Mucus produced by goblet cells in the gastrointestinal tract forms a biological barrier that protects the intestine from invasion by commensals and pathogens. However, the host-derived regulatory network that controls mucus secretion and thereby changes gut microbiota has not been well studied. Here, we identify that Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines intestinal homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) results in defects in goblet cell autophagy and mucus secretion, leading to an impaired gut microenvironment and dysbiosis. Subsequently, due to changes in microbiota and disruption in microbiome metabolites of short-chain fatty acids, Foxo1 deficiency results in altered organization of tight junction proteins and enhanced susceptibility to intestinal inflammation. Our study demonstrates that Foxo1 is crucial for IECs to establish commensalism and maintain intestinal barrier integrity by regulating goblet cell function.
Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion
Disclosures: S.B. Snapper reported personal fees from Pandion, IFM Therapeutics, Hoffman La Roche, Amgen, Lilly, Takeda, Kyverna, Pfizer, Merck, and Third Rock outside the submitted work. S. Xiao is an employee of Celsius Therapeutics. V.K. Kuchroo has an ownership interest in and is a member of the scientific advisory board for Tizona Therapeutics, Bicara Therapeutics, Compass Therapeutics, Larkspur Biosciences, and Trishula Therapeutics. The interests of V.K. Kuchroo were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict-of-interest policies. No other disclosures were reported.
S. Xiao’s present address is Celsius Therapeutics, Cambridge, MA.
- Award Id(s): 479689
- Award Id(s): 1-16-INI-16
- Award Id(s): P30-EY026877
- Award Id(s): TA 3059-A-2
- Award Id(s): R01 AI139536
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Zuojia Chen, Jialie Luo, Jian Li, Girak Kim, Eric S. Chen, Sheng Xiao, Scott B. Snapper, Bin Bao, Dingding An, Richard S. Blumberg, Cheng-hui Lin, Sui Wang, Jiaxin Zhong, Kuai Liu, Qiyuan Li, Chuan Wu, Vijay K. Kuchroo; Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion. J Exp Med 6 September 2021; 218 (9): e20210324. doi: https://doi.org/10.1084/jem.20210324
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