PMID- 35422042 OWN - NLM STAT- MEDLINE DCOM- 20220418 LR - 20220716 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 20 IP - 1 DP - 2022 Apr 15 TI - Ketone body beta-hydroxybutyrate ameliorates colitis by promoting M2 macrophage polarization through the STAT6-dependent signaling pathway. PG - 148 LID - 10.1186/s12916-022-02352-x [doi] LID - 148 AB - BACKGROUND: Ketone body beta-hydroxybutyrate (BHB) has received more and more attentions, because it possesses a lot of beneficial, life-preserving effects in the fields of clinical science and medicine. However, the role of BHB in intestinal inflammation has not yet been investigated. METHODS: Colonic mucosa of inflammatory bowel disease (IBD) patients and healthy controls were collected for evaluation of BHB level. Besides, the therapeutic effect of exogenous BHB in a murine model of acute dextran sulfate sodium (DSS)-induced colitis were assessed by body weight change, colon length, disease activity index, and histopathological sections. The regulatory effectors of BHB were analyzed by RT-qPCR, immunofluorescence, and microbe analysis in vivo. Moreover, the molecular mechanism of BHB was further verified in bone marrow-derived macrophages (BMDMs). RESULTS: In this study, significantly reduced BHB levels were found in the colonic mucosa from IBD patients and correlated with IBD activity index. In addition, we demonstrated that the administration of exogenous BHB alleviated the severity of acute experimental colitis, which was characterized by less weight loss, disease activity index, colon shortening, and histology scores, as well as decreased crypt loss and epithelium damage. Furthermore, BHB resulted in significantly increased colonic expression of M2 macrophage-associated genes, including IL-4Ra, IL-10, arginase 1 (Arg-1), and chitinase-like protein 3, following DSS exposure, suggesting an increased M2 macrophage skewing in vivo. Moreover, an in vitro experiment revealed that the addition of BHB directly promoted STAT6 phosphorylation and M2 macrophage-specific gene expression in IL-4-stimulated macrophages. Besides, we found that BHB obviously increased M2 macrophage-induced mucosal repair through promoting intestinal epithelial proliferation. However, the enhancement effect of BHB on M2 macrophage-induced mucosal repair and anti-inflammation was completely inhibited by the STAT6 inhibitor AS1517499. CONCLUSIONS: In summary, we show that BHB promotes M2 macrophage polarization through the STAT6-dependent signaling pathway, which contributes to the resolution of intestinal inflammation and the repair of damaged intestinal tissues. Our finding suggests that exogenous BHB supplement may be a useful therapeutic approach for IBD treatment. CI - (c) 2022. The Author(s). FAU - Huang, Chongyang AU - Huang C AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Wang, Jun AU - Wang J AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Liu, Hongbin AU - Liu H AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Huang, Ruo AU - Huang R AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Yan, Xinwen AU - Yan X AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Song, Mengyao AU - Song M AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Tan, Gao AU - Tan G AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. tgao0316@163.com. FAU - Zhi, Fachao AU - Zhi F AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. zhifc41532@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220415 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 RN - 0 (STAT6 Transcription Factor) RN - 0 (STAT6 protein, human) RN - 0 (Stat6 protein, mouse) RN - 9042-14-2 (Dextran Sulfate) RN - TZP1275679 (3-Hydroxybutyric Acid) SB - IM MH - 3-Hydroxybutyric Acid/metabolism/pharmacology/therapeutic use MH - Animals MH - *Colitis/chemically induced/drug therapy/metabolism MH - Dextran Sulfate/adverse effects/metabolism MH - Disease Models, Animal MH - Humans MH - Inflammation/metabolism MH - *Inflammatory Bowel Diseases/drug therapy MH - Macrophages MH - Mice MH - Mice, Inbred C57BL MH - STAT6 Transcription Factor/metabolism/pharmacology MH - Signal Transduction PMC - PMC9011974 OTO - NOTNLM OT - Inflammatory bowel disease OT - M2 macrophage OT - STAT6 OT - Tissue repair OT - beta-Hydroxybutyrate COIS- The authors declare that they have no competing interests. EDAT- 2022/04/16 06:00 MHDA- 2022/04/19 06:00 PMCR- 2022/04/15 CRDT- 2022/04/15 05:10 PHST- 2021/11/26 00:00 [received] PHST- 2022/03/24 00:00 [accepted] PHST- 2022/04/15 05:10 [entrez] PHST- 2022/04/16 06:00 [pubmed] PHST- 2022/04/19 06:00 [medline] PHST- 2022/04/15 00:00 [pmc-release] AID - 10.1186/s12916-022-02352-x [pii] AID - 2352 [pii] AID - 10.1186/s12916-022-02352-x [doi] PST - epublish SO - BMC Med. 2022 Apr 15;20(1):148. doi: 10.1186/s12916-022-02352-x.