before elicitation of contact hypersensitivity (CHS) responses. They observed that CHS responses were suppressed and that the number of Foxp3+ Tregs was increased significantly in SB-treated skin. CHS responses were not suppressed in either Foxp3+ cell-depleted mice or anti-IL-10 antibody–treated mice, suggesting that the suppressive effect of SB depends on IL-10–producing skin Tregs. Schwarz et al., 2017Schwarz A. Brushs A. Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system.J Invest Dermatol. 2017; 137: 855-864Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar also attempted to address whether SB treatment had promoted the conversion of CD4+ non-Tregs to Tregs in the skin. SCFAs act on leukocytes mainly via two mechanisms: activation of G-protein coupled receptors GPR41/GPR43 and inhibition of histone deacetylase. Histone acetylation is known to be essential for the development of Tregs (Smith et al., 2013Wang Z. Zang C. Rosenfeld J.A. Schones D.E. Barski A. Cuddapah S. et al.Combinatorial patterns of histone acetylations and methylations in the human genome.Nat Genet. 2008; 40: 897-903Crossref PubMed Scopus (1723) Google Scholar). Most Tregs found in the SB-treated skin were GPR43+, and the topical administration of SB induced the histone acetylation of CD4+ non-Treg cells and enhanced their production of IL-10. Furthermore, ex vivo culture of human skin samples with SB resulted in an increase of FoxP3+ cells in the skin. These results suggest that SB might have the ability to increase the number of skin-resident Tregs directly by converting CD4+ non-Treg cells to Tregs, which, in turn, would suppress or terminate skin inflammation. Schwarz et al., 2017Schwarz A. Brushs A. Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system.J Invest Dermatol. 2017; 137: 855-864Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar shows that SCFAs may act on the skin-resident Treg pool in the same way as has been reported for gut Tregs (Smith et al., 2013Smith P.M. Howitt M.R. Panikov N. Michaud M. Gallini C.A. Bohlooly-Y M. et al.The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013; 341: 569-573Crossref PubMed Scopus (3048) Google Scholar). Their study extends the earlier findings in that (i) SCFAs increase the number of Tregs in the skin relatively quickly (within 24 hours) and (ii) this effect is mediated by the conversion of non-Tregs to Tregs. For the gut, it is reported that SCFAs, administered over 3 weeks in drinking water, act on Tregs and induce Treg expansion without affecting other T-cell populations (Smith et al., 2013Smith P.M. Howitt M.R. Panikov N. Michaud M. Gallini C.A. Bohlooly-Y M. et al.The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013; 341: 569-573Crossref PubMed Scopus (3048) Google Scholar). The rapid change and plasticity of T cells in the skin is impressive and intriguing. Several questions remain: (i) Do SCFAs affect skin-resident Tregs/non-Tregs under normal physiological conditions? (ii) Do skin commensal bacteria affect the Treg function in vivo? and (iii) Does the interaction between skin commensal bacteria and skin-resident Tregs modulate systemic immunity? Additional studies using germ-free mice will be needed to address these questions. In the colon, the SCFA concentration is relatively high (80–120 mmol/L), and a deficiency in SCFAs is linked to worsening inflammatory bowel diseases. In contrast, drinking SCFA-containing water (150 mmol/L) prevents the development of experimental colitis in an animal model (Smith et al., 2013Smith P.M. Howitt M.R. Panikov N. Michaud M. Gallini C.A. Bohlooly-Y M. et al.The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013; 341: 569-573Crossref PubMed Scopus (3048) Google Scholar). Furthermore, some clinical studies have shown that an SCFA enema would result in significant improvement in clinical scores for patients with ulcerative colitis (Scheppach, 1996Scheppach W. German-Austrian SCFA Study GroupTreatment of distal ulcerative colitis with short-chain fatty acid enemas a placebo-controlled trial.Dig Dis Sci. 1996; 41: 2254-2259Crossref PubMed Scopus (172) Google Scholar). These facts support the idea that SCFAs are a good candidate for therapeutic application to inflammatory bowel diseases. Could the use of SFCAs be considered for the skin? Although measurements of SCFA concentrations in the skin have not yet been performed, the physiological concentration in the skin should be low compared with that found in the gut, because SCFAs are produced under anaerobic conditions. It seems unlikely that SCFAs control the number of Tregs in the skin under normal physiological conditions. Schwarz et al., 2017Schwarz A. Brushs A. Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system.J Invest Dermatol. 2017; 137: 855-864Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar showed that the administration of SB, via both intradermal injection and topical application, prevents the expression of hapten-specific skin inflammation in previously sensitized mice. They also showed that SB application was still effective even when applied after elicitation of the CHS response, suggesting a “curative” potential once inflammation has developed. SB showed immunosuppressive effects in the skin at a relatively lower concentration (1 mmol/L) when applied topically. This suggests that topically applied SB can reach skin Tregs with efficiency. Schwarz et al.’s findings raise the possibility that the administration of SCFAs, even topically, may be used to control inflammatory disorders in the skin. Further research may lead to improved control strategies for skin inflammation using derivatives from bacteria. The authors state no conflict of interest. The Short-Chain Fatty Acid Sodium Butyrate Functions as a Regulator of the Skin Immune SystemJournal of Investigative DermatologyVol. 137Issue 4PreviewThere is evidence that gut commensal microbes affect the mucosal immune system via expansion of regulatory T cells (Tregs) in the colon. This is mediated via short-chain fatty acids, bacterial metabolites generated during fiber fermentation, which include butyrate, propionate, and acetate. We postulated that short-chain fatty acids produced by commensal skin bacteria may also activate resident skin Tregs, the activity of which is diminished in certain inflammatory dermatoses. Sodium butyrate (SB) either injected subcutaneously or applied topically onto the ears of hapten-sensitized mice significantly reduced the contact hypersensitivity reaction. Full-Text PDF Open Archive