NFAT5 dictates crosstalk between intestinal epithelial regenerative capacity and microbiota in murine colitis models
Se-Hyeon Park, Dae Hee Cheon, Yu-Mi Kim, Yeji Choi, Yong-Joon Cho, Bong-Ki Hong, Sang-Hyun Cho, Mi-Na Kweon, Hyug Moo Kwon, Eugene B. Chang, Donghyun Kim, Wan-Uk Kim
Se-Hyeon Park, Dae Hee Cheon, Yu-Mi Kim, Yeji Choi, Yong-Joon Cho, Bong-Ki Hong, Sang-Hyun Cho, Mi-Na Kweon, Hyug Moo Kwon, Eugene B. Chang, Donghyun Kim, Wan-Uk Kim
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Research Article Gastroenterology Immunology

NFAT5 dictates crosstalk between intestinal epithelial regenerative capacity and microbiota in murine colitis models

Abstract

Hypertonic and hyperosmolar stimuli frequently pose challenges to the intestinal tract. Therefore, a resilient epithelial barrier is essential for maintaining gut homeostasis in the presence of osmotic perturbations. Nuclear factor of activated T cells 5 (NFAT5), an osmosensitive transcription factor, primarily maintains cellular homeostasis under hypertonic conditions. However, the osmoprotective role of NFAT5 in enterocyte homeostasis is poorly understood. Here, we demonstrate that NFAT5 was critical for the survival and proliferation of intestinal epithelial cells (IECs) and that its deficiency accelerated chemically induced or spontaneous colitis in mice. Mechanistically, NFAT5 promoted the survival of IECs and the renewal of intestinal stem cells, thereby regulating the production of mucus and antimicrobial compounds, including RegIII and lysozyme, which consequently shape the gut microbial composition to prevent colitis. Transcriptome analysis identified HSP70 as a key downstream target of NFAT5 in epithelial regeneration. Loss- and gain-of-function experiments involving HSP70 revealed that NFAT5 mitigated experimental colitis through IEC Hsp70, which protected stem cells from inflammation-induced injury and maintained barrier function. In conclusion, our study demonstrates what we believe to be a previously unknown role for NFAT5 in dictating the crosstalk between intestinal stem cells and the microbiota, underscoring the importance of the NFAT5/HSP70 axis in maintaining epithelial regeneration related to gut barrier function, balancing microbial composition, and subsequently preventing colitis progression.

Authors

Se-Hyeon Park, Dae Hee Cheon, Yu-Mi Kim, Yeji Choi, Yong-Joon Cho, Bong-Ki Hong, Sang-Hyun Cho, Mi-Na Kweon, Hyug Moo Kwon, Eugene B. Chang, Donghyun Kim, Wan-Uk Kim

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Figure 3

Fecal microbiota are indispensable for driving the progression of colitis associated with NFAT5 deficiency.

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Fecal microbiota are indispensable for driving the progression of coliti...
Mice were given ad libitum access to water supplemented with DSS for 5 days, followed by fresh drinking water for the duration of the experimental period. (A–F) Body weight changes and DAI scores of separately housed (A) and cohoused (D) Nfat5fl/fl and Nfat5IEC-KO mice. Day-14 macroscopic images of separately housed (B) and cohoused (E) Nfat5fl/fl and Nfat5IEC-KO mice, along with analyses of colon lengths. On day 5, H&E staining was performed on colonic tissues from separately housed (C) and cohoused (F) Nfat5fl/fl and Nfat5IEC-KO mice, and corresponding histological scores were assessed, as detailed in Supplemental Table 3. (G–L) Recipient mice were pretreated ad libitum with an antibiotic cocktail for 3 weeks and then transplanted 3 times, every other day, with feces obtained from donor mice. DSS was then provided ad libitum for 5 days, followed by fresh drinking water for 9 days. Body weight changes and the DAI were assessed for Nfat5+/+ and Nfat5+/– recipient mice (G), which were transplanted with feces derived from Nfat5+/– donor mice. (H) Macroscopic images and colon lengths were analyzed on day 14. (I) H&E-staining of distal colonic tissues collected on day 5, along with corresponding histological scores were evaluated. (J–L) Body weight changes and the DAI in different combinations (shown in indices) of donor mouse feces and FMT recipient mice were evaluated for the indicated durations. Data are presented as the mean ± SEM (A, D, G, and J–L). Data shown in A–L are representative of at least 2 independent experiments. Each dot represents an individual mouse, with mean values indicated by lines (B, C, E, F, H, and I). Scale bars: 1,000 μm and 50 μm (enlarged insets) (C and I). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.000, by 2-way, repeated-measures ANOVA with Šídák’s multiple-comparison test (A, D, G, and J–L) and Mann-Whitney U test (B, C, E, F, H, and I).