Akkermansia muciniphila associated with improved child health produces the peptode larazotide that affects colonic epithelial cells

Akkermansia muciniphila, a bacterium, is associated with good health, but data are lacking whether it confers health benefits on children in low income countries and by which mechanisms. In a case-control study of children <5 years old with (n=1717) or without (n=1524) diarrhea, the presence of A. muciniphila reduces the odds ratio of symptoms of diarrhea from six diarrheal pathogens. A. muciniphila is found more frequently among children who are growing well compared with those who are growing poorly. In silico analysis of 1487 A. muciniphila genomes revealed the presence of DNA encoding the peptide larazotide known to benefit human health by improving tight junctions. Although previously considered synthetic, we demonstrated that larazotide is secreted by A. muciniphila. Larazotide is found in the nucleus of colonic epithelial cells and its exogenous application alters gene expression. When larazotide is applied to colonic organoid cultures, the amount of mucin (MUC2) is increased significantly (p<0.005). Our analyses are consistent with A. muciniphila secreting larazotide and intestinal epithelial cells responding by increasing MUC2, potentially creating a positive feedback loop that increases mucin production, which may itself increase abundance of the mucin-metabolizing A. muciniphila. This cycle may confer positive health outcomes for children. Six samples, three untreated and three treated with larazotide

嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila）是一种与健康状态良好相关的细菌，但目前尚缺乏其能否为低收入国家儿童带来健康益处，以及具体作用机制的相关研究数据。本研究针对5岁以下腹泻患儿（n=1717）与非腹泻患儿（n=1524）开展病例对照研究，结果显示，嗜黏蛋白阿克曼氏菌的存在可降低6种腹泻致病菌引发的腹泻症状的比值比。相较于生长发育不良的儿童，生长发育良好的儿童中嗜黏蛋白阿克曼氏菌的检出率更高。对1487株嗜黏蛋白阿克曼氏菌基因组的计算机模拟（in silico）分析显示，其基因组中携带编码肽larazotide的DNA序列，该肽可通过改善肠道上皮紧密连接而有益于人体健康。尽管此前学界认为larazotide为人工合成物质，但本研究证实，嗜黏蛋白阿克曼氏菌可分泌该肽。larazotide可定位于结肠上皮细胞的细胞核内，外源性施加该肽可改变细胞的基因表达谱。将larazotide应用于结肠类器官培养体系后，黏蛋白MUC2的表达量显著升高（p<0.005）。本研究分析结果支持以下结论：嗜黏蛋白阿克曼氏菌可分泌larazotide，肠道上皮细胞则通过上调MUC2的表达产生应答，由此可能形成一个正反馈循环，促进黏蛋白生成，而黏蛋白的增加又可进一步提升嗜黏蛋白阿克曼氏菌（一种以黏蛋白为代谢底物的细菌）的丰度。这一循环或可为儿童带来积极的健康结局。本研究共纳入6份样本，其中3份为未处理对照组，3份为larazotide处理组。