炎症性肠病(IBD)的发病率和患病率在全球范围内逐渐上升。已知高脂饮食(HFD)会破坏肠道稳态并加重IBD,然而,潜在的机制在很大程度上仍然不确定。这里,在IBD患者和小鼠结肠炎模型中,观察到膳食脂肪摄入与疾病严重程度呈正相关.HFD诱导吲哚-3-乙酸(IAA)的显著降低并导致肠屏障损伤。此外,IAA补充增强肠粘蛋白硫酸化并有效缓解结肠炎。机械上,IAA上调参与粘蛋白硫酸化的关键分子,包括3'-磷酸腺苷5'-磷酸硫酸合酶2(Papss2)和溶质载体家族35成员B3(Slc35b3),3'-磷酸腺苷-5'-磷酸硫酸盐(PAPS)的合成酶和转移酶,通过芳烃受体(AHR)。更重要的是,AHR可以直接结合Papss2的转录起始位点。口服罗伊氏乳杆菌,可以产生IAA,有助于防止结肠炎和促进粘蛋白硫酸化,而缺乏iaaM基因(乳杆菌ΔiaM)和产生IAA的能力的改良罗伊乳杆菌菌株未能表现出这种作用。总的来说,IAA通过AHR-Papss2-Slc35b3途径增强肠粘蛋白硫酸化,有助于保护肠道平衡。
HFD可通过破坏肠道微生物组中的色氨酸代谢和降低IAA水平而导致结肠炎的发展。已显示补充IAA可缓解小鼠结肠炎并改善肠屏障功能。认为IAA可激活AHR上调Papss2和Slc35b3的表达,促进粘蛋白的硫酸化修饰,保护肠屏障。HFD,高脂肪饮食;AHR,芳烃受体;IAA,吲哚-3-乙酸;Papss2,3'-磷酸腺苷5'-磷酸硫酸合酶2;Slc35b3,溶质载体家族35成员B3。
The global incidence and prevalence of inflammatory bowel disease (IBD) are gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and murine colitis models is observed. A HFD induces a significant decrease in indole-3-acetic acid (IAA) and leads to intestinal barrier damage. Furthermore, IAA supplementation enhances intestinal mucin
sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin
sulfation, including 3\'-phosphoadenosine 5\'-phosphosulfate synthase 2 (Papss2) and solute carrier family 35 member B3 (Slc35b3), the synthesis enzyme and the transferase of 3\'-phosphoadenosine-5\'-phosphosulfate (PAPS), via the aryl hydrocarbon receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin
sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fail to exhibit such effects. Overall, IAA enhances intestinal mucin
sulfation through the AHR-Papss2-Slc35b3 pathway, contributing to the protection of intestinal homfeostasis.
A HFD can lead to the development of colitis by disrupting tryptophan metabolism in the gut microbiome and lowering levels of IAA. Supplementation with IAA has been shown to alleviate colitis in mice and improve intestinal barrier function. It is believed that IAA may activate the AHR to upregulate the expression of Papss2 and Slc35b3, promoting
sulfation modification of mucins and protecting the intestinal barrier. HFD, high-fat diet; AHR, aryl hydrocarbon receptor; IAA, indole-3-acetic acid; Papss2, 3’-phosphoadenosine 5’-phosphosulfate synthase 2; Slc35b3, solute carrier family 35 member B3.