Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 167; no. 4; pp. 733 - 749.e3
• Main Authors: Wang, Rui, Li, Bo, Huang, Bingyuan, Li, Yikang, Liu, Qiaoyan, Lyu, Zhuwan, Chen, Ruiling, Qian, Qiwei, Liang, Xueying, Pu, Xiting, Wu, Yi, Chen, Yu, Miao, Qi, Wang, Qixia, Lian, Min, Xiao, Xiao, Leung, Patrick S.C., Gershwin, M. Eric, You, Zhengrui, Ma, Xiong, Tang, Ruqi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2024
• Subjects: Animals; Autoimmune Liver Disease; Butyrates - metabolism; Butyrates - pharmacology; Cellular Reprogramming - drug effects; Disease Models, Animal; Dysbiosis; Epigenesis, Genetic - drug effects; Fatty Acid Oxidation; Feces - chemistry; Feces - microbiology; Female; Gastrointestinal Microbiome - drug effects; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Liver Cirrhosis, Biliary - drug therapy; Liver Cirrhosis, Biliary - genetics; Liver Cirrhosis, Biliary - immunology; Liver Cirrhosis, Biliary - metabolism; Liver Cirrhosis, Biliary - microbiology; Male; Metabolic Reprogramming; Mice; Mice, Inbred C57BL; Microbial Metabolite; Myeloid Cells; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Ursodeoxycholic Acid - pharmacology; MDSC; 2OA; ALP; GPR; OXPHOS; UDCA; BM; Microbial Metabolite; Myeloid Cells; PBC; BSA; PPAR; GM-CSF; Fatty Acid Oxidation; iNOS; H3K27ac; Treg; Autoimmune Liver Disease; PBMC; SCFA; PMN; IL6; FAO; ROS; HC; ATP; HDAC
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2024.05.014

Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. We measured fecal short-chain fatty acids levels using targeted gas chromatography–mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation–quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography–mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin–induced cholangitis murine model. Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid β-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC. [Display omitted] Gut microbiota-derived butyrate promotes the expansion and immunosuppressive function of myeloid-derived suppressor cells, presenting promising avenues for immune-based therapeutic strategies in primary biliary cholangitis.