Rayomand Katrak

Introduction. Ulcerative colitis is a chronic inflammatory disease that presents with mucosal inflammation starting in the rectum and extending proximally in the colon⁹. Ulcerative colitis is believed to be caused by dysbiosis between intestinal microbiota and mucosal immunity, leading to decreased levels of short chain fatty acids (SCFAs) – in particular, butyrate^2,6. Butyrate is an important factor in the generation of regulatory T cells (Tregs) which play an important role in modulating the immune system and preventing inflammation¹. In addition to butyrate, TGFb1 has also been shown to be essential to Treg formation⁴. Methods. To determine the role of butyrate in Treg formation, dendritic and splenic cells from mice were cultured in the presence or absence of butyrate. IL-10 and Aldh1a1 levels were measured using qPCR^4. The role of TGFb1 in Treg formation was determined using peptidoglycan (TLR2 ligand) from C. butyricum to activate the ERK-AP-1 pathway. TGFb1 and neuropilin-1 levels were measured using a bioassay with MFB-F11 cells¹. Results. qPCR revealed showed higher levels of IL-10 and Aldh1a1 in cells primed with butyrate than the controlled cells. IL-10 and Aldha1a favor differentiation of naïve T cells in Tregs. Butyrate acts on the GPR109A – encoded by Niarc1, mice with Niarc1^-/- showed significantly lower levels of IL-10 and Aldh1a1⁷. Stimulation of bone marrow derived dendritic cells with peptidoglycan led to recruitment of Activator Protein 1 (AP-1) and c-Fos to the CNS2 region of the TGFb1 promotor. Recruitment of AP-1 led to transcriptionally active histone modifications in the TGFb1 promotor. Mice with c-Fos knockout did not show TGFb1 production and histone modifications. Neuropilin-1 expression correlates with Treg expression in the colon and was reduced in mice with c-Fos knockout³. Conclusions. Although there are decreased levels of other SCFAs in ulcerative colitis, butyrate stands out for its importance in the formation of Tregs in the colon. Because of the dysbiosis seen in ulcerative colitis, both butyrate and TGFb1 are reduced leading to lower levels of Tregs causing higher than normal levels of inflammation. Therapies such as Fecal Microbiota Transfer (FMT) and Adoptive Cell Transfer (ACT) are aiming to reduce the dysbiosis and return Tregs to normal levels, thus controlling inflammation. Future research is needed to standardize FMT and ACT to help lower symptoms and induce remission in patients with ulcerative colitis^5,8.

1. Biagioli M, Capobianco D, Carino A, et al. Divergent Effectiveness of Multispecies Probiotic Preparations on Intestinal Microbiota Structure Depends on Metabolic Properties. Nutrients. 2019;11(2):325. doi:10.3390/nu11020325. (5.2)
2. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer R-J. Review article: the role of butyrate on colonic function. Alimentary Pharmacology & Therapeutics. 2007;27(2):104-119. doi:10.1111/j.1365-2036.2007.03562.x. (2.1)
3. Kashiwagi I, Morita R, Schichita T, et al. Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells. Immunity. 2015;43(1):65-79. doi:10.1016/j.immuni.2015.06.010. (1.2)
4. Martin-Gallausiaux C, Béguet-Crespel F, Marinelli L, et al. Butyrate produced by gut commensal bacteria activates TGF-beta1 expression through the transcription factor SP1 in human intestinal epithelial cells. Scientific Reports. 2018;8(1). doi:10.1038/s41598-018-28048-y. (2.2)
5. Moayyedi P, Surette MG, Kim PT, et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology. 2015;149(1). doi:10.1053/j.gastro.2015.04.001. (3.2)
6. Sasaki K, Inoue J, Sasaki D, et al. Construction of a Model Culture System of Human Colonic Microbiota to Detect Decreased Lachnospiraceae Abundance and Butyrogenesis in the Feces of Ulcerative Colitis Patients. Biotechnology Journal. 2019:1800555. doi:10.1002/biot.201800555. (4.1)
7. 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(1):128-139. doi:10.1016/j.immuni.2013.12.007. (4.2)
8. Steinmeyer S, Howsmon DP, Alaniz RC, Hahn J, Jayaraman A. Empirical modeling of T cell activation predicts interplay of host cytokines and bacterial indole. Biotechnology and Bioengineering. 2017;114(11):2660-2667. doi:10.1002/bit.26371. (x.x)
9. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel J-F. Ulcerative Colitis . The Lancet. 389(10080):1756-1770. doi:https://doi.org/10.1016/S0140-6736(16)32126-2. (7.1)