肠道菌群色氨酸（Trp）代谢产物通过激活孕烷X受体（PXR）和/或芳烃受体（AhR），影响肠屏障功能，然而尚不清楚肠道共生菌间如何互作代谢Trp。申请人前期研究发现菊粉能促进菌群Trp代谢生成吲哚丙酸（IPA），并增殖特定产吲哚乳酸（ILA）菌，由此推测产ILA菌（如双歧杆菌）可能通过与利用ILA为底物的产IPA菌间的代谢互养，提供肠道PXR/AhR激动剂，从而平衡肠道宿主和菌群的Trp代谢，改善肠屏障功能。本项目拟采用靶向代谢组学、同位素示踪、RNAi、RNA-seq等技术，从分子、细胞及动物水平明确产ILA菌与产IPA菌的互养关系；探讨PXR/AhR信号通路在两菌Trp代谢产物保护肠屏障功能中的地位和作用；揭示两菌的Trp代谢互养对肠屏障功能损伤的保护机制。研究结果将为开发下一代益生菌调控肠道Trp代谢平衡和维持肠稳态提供新思路和新靶点。

Tryptophan (Trp) metabolites derived from gut microbiota affect the intestinal barrier function by activating the pregnane X receptor (PXR) and/or aromatic hydrocarbon receptor (AhR). However, how gut commensal bacteria interact with each other to metabolize Trp remains unclear. We have previously found that inulin promotes gut microbes to metabolize Trp to indole propionic acid (IPA), and proliferates specific indole lactic acid (ILA)-producing bacteria. Thus, we hypothesized that ILA-producing bacteria (e.g. Bifidobacterium) may provide intestinal PXR/AhR agonists by cross-feeding with IPA-producing bacteria which use ILA precursors, thereby balancing gut host and microbiota Trp metabolism and improving the intestinal barrier function. In order to test the hypothesis, technologies such as targeted metabolomics, isotope tracing, RNAi, RNA-seq will be employed. The aim of the study was to clarify the cross-feeding relationship between ILA-producing bacteria and IPA-producing bacteria, and to explore the role of PXR/AhR in protecting the gut barrier function of Trp metabolites of these two bacteria. Ultimately, the mechanism of Trp metabolites of ILA-producing bacteria and IPA-producing bacteria in protection of intestinal barrier injury will be elucidated at the molecular, cellular and animal levels. Results from the project will provide new ideas and new targets for the development of the next generation probiotics to balance gut tryptophan metabolism and maintain gut homeostasis.