Live Akkermansia muciniphila boosts dendritic cell retinoic acid synthesis to modulate IL-22 activity and mitigate colitis in mice
Hongbin Liu,
Ruo Huang,
Binhai Shen,
Chongyang Huang,
Qian zhou,
Jiahui Xu,
Shengbo Chen,
Xinlong Lin,
Jun Wang,
Xinmei Zhao,
Yandong Guo,
Xiuyun Ai,
Yangyang Liu,
Ye Wang,
Wendi Zhang,
Fachao Zhi
Affiliations
Hongbin Liu
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Ruo Huang
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Binhai Shen
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Chongyang Huang
Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine
Qian zhou
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Jiahui Xu
Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University
Shengbo Chen
Department of Gastroenterology, Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University
Xinlong Lin
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Jun Wang
Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine
Xinmei Zhao
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Yandong Guo
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Xiuyun Ai
Huiqiao Medical Center, Nanfang Hospital, Southern Medical University
Yangyang Liu
Guangzhou ZhiYi Biotechnology Co., Ltd
Ye Wang
Guangzhou ZhiYi Biotechnology Co., Ltd
Wendi Zhang
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Fachao Zhi
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University
Abstract Background The interplay between gut microbiota and immune responses is crucial in ulcerative colitis (UC). Though Akkermansia muciniphila (Akk) shows therapeutic potential, the mechanisms remain unclear. This study sought to investigate differences in therapeutic efficacy among different forms or strains of Akk and elucidate the underlying mechanisms. Results Employing a dextran sulfate sodium (DSS)-induced colitis mouse model, we assessed Akk’s impact on colitis using cellular cytokine analysis, immune phenotyping, proteomics, and biochemical methods. Our results suggest that treatment with live Akk effectively reduced colitis in the DSS-induced model, whereas heat-inactivated Akk did not yield the same results. Notably, Akk exhibited protective properties by promoting the secretion of IL-22 by Group 3 innate lymphoid cells (ILC3s), as evidenced by the absence of protection in IL-22 knockout mice. Additionally, Akk augmented the population of CD103+CD11b− dendritic cells (DCs) and enhanced their retinoic acid (RA) synthesis through the modulation of RALDH2, a crucial enzyme in RA metabolism. The depletion of RALDH2 in DCs diminished Akk’s protective properties and impaired IL-22-mediated mucosal healing. Mechanistically, Akk activated RA production in DCs by enhancing the JAK2-STAT3 signaling pathway. Additionally, various strains of Akk may exhibit differing abilities to alleviate colitis, with the novel strain Am06 derived from breast milk showing consistent efficacy similar to the reference strain. Conclusions In summary, our findings indicate that certain strains of Akk may mitigate colitis through the promotion of RA synthesis and IL-22 secretion, underscoring the potential efficacy of Akk as a therapeutic intervention for the management of UC. Video Abstract
