Lactiplantibacillus plantarum attenuate gossypol-induced hepatic lipotoxicity by altering intestinal microbiota for enriching microbial tryptophan metabolites in Nile tilapia (Oreochromis niloticus).
Fei-Fei Ding, Nan-Nan Zhou, Yue-Jian Mao, Jing Yang, Samwel M Limbu, Jorge Galindo-Villegas, Zhen-Yu Du, Mei-Ling Zhang
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Abstract
Background: Free fatty acids (FFAs) are the main cause of fatty liver disease, which can be alleviated by modulation of intestinal microbiota. Lactiplantibacillus plantarum plays a key role in maintaining liver health, but the underlying mechanism remains unclear.
Results: Here, a strain affiliated to Lactiplantibacillus plantarum was isolated from the intestine of Nile tilapia (Oreochromis niloticus). We used a gossypol-induced fatty liver disease model, which only increased the FFAs level in liver, to investigate the effectiveness of L. plantarum (YC17) in alleviating FFAs-induced lipotoxicity liver injury. We found that dietary gossypol (GOS) induced a significant increase of FFAs in liver, resulting in lipotoxicity in Nile tilapia compared to control. L. plantarum YC17 supplementation reduced FFAs content by restoring esterification process, and then relieved liver injury. Addition of L. plantarum YC17 effectively increased the abundances of Lactobacillus, Clostridium and Cetobacterium in fish intestine, as well as serum levels of the microbial tryptophan metabolites, notably indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA). The addition of L. plantarum YC17 significantly inhibited P53 signaling pathway and up-regulated the expression of FFAs esterification genes. In vitro experiments demonstrated that IPA inhibited P53 through ubiquitination and enhanced FFAs esterification in an aryl hydrocarbon receptor (Ahr) dependent manner.
Conclusion: The gut microbiota-derived tryptophan metabolites (IPA and IAA) alleviated FFAs induced lipotoxic liver injury by activating Ahr, which promoted P53 ubiquitination, leading to the enhanced FFAs esterification. Our findings demonstrated that gut microbial metabolites alleviated lipotoxicity by promoting the esterification of FFAs in the liver, offering new insights into the study of probiotics and microbial tryptophan metabolites in fatty liver disease. Video Abstract.
背景：游离脂肪酸（FFAs）是引起脂肪肝的主要原因，可通过调节肠道菌群来缓解。植物乳杆菌在维持肝脏健康中起关键作用，但其潜在机制尚不清楚。结果：从尼罗罗非鱼（Oreochromis niloticus）肠道中分离到一株植物乳杆菌。我们采用棉酚诱导的脂肪性肝病模型，仅增加肝脏中FFAs的水平，研究植物乳酸菌（L. plantarum, YC17）减轻FFAs诱导的脂肪毒性肝损伤的有效性。我们发现，与对照组相比，膳食棉酚（GOS）诱导尼罗罗非鱼肝脏中游离脂肪酸显著增加，导致其脂肪毒性。添加L. plantarum YC17通过恢复酯化过程降低FFAs含量，从而减轻肝损伤。添加L. plantarum YC17可有效提高鱼肠中乳杆菌、梭状芽胞杆菌和鲸杆菌的丰度，以及血清中微生物色氨酸代谢物，特别是吲哚-3-丙酸（IPA）和吲哚-3-乙酸（IAA）的水平。植物乳杆菌YC17的添加显著抑制了P53信号通路，上调了FFAs酯化基因的表达。体外实验表明，IPA通过泛素化抑制P53，并以芳烃受体（Ahr）依赖的方式增强FFAs酯化。结论：肠道菌源性色氨酸代谢物（IPA和IAA）通过激活Ahr来减轻FFAs诱导的脂毒性肝损伤，Ahr促进P53泛素化，导致FFAs酯化反应增强。我们的研究结果表明，肠道微生物代谢物通过促进肝脏中游离脂肪酸的酯化来减轻脂肪毒性，为脂肪性肝病中益生菌和微生物色氨酸代谢物的研究提供了新的见解。视频摘要。
期刊介绍：
Microbiome is a journal that focuses on studies of microbiomes in humans, animals, plants, and the environment. It covers both natural and manipulated microbiomes, such as those in agriculture. The journal is interested in research that uses meta-omics approaches or novel bioinformatics tools and emphasizes the community/host interaction and structure-function relationship within the microbiome. Studies that go beyond descriptive omics surveys and include experimental or theoretical approaches will be considered for publication. The journal also encourages research that establishes cause and effect relationships and supports proposed microbiome functions. However, studies of individual microbial isolates/species without exploring their impact on the host or the complex microbiome structures and functions will not be considered for publication. Microbiome is indexed in BIOSIS, Current Contents, DOAJ, Embase, MEDLINE, PubMed, PubMed Central, and Science Citations Index Expanded.
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