植物乳桿菌改善potassium oxonate誘發大鼠高尿酸血症透過調節腸道菌群與分子作用機轉

高尿酸血症為第二大代謝疾病，與許多慢性疾病密切相關。長期高血液尿酸會引起腸道菌群失衡，進而導致免疫功能紊亂，加重了疾病之進展。過去文獻指出，乳桿菌具有抗氧化、調節免疫和抗發炎等功效。此外，乳桿菌能調節腸道菌群組成，且參與嘌呤代謝。因此，本篇研究利用氧嗪酸鉀 (potassium oxonate, PO) 誘導動物高尿酸血症模式，來評估植物乳桿菌 (Lactobacillus plantarum) 對於改善高尿酸血症之功效性，以及其對腸道菌相和分子機轉之影響。將48隻雄性SD大鼠隨機分為六組 (n=8/組)：控制組 (control, C)、高尿酸誘導組 (hyperuricemia control, HC)、高尿酸誘導大鼠給予低劑量之L. plantarum (HC + low dose, HC+LD)、高尿酸誘導大鼠給予中劑量之L. plantarum (HC + medium dose, HC+MD)、高尿酸誘導大鼠給高劑量之L. plantarum (HC + high dose, HC+HD) 以及高尿酸誘導大鼠給予別嘌呤醇 (HC + allopurinol, HC+AP)。除了控制組外，所有組別以腹腔注射PO (250 mg/kg rat) 為期四週之誘導。本研究結果顯示，高尿酸血症大鼠補充L. plantarum後，可透過抑制肝臟XOD活性，有效降低血液尿酸濃度，且顯著增加尿液尿酸濃度。由腸道菌相之結果顯示，L. plantarum能提升菌群豐富度、增加與SCFAs相關之菌群，並提高SCFAs含量。此外，還降低與發炎反應呈正相關之菌株，更能改善高尿酸血症相關菌群豐富度。在分子機轉上，腎臟及迴腸組織基因結果皆顯示，給予L. plantarum可提升ABCG2之基因表現 (尿酸分泌)，且降低GLUT9之基因表現 (尿酸再吸收)。另外，發現迴腸中TNF-α、IL-6及IL-1β之基因表現亦降低 (促發炎)。綜合上述結果得知，藉由補充L. plantarum能逆轉高尿酸血症相關菌群組成，以及提高糞便中SCFAs含量。因此，減輕高尿酸血症所造成之發炎反應，從而降低肝臟XOD活性，並調節腎臟及腸道中尿酸鹽轉運蛋白之表達。總結，L. plantarum可有效預防PO誘導之高尿酸血症和調節腸道菌群之作用。

Hyperuricemia has become the second most common metabolic disease and been closely associated with many chronic diseases. Meanwhile, elevated levels of serum uric acid cause gut dysbiosis, leading to immune dysfunction and aggravates disease progression. Previous studies have shown that Lactobacillus has anti-oxidant, immunoregulatory and anti-inflammatory effects. In addition, Lactobacillus regulates the gut microbiota and participates in purine metabolism. Therefore, we investigated the anti-hyperuricemia effects of L. plantarum as well as its gut microbiota and molecular mechanism in PO-induced hyperuricemia in SD rats. Forty-eight male SD rats were randomly divided into six groups (n=8/group): control (C), hyperuricemia control (HC), HC + L. plantarum of low dose (HC+LD), HC + L. plantarum of medium dose (HC+MD), HC + L. plantarum of high dose (HC+HD), and HC + allopurinol (HC+AP). All groups excluding control group were induced by intraperitoneal injection of PO (250 mg/kg rat) for four weeks. The results showed that hyperuricemia rats administrated with L. plantarum have significantly decreased serum uric acid levels by inhibiting liver XOD activity and significantly increased urine uric acid levels. In the gut microbiota, L. plantarum increased the diversity of the microbiota, SCFAs-related bacteria, and the content of SCFAs. Furtheromore, L. plantarum reduced the strains that were positively correlated with the inflammation and ameliorated the abundance of bacteria related to hyperuricemia. In the molecular mechanism, L. plantarum increased the expression of ABCG2 gene (reabsorption) and decreased the expression of GLUT9 gene (secretion) in the kidney and ileum. Furthmore, in the ileum the gene expressions of TNF-α, IL-6, and IL-1β (pro-inflammatory) were downregulated. These results demonstrated that supplementation with L. plantarum can reversed the composition of the gut microbiota associated with hyperuricemia and increase SCFAs in the feces. Therefore, it can reduce the inflammatory response caused by hyperuricemia which decreases the activity of liver XOD and regulates the expression of the urate transporter in the kidney and ileum. In conclusion, L. plantarum is effective in preventing PO-induced hyperuricemia and modulating the gut microbiota.