益生菌介入對順鉑誘導之慢性腎損傷的代謝體學與腸道菌相之影響

順鉑是一種常用的抗癌化療藥物，卻伴隨顯著嚴重的腎毒性傷害。近年研究指出，腸道菌群組成與腎臟健康息息相關，兩者藉由「腸-腎軸」機制互相調控，形成動態回饋循環。研究證實，益生菌具有抗發炎、抗氧化、調節腸道菌相等能力。本研究旨在探討補充混合益生菌 (Lactobacillus reuteri與Clostridium butyricum MIYAIRI 588, LCs)對順鉑誘導腎毒性大鼠之腸道菌相、腎功能與代謝體變化的影響。我們於順鉑施打前10天每日管餵LCs直至實驗第24天，並於實驗第1、8、15、22天施打順鉑5 mg/kg，大鼠於第25天犧牲。結果顯示，補充LCs可以 (1) 減緩順鉑誘導的體重與攝食量下降，明顯改善腎臟組織病理變化與血清腎功能指標，免疫球蛋白含量、胸腺相對重量顯著回升以及降低血液吲哚硫酸濃度；(2) 具有改善順鉑誘導之腎臟細胞凋亡與細胞焦亡的潛力、降低氧化壓力及調降p16/p21/p53等老化蛋白表現的趨勢，並在部分鐵凋亡蛋白表現上顯現抑制效果。代謝體分析顯示，順鉑改變腎臟與糞便的代謝物譜，干擾多條代謝途徑如色胺酸、嘌呤與嘧啶代謝；補充LCs後，可逆轉部分有害代謝物如尿酸、pseudouridine與p-cresol sulfate的累積，恢復保護性代謝物如IAA (Indole-3-acetic acid)與IPA (Indole-3-propionic acid)。腸道菌相分析顯示，順鉑顯著降低厚壁菌門與多種共生菌如Romboutsia與Muribaculaceae的豐富度，增加變形菌門與Bifidobacterium，而LCs則可調整腸道菌群結構來改變優勢菌的相對豐度。整合分析發現，部分菌屬與代謝物具明顯正相關，顯示腸道菌群組成與代謝體水平之間具有交互作用關係。綜合以上結果，本研究證實益生菌LCs對順鉑誘導之腎毒性具有保護作用，其作用機制可能與優化腸道菌群結構，進而調控代謝物的生成與轉化有關。

Cisplatin is a commonly used chemotherapeutic agent; however, it is accompanied by significant and severe nephrotoxic effects. Recent studies have indicated that the composition of gut microbiota is closely associated with kidney health, with both interacting through the “gut-kidney axis” in a dynamic feedback loop. Probiotics have been shown to possess anti-inflammatory, antioxidant, and microbiota-regulating properties. This study aimed to investigate the effects of supplementing with a mixed probiotic formulation (Lactobacillus reuteri and Clostridium butyricum MIYAIRI 588, LCs) on gut microbiota composition, kidney function, and metabolomic changes in a rat model of cisplatin-induced nephrotoxicity. LCs were administered by daily oral gavage for 10 days before the first cisplatin injection and continued until day 24 of the experiment. Cisplatin (5 mg/kg) was administered intraperitoneally on days 1, 8, 15, and 22, and the rats were sacrificed on day 25. The results showed that LCs supplementation could: (1) Attenuate cisplatin-induced reductions in body weight and food intake; significantly improve renal histopathological changes and serum renal function markers; increase immunoglobulin levels and thymus-to-body weight ratio; and reduce blood indoxyl sulfate concentrations. (2) Demonstrate potential to alleviate cisplatin-induced renal apoptosis and pyroptosis; reduce oxidative stress; and downregulate the expression of aging-related proteins such as p16, p21, and p53, with partial inhibition of ferroptosis-related protein expression.Metabolomic analysis revealed that cisplatin altered the metabolic profiles of kidney and fecal samples, disrupting multiple pathways such as tryptophan, purine, and pyrimidine metabolism. After LCs supplementation, the accumulation of harmful metabolites such as uric acid, pseudouridine, and p-cresol sulfate was reversed, while levels of protective metabolites such as IAA (Indole-3-acetic acid) and IPA (Indole-3-propionic acid) were restored. Gut microbiota analysis showed that cisplatin significantly decreased the abundance of Firmicutes and various commensal genera such as Romboutsia and Muribaculaceae, while increasing the abundance of Proteobacteria and Bifidobacterium. LCs supplementation altered the structure of the gut microbiota and modulated the relative abundance of dominant genera.Integrative analysis revealed strong positive correlations between specific bacterial taxa and metabolites, suggesting an interactive relationship between gut microbial composition and the host metabolome.In conclusion, this study demonstrates that the probiotic combination LCs confers protective effects against cisplatin-induced nephrotoxicity, potentially through modulation of gut microbiota composition and regulation of metabolite production and transformation.