Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Massachusetts, Cambridge, USA.
FASEB J. 2023 Oct;37(10):e23201. doi: 10.1096/fj.202300982R.
Depletion of gut microbiota is associated with inefficient energy extraction and reduced production of short-chain fatty acids from dietary fibers, which regulates colonic proglucagon (Gcg) expression and small intestinal transit in mice. However, the mechanism by which the gut microbiota influences dietary protein metabolism and its corresponding effect on the host physiology is poorly understood. Enteropeptidase inhibitors block host protein digestion and reduce body weight gain in diet-induced obese rats and mice, and therefore they constitute a new class of drugs for targeting metabolic diseases. Enteroendocrine cells (EECs) are dispersed throughout the gut and possess the ability to sense dietary proteins and protein-derived metabolites. Despite this, it remains unclear if enteropeptidase inhibition affects EECs function. In this study, we fed conventional and antibiotic treated mice a western style diet (WSD) supplemented with an enteropeptidase inhibitor (WSD-ETPi), analyzed the expression of gut hormones along the length of the intestine, and measured small intestinal transit under different conditions. The ETPi-supplemented diet promoted higher Gcg expression in the colon and increased circulating Glucagon like peptide-1 (GLP-1) levels, but only in the microbiota-depleted mice. The increase in GLP-1 levels resulted in slower small intestinal transit, which was subsequently reversed by administration of GLP-1 receptor antagonist. Interestingly, small intestinal transit was normalized when an amino acid-derived microbial metabolite, p-cresol, was supplemented along with WSD-ETPi diet, primarily attributed to the reduction of colonic Gcg expression. Collectively, our data suggest that microbial dietary protein metabolism plays an important role in host physiology by regulating GLP-1-mediated intestinal transit.
肠道微生物群的耗竭与膳食纤维中短链脂肪酸的产生效率降低有关，这会调节小鼠结肠 proglucagon (Gcg) 的表达和小肠转运。然而，肠道微生物群影响饮食蛋白代谢的机制及其对宿主生理的相应影响尚不清楚。肠肽酶抑制剂可阻断宿主蛋白消化，减少饮食诱导肥胖大鼠和小鼠的体重增加，因此它们构成了靶向代谢疾病的一类新药。肠内分泌细胞 (EEC) 分布于整个肠道，具有感知饮食蛋白和蛋白衍生代谢物的能力。尽管如此，肠肽酶抑制是否会影响 EEC 功能仍不清楚。在这项研究中，我们用西方饮食 (WSD) 喂养常规和抗生素处理的小鼠，并添加肠肽酶抑制剂 (WSD-ETPi)，分析了沿肠道长度的肠道激素表达，并在不同条件下测量了小肠转运。补充 ETPi 的饮食促进了结肠中 Gcg 的更高表达，并增加了循环胰高血糖素样肽-1 (GLP-1) 水平，但仅在微生物耗竭的小鼠中。GLP-1 水平的增加导致小肠转运速度变慢，随后用 GLP-1 受体拮抗剂治疗可逆转。有趣的是，当与 WSD-ETPi 饮食一起补充氨基酸衍生的微生物代谢物对甲酚时，小肠转运恢复正常，主要归因于结肠 Gcg 表达的降低。总的来说，我们的数据表明，微生物饮食蛋白代谢通过调节 GLP-1 介导的肠道转运在宿主生理中发挥重要作用。
