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Low protein diet exacerbates experimental mouse models of colitis through epithelial autonomous and non-autonomous mechanisms.

Sumeet Solanki,Joseph G. Taranto,Ryan J. Rebernick,Cristina Castillo,Varun Ponnusamy,Madeline L. Sykes,S. Leiser,Jun Hee Lee,Thomas M. Schmidt,Yatrik M. Shah

Published 2025 in Journal of NutriLife

ABSTRACT

BACKGROUND Inflammatory bowel diseases (IBD) patients are at risk of protein malnutrition due to increased protein loss or reduced dietary intake. The consequences of protein malnutrition on intestinal epithelial metabolism and disease progression remains poorly understood. OBJECTIVES Given the critical role of mechanistic target of rapamycin complex 1 (mTORC1) as an amino acid sensor and a key regulator of intestinal epithelial metabolism and homeostasis, along with the well-established influence of diet on the gut microbiota and IBD, we focused to assess the role of dietary protein in modulating intestinal epithelial mTORC1, determine the contributions of specific amino acids such as leucine and arginine, and examine the interplay between protein malnutrition and gut microbiota driving IBD. METHODS C57BL/6 mice were assigned to a control (20% protein, n = 6), a low protein (4% protein, n = 7), or diets selectively deficient in leucine, arginine and other essential amino acids (n = 5-6). Colitis was induced by administering 2.5% dextran sulfate sodium (DSS) in drinking water for 6 days. Intestinal epithelial mTORC1 activity was assessed by immunoblotting. Gut microbiota composition was characterized using 16S sequencing, and the microbiota's role in colitis was evaluated through broad-spectrum antibiotic treatment. Disease severity was quantified by monitoring weight loss, colon shortening, histopathological damage, inflammatory cytokine expression. RESULTS Protein restriction increased the severity of DSS-induced colitis compared to control diet (***p < 0.001). Mice fed arginine restricted diets exhibited increased colitis (*p < 0.05). Protein restriction induced significant alterations in gut microbiota composition, and antibiotic-mediated microbiota depletion partially ameliorated colitis severity, revealing a microbiota-dependent mechanism underlying disease exacerbation. CONCLUSIONS Our study demonstrates a complex interplay between dietary protein, epithelial mTORC1 signaling, and gut microbiota in modulating IBD pathogenesis and highlight the potential for targeted dietary strategies, including amino acid supplementation, to improve disease management in IBD patients.

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