Zearalenone disturbs the reproductive-immune axis in pigs: the role of gut microbial metabolites

作者全名："Wang, Shujin; Fu, Wei; Zhao, Xueya; Chang, Xiaojiao; Liu, Hujun; Zhou, Lin; Li, Jian; Cheng, Rui; Wu, Xin; Li, Xi; Sun, Changpo"

作者地址："[Wang, Shujin; Zhao, Xueya; Cheng, Rui; Li, Xi] Chongqing Med Univ, Inst Life Sci, Peoples Republ China, Chongqing 400032, Peoples R China; [Wang, Shujin; Wu, Xin] Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Peoples Republ China, Tianjin 300308, Peoples R China; [Fu, Wei; Li, Jian] Southwest Minzu Univ, Key Lab Qinghai Tibetan Plateau Anim Genet Resourc, Minist Educ, Chengdu 610000, Peoples R China; [Chang, Xiaojiao; Liu, Hujun; Sun, Changpo] Acad Natl Food, Strateg Reserv Adm, Peoples Republ China, Beijing 100037, Peoples R China; [Zhou, Lin] Shenzhen Premix INVE Nutr LTD, Shenzhen 518100, Peoples R China; [Wu, Xin] Chinese Acad Sci, Inst Subtrop Agr, CAS Key Lab Agroecol Proc Subtrop Reg, Changsha 410125, Peoples R China; [Sun, Changpo] Strateg Reserv Adm, Stand & Qual Ctr Natl Food, Beijing 100037, Peoples R China"

通信作者："Wang, SJ; Li, X (通讯作者)，Chongqing Med Univ, Inst Life Sci, Peoples Republ China, Chongqing 400032, Peoples R China.; Wang, SJ; Wu, X (通讯作者)，Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Peoples Republ China, Tianjin 300308, Peoples R China.; Sun, CP (通讯作者)，Acad Natl Food, Strateg Reserv Adm, Peoples Republ China, Beijing 100037, Peoples R China.; Wu, X (通讯作者)，Chinese Acad Sci, Inst Subtrop Agr, CAS Key Lab Agroecol Proc Subtrop Reg, Changsha 410125, Peoples R China.; Sun, CP (通讯作者)，Strateg Reserv Adm, Stand & Qual Ctr Natl Food, Beijing 100037, Peoples R China."

来源：MICROBIOME

ESI学科分类：MICROBIOLOGY

WOS号：WOS:000901429400001

JCR分区：Q1

影响因子：15.5

年份：2022

卷号：10

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Mycotoxin; Mycoestrogen; Zearalenone; Butyrate; Lipopolysaccharides; Immunity; Reproductive system; Immune system; Gastrointestinal tract; Sus scrofa

摘要："Background: Exposure to zearalenone (ZEN, a widespread Fusarium mycotoxin) causes reproductive toxicity and immunotoxicity in farm animals, and it then poses potential threats to human health through the food chain. A systematic understanding of underlying mechanisms on mycotoxin-induced toxicity is necessary for overcoming potential threats to farm animals and humans. The gastrointestinal tract is a first-line defense against harmful mycotoxins; however, it remains unknown whether mycotoxin (e.g., ZEN)-induced toxicity on the reproductive-immune axis is linked to altered gut microbial metabolites. In this study, using pigs (during the three phases) as an important large animal model, we investigated whether ZEN-induced toxicity on immune defense in the reproductive-immune axis was involved in altered gut microbial-derived metabolites. Moreover, we observed whether the regulation of gut microbial-derived metabolites through engineering ZEN-degrading enzymes counteracted ZEN-induced toxicity on the gut-reproductive-immune axis. Results: Here, we showed ZEN exposure impaired immune defense in the reproductive-immune axis of pigs during phase 1/2. This impairment was accompanied by altered gut microbial-derived metabolites [e.g., decreased butyrate production, and increased lipopolysaccharides (LPS) production]. Reduction of butyrate production impaired the intestinal barrier via a GPR109A-dependent manner, and together with increased LPS in plasma then aggravated the systemic inflammation, thus directly and/or indirectly disturbing immune defense in the reproductive-immune axis. To validate these findings, we further generated recombinant Bacillus subtilis 168-expressing ZEN-degrading enzyme ZLHY-6 (the Bs-Z6 strain) as a tool to test the feasibility of enzymatic removal of ZEN from mycotoxin-contaminated food. Notably, modified gut microbial metabolites (e.g., butyrate, LPS) through the recombinant Bs-Z6 strain counteracted ZEN-induced toxicity on the intestinal barrier, thus enhancing immune defense in the reproductive-immune axis of pigs during phase-3. Also, butyrate supplementation restored ZEN-induced abnormalities in the porcine small intestinal epithelial cell. Conclusions: Altogether, these results highlight the role of gut microbial-derived metabolites in ZEN-induced toxicity on the gut-reproductive-immune axis. Importantly, targeting these gut microbial-derived metabolites opens a new window for novel preventative strategies or therapeutic interventions for mycotoxicosis associated to ZEN."

基金机构："Basic Scientific Research Funds Programs in National Non-profit Scientific Research Institutes; National key R&D program of China [ZX2017, JY2001]; Southwest Minzu University [2021YFD1301002]; [2021PTJS20]"

基金资助正文："This work was supported by the Basic Scientific Research Funds Programs in National Non-profit Scientific Research Institutes (ZX2017, JY2001); National key R & D program of China (2021YFD1301002); ""the Fundamental Research Funds for the Central Universities,"" Southwest Minzu University (2021PTJS20)."