| 摘要: | 發炎性腸道疾病 (inflammatory bowel disease, IBD) 與黏膜屏障損壞及過度發炎反應相關。研究發現 IBD 患者往往伴隨有肺部之疾病，因為腸道和呼吸系統擁有相似的黏膜免疫構造，因此腸道內的代謝物、病菌等會隨著血液及淋巴而使腸與肺相互影響，甚至提高患者肺部遭受感染之風險。色胺酸 (tryptophan, Trp) 經腸道菌代謝後產生芳香烴受體 (aryl hydrocarbon receptor, AhR) 配體，可活化 AhR 並促進 interleukin (IL)-22 分泌而維持腸屏障完整性，進而改善 IBD。目前尚未有研究探討 Trp 代謝物活化 AhR 路徑後，可否改善急性肺損傷 (acute lung injury, ALI)。故本實驗給予小鼠 Trp 補充後誘發腸炎及 ALI 以探討 Trp 與黏膜免疫之影響。實驗採用雄性 C57BL/6 小鼠，分為正常飲食組 (給予 AIN-93M 飼料) 與補充 Trp 飲食組 (以 AIN-93M 為基礎添加 0.5% (w/w) Trp)，3 週後給予 2% 葡聚醣硫酸鈉 (dextran sulfate sodium, DSS) 飲用水 5 天，再給予 5 天正常飲水以誘發腸炎。將腸炎引致成功的小鼠再依照是否誘發 ALI 分為下列四組：正常飲食腸炎組 (ND+Saline)、正常飲食腸炎加 ALI 組 (ND+LPS)、補充 Trp 飲食腸炎組 (TD+Saline)、補充 Trp 飲食腸炎加 ALI 組 (TD+LPS)。ALI 手術方式為氣管給予脂多醣 (lipopolysaccharide, LPS) 2 ?g/mg BW 並於 24 小時後犧牲。結果顯示誘發 ALI 之小鼠肺部受損程度顯著增加。而飼料補充 Trp 可活化肺部 AhR 路徑，促進 zonula occludens (ZO-1)、claudin-5 表現，降低肺病理切片受損。因此可推論飲食中給予 Trp 補充可減輕 LPS 引致腸炎小鼠之 ALI。
Inflammatory bowel disease (IBD) leads to damage of the mucosal barrier and excessive inflammation. Patients with IBD often have concurrent lung diseases. Since the inner lining structure of the mucosal layers of the intestinal and respiratory systems are similar, the gut microbiota or its byproducts can affect both organs through the circulating or lymphatic systems. Tryptophan (Trp), an essential amino acid, is processed by gut microbiota and produces aryl hydrocarbon receptor (AhR) ligands. These ligands can activate the AhR pathway, promote the secretion of interleukin (IL)-22 from the intestine, and preserve the integrity of the intestinal barrier, thus improve IBD. In this study, we investigated the effects of Trp on mucosal immunity in colitis mice with acute lung injury (ALI). Colitis was induced by adding dextran sulfate sodium (DSS) in the drinking water. ALI was induced by administering 2 ?g/mg BW of lipopolysaccharide (LPS) through the trachea. Four experimental groups were included in the study: a normal diet colitis group with saline administered (ND+Saline), a normal diet colitis group with ALI (ND+LPS), a Trp diet colitis group with saline (TD+Saline), and a Trp diet colitis group with ALI (TD+LPS). The mice were sacrificed 24 hours after the onset of ALI. The results showed that DSS resulted in inflammation, oxidative stress, and structural damage in the colon. Following induction of ALI in colitis mice, neutrophil populations, and levels of inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) increased. In the lung tissues, the expression of mRNA associated with TLR4 pathway, RAS system, and inflammatory cytokines elevated, leading to increased oxidative stress. Additionally, tight junction protein levels in the lung tissues decreased, further aggravate lung injury. Dietary supplementation of Trp decreased circulating pro-inflammatory cytokines and LPS levels, alleviated intestinal inflammation through Trp metabolites produced, which activated the AhR/IL22/IL22R pathway. Attenuated inflammation, oxidative stress, and damage to the epithelial structure in the lungs were also noted when Trp was administered. These findings provide evidence and imply that Try may be considered as a potential therapeutic agent to treat IBD patients with lung infections. |
