Abstract
Dietary nutrients have emerged as potential therapeutic adjuncts for inflammatory bowel disease (IBD) given their impact on intestinal homeostasis through the modulation of immune response, gut microbiota composition and epithelial barrier stability. Several nutrients have already been associated with a protective phenotype. Yet, there is a lack of knowledge toward the most promising ones as well as the most adequate phase of action. To unveil the most prominent therapy candidates we characterized the colon metabolic profile during colitis development. We have observed a twofold decrease in threonine levels in mice subjected to DSS-induced colitis. We then assessed the effect of threonine supplementation in the beginning of the inflammatory process (DSS + Thr) or when inflammation is already established (DSS + Thr D8). Colitis progression was similar between the treated groups and control colitic mice, yet threonine had a surprisingly detrimental effect when administered in the beginning of the disease, with mice displaying a delayed recovery when compared to control mice and mice supplemented with threonine after day 8. Although no major changes were found in their metabolic profile, DSS + Thr mice displayed altered expression in mucin-encoding genes, as well as in goblet cell counts, unveiling an impaired ability to produce mucus. Moreover, IL-22 secretion was decreased in DSS + Thr mice when compared to DSS + Thr D8 mice. Overall, these results suggest that supplementation with threonine during colitis induction impact goblet cell number and delays the recovery period. This reinforces the importance of a deeper understanding regarding threonine supplementation in IBD.
Highlights
Inflammatory bowel disease (IBD) is a complex debilitating disorder of the gastrointestinal tract which comprises both Crohn’s disease and ulcerative colitis
To characterize the colon metabolic profile during colitis development, metabolites present on colonic extracts of mice prior and after 5 days of dextran sulfate sodium (DSS)-induced colitis were analyzed by Nuclear Magnetic Resonance (NMR) (Figure 1A)
Univariate analyses performed on the metabolites allow to discriminate ADP and threonine as significantly altered from day 0 to day 5 (Figures 1C,D)
Summary
Inflammatory bowel disease (IBD) is a complex debilitating disorder of the gastrointestinal tract which comprises both Crohn’s disease and ulcerative colitis. Recent evidence has revealed that fiber-enriched diets promote protection against IBD development, since dietary fiber is mainly fermented by intestinal microbiota into short-chain fatty acids (SCFAs), such as butyrate, acetate and propionate (den Besten et al, 2013). The protective properties of these metabolites are widely described by their impact on immune cell activation and epithelial barrier stability (Kelly et al, 2015; Macia et al, 2015), with decreased levels of SCFAs being found in colon samples from IBD patients (HudaFaujan et al, 2010). Using distinct animal models of colitis, diets enriched in threonine, serine, proline and cysteine, given before and throughout disease development, have been shown to restore mucin synthesis and stabilization of gut microbiota (Faure et al, 2006). Clinical signs of colitis were monitored daily and scored as a disease activity index (DAI; Supplementary Table S1). Crypts cut longitudinally from crypt opening to bottom were analyzed
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