Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, Equipe Labellisée Ligue contre le Cancer, 34000 Montpellier, France.
Paris-Saclay University, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), MetaGenoPolis, 78350, Jouy-en-Josas, France.
Proc Natl Acad Sci U S A. 2023 Jun 20;120(25):e2219431120. doi: 10.1073/pnas.2219431120. Epub 2023 Jun 12.
Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.
肠道微生物群落失衡（失调）与胃肠道内外的病理状况越来越相关。肠 Paneth 细胞被认为是肠道微生物群落的守护者，但 Paneth 细胞功能障碍与失调之间的联系尚不清楚。我们报告了一个失调起始的三步骤机制。最初在肥胖症和炎症性肠病患者中经常观察到的 Paneth 细胞改变导致微生物群落的轻度重塑，产琥珀酸盐的物种扩增。SucnR1 依赖性的上皮簇细胞激活触发 2 型免疫反应，反过来又加重 Paneth 细胞缺陷，促进失调和慢性炎症。因此，我们揭示了簇细胞在 Paneth 细胞缺陷后促进失调的功能，以及 Paneth 细胞在维持平衡的微生物群落中未被重视的重要作用，以防止簇细胞的不当激活和有害的失调。这种琥珀酸-簇细胞炎症回路也可能导致患者中观察到的慢性失调。
