背景: 隨著兒童肥胖的流行，非酒精性脂肪肝疾病成為全球新興的健康問題，目前仍無美國食品藥品管理局核准治療非酒精性脂肪肝炎之藥物。腸道菌叢及其代謝物在肥胖及非酒精性脂肪肝疾病的發生扮演重要角色。柔嫩梭狀桿菌是大腸內盛產丁酸鹽的腸道菌之一，研究顯示丁酸鹽藉由與G蛋白偶聯受體(GPR)作用產生抗發炎及免疫調節功能。然而，丁酸鹽與G蛋白偶聯受體在非酒精性脂肪肝疾病致病機轉及治療扮演的角色仍不明確，本研究目的是探討腸道菌叢、短鏈脂肪酸以及G蛋白偶聯受體可能提供青少年非酒精性脂肪肝疾病致病機轉及治療的新知。
目標: 探討柔嫩梭狀桿菌、丁酸鹽及G蛋白偶聯受體在青少年非酒精性脂肪肝疾病扮演之角色。
方法: 此橫斷性研究於成大醫院收案12-18歲肥胖且具非酒精性脂肪肝疾病和正常體重青少年(對照組)。非酒精性脂肪肝疾病組收案條件為肥胖且超音波檢查顯示脂肪肝者，排除條件為罹患與非酒精性脂肪肝疾病無關之急性或慢性系統性疾病、於收案前一個月內曾服用抗生素或益生菌者。收集受試者糞便檢體，使用定量即時聚合酶連鎖反應分析柔嫩梭狀桿菌相對菌量，並以高效液相色谱法檢測糞便丁酸鹽濃度，檢測血漿代謝指標及細胞激素。同時分離出周邊血單核細胞以定量逆轉錄聚合酶連鎖反應分析其GPR41及GPR43 mRNA表現量。
結果: 本研究自2019年7月起已收案16位非酒精性脂肪肝疾病及9位體重正常之青少年。非酒精性脂肪肝疾病組之糞便柔嫩梭狀桿菌菌量及丁酸鹽濃度均顯著低於對照組(P = 0.003於柔嫩梭狀桿菌比較; P = 0.02於丁酸鹽比較)。此外，非酒精性脂肪肝疾病組之血漿IL-10低於對照組(P = 0.06)。根據超音波檢測結果，嚴重脂肪肝組之糞便柔嫩梭狀桿菌菌量顯著低於對照組(P = 0.01)。隨著超音波檢測脂肪肝嚴重度增加，糞便丁酸鹽濃度有逐漸下降之趨勢(P = 0.05)。糞便丁酸鹽濃度和血漿IL-10呈正相關(rs = 0.50, P = 0.007)，與身體質量指數呈負相關(rs = -0.42, P = 0.02)。
結論: 非酒精性脂肪肝疾病組之糞便柔嫩梭狀桿菌菌量及丁酸鹽濃度均顯著低於對照組。IL-10可能與丁酸鹽於非酒精性脂肪肝疾病的抗發炎效果有關。關於柔嫩梭狀桿菌及丁酸鹽在非酒精性脂肪肝疾病之抗發炎機轉有待後續研究進一步探討。

Background: Concurrent with the epidemic of pediatric obesity, nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health problem worldwide. No Food and Drug Administration-approved treatment for non-alcoholic steatohepatitis (NASH) currently exists. Intestinal microbiota and short-chain fatty acids (SCFAs) play important roles in the development of obesity and NAFLD. Faecalibacterium prausnitzii is one of the most abundant butyrate-producing bacteria in the colon. Butyrate has been reported to modulate immune and inflammatory responses via the interactions with G protein-coupled receptors (GPRs). However, the role of SCFA-GPR axis in the pathogenesis and treatment of NAFLD is still unclear. Our investigation of microbiota-SCFA-GPR axis may provide a new insight of the pathogenesis and treatment of adolescent NAFLD.
Aims: This study aimed to explore the role of F. prausnitzii-butyrate-GPR axis in adolescent NAFLD.
Methods: In this cross-sectional study, obese adolescents aged 12-18 years with sonographic evidence of fatty liver (NAFLD group) and normal-weight healthy adolescents (control group) were recruited from the National Cheng Kung University Hospital. Eligibility criteria of the NAFLD group include obesity with sonographic evidence of fatty liver. Exclusion criteria include any acute or chronic systemic diseases unrelated to NAFLD, and use of antibiotics or probiotics within one month preceding the enrollment. Overnight fasting blood samples and fecal samples were collected. Fecal F. prausnitzii relative quantity was measured by quantitative real-time polymerase chain reaction analysis, and SCFAs were detected by high performance liquid chromatography. Plasma metabolic parameters and cytokine profiles were examined, and peripheral blood mononuclear cells were collected for GPR41 and GPR43 mRNA expression by quantitative reverse transcription- polymerase chain reaction.
Results: Sixteen obese adolescents with sonographic evidence of fatty liver (NAFLD group) and nine normal-weight volunteers (control group) have been enrolled since July, 2019. The NAFLD group had significantly lower fecal F. prausnitzii abundance (P = 0.003) and lower butyrate concentration (P = 0.02) than the control group. Furthermore, the NAFLD group had lower plasma IL-10 concentration than control group (P = 0.06). According to the sonographic grading of fatty liver, fecal F. prausnitzii abundance of the severe fatty liver group was significantly lower than the normal group (P = 0.01). There was a trend that the fecal butyrate concentrations gradually decreased as the fatty liver became more severe (P = 0.005). Fecal butyrate concentration was positively associated with plasma IL-10 level (rs = 0.50, P = 0.007), but butyrate correlated negatively with body mass index (rs = -0.42, P = 0.02).
Conclusion: Lower fecal F. prausnitzii abundance and lower butyrate concentration was associated with adolescent NAFLD. IL-10 may play a role in the anti-inflammatory effect of butyrate in NAFLD. Further studies are needed to clarify the anti-inflammatory mechanism of F. prausnitzii and butyrate in NAFLD.

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