Data_Sheet_1_L-Threonine Supplementation During Colitis Onset Delays Disease Recovery.docx

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.

膳食营养素可通过调节免疫应答、肠道菌群组成及上皮屏障稳定性影响肠道稳态，因此成为炎症性肠病（IBD）潜在的治疗辅助手段。已有多种营养素被证实可表现出保护性表型，但目前对于其中最具潜力的营养素，以及其发挥作用的最佳阶段，仍缺乏足够认知。为筛选出最具前景的治疗候选营养素，本研究对结肠炎发生过程中的结肠代谢组特征进行了表征。研究观察到，在葡聚糖硫酸钠（Dextran Sulfate Sodium, DSS）诱导的结肠炎模型小鼠体内，苏氨酸（Threonine, Thr）水平较对照组降低了一倍。随后，本研究分别在炎症反应启动阶段（DSS+Thr组）及炎症已建立阶段（DSS+Thr D8组）评估了补充苏氨酸的干预效果。各组结肠炎的进展速率与结肠炎模型对照组小鼠并无显著差异，但在疾病早期给予苏氨酸干预却表现出意外的有害作用：与对照组及DSS+Thr D8组小鼠相比，该组小鼠的恢复过程显著延迟。尽管DSS+Thr组小鼠的代谢组特征未出现明显改变，但其黏蛋白编码基因的表达及杯状细胞数量均发生异常，提示其黏液产生能力受损。此外，与DSS+Thr D8组相比，DSS+Thr组小鼠的白细胞介素-22（Interleukin-22, IL-22）分泌水平显著降低。综合来看，上述结果表明，在结肠炎诱导阶段补充苏氨酸会降低杯状细胞数量，并延缓小鼠的恢复周期。这一发现进一步凸显了深入探究苏氨酸补充疗法在炎症性肠病中应用价值的必要性。