Lactobacillus rhamnosus GG 對於食源性肥胖小鼠之腸道菌相 調節、體內瘦體素敏感度度與能量量代謝的影響

Abstract

肥胖現今已成為全球公共衛生中一大議題，且與代謝症候群及台灣十大死因呈高度相關。瘦體素（leptin）由脂肪細胞分泌，能夠刺激腦部下視丘（hypothalamus）產生飽足感，在腦部發揮抑制食慾的功能。雖然肥胖者瘦體素濃度普遍較高，但因肥胖者的瘦體素受器敏感度降低，產生瘦體素抗性（resistance），故無法依靠瘦體素減低熱量攝取而降低體重。Suppressor of cytokine signaling（SOCS）蛋白為瘦體素的負調控劑，它透過抑制signal transducer and activator of transcription-3（STAT3）的磷酸化來避免下視丘中瘦體素濃度過高。鼠李糖乳桿菌（Lactobacillus rhamnosus GG, LGG）會參與調控SOCS3表現。本實驗目的為探討LGG與宿主之間能量代謝的關係。本研究使用八周齡C57BL/6J品系公鼠，隨機分成四組後，餵飼高脂飼料誘導肥胖與瘦體素抗性，其中兩組每日管餵鼠李糖乳桿菌108與1010 CFU，連續餵食10周後，體重與攝食量並無顯著差異，肝臟切片顯示給予LGG能夠預防高脂飲食所造成的脂肪肝。餵食10周後以腹腔注射人工瘦體素，並發現LGG能夠提高瘦體素敏感度，在測量下視丘中SOCS3之後，給予高劑量LGG小鼠，注射食鹽水之後，SOCS3表現低；在注射人工瘦體素之後，SOCS3表現量立即升高，表示LGG會使下視丘仍對於瘦體素保持高度敏感。迴腸組織切片顯示L. rhamnosus GG的給予，能夠使小腸腔內絨毛保持長度，絨毛長度與腺窩比例保持於健康狀態，不被高脂飲食所影響。經由變性梯度膠體電泳與次世代定序（next-generation sequencing）分析之結果顯示，飲食的不同會立即改變腸道微生物的組成，食用高脂飼糧會使分解多醣類微生物增加，使得宿主吸收額外的熱量，造成肥胖。而L. rhamnosus GG能夠改變腸道菌相，使得腸內益菌增加，維持腸道健康。經由此研究，能夠更加闡明益生菌抗肥胖功能的調控機制，並改善人類與動物因肥胖所引起相關疾病的發生，也讓微生物與能量代謝的關係有更進一步的發現與突破。

Obesity, which has reached epidemic proportions globally, may induce metabolic syndromes in relation to cause of death. Leptin can suppress food intake and thereby lead to weight loss through binding leptin receptor on the hypothalamus. Suppressor of cytokine signaling (SOCS) proteins is one of the mediator reducing leptin sensitivity by inhibition of the phosphorylation of signal transducer and activator of transcription-3 (STAT3), an intracellular leptin-signaling mediator. Lactobacillus rhamnosus GG (LGG) was proved to be highly correlated with SOCS3. The purpose of this study is to expand the comprehension of the relation between L. rhamnosus GG and host energy metabolism. 8-week-old of C57BL/6J male mice were devided into treatment groups, ND (normal diet / PBS treatment) , HFD (high-fat diet / PBS treatment), LL (high-fat diet / 108 CFU L. rhamnosus GG) and LH (high-fat diet / 1010 CFU/mL L. rhamnosus GG). The grow performance, leptin sensitivity, and gut microbiota composition of the mice were assayed. The results show that, L. rhamnosus GG may decrease lipid deposition, high-dosed L. rhamnosus GG effectively maintained leptin sensitivity. In LH group, their body weight dropped off more clearly after leptin i.p. injection than saline i.p. injection. Also, the levels of serum leptin were significantly higher in L. rhamnosus GG -treated mice than those in the PBS-treated mice (p<0.05). In addition, leptin-injected mice presented significantly higher expression of SOCS-3 in hypothalamus than saline-injected mice (p<0.001) in LH group. Finally, L. rhamnosus GG could establish a healthy intestinal environment to prevent the damage cause by pathogens. Ileum sections showed that L. rhamnosus GG -treated mice had significant longer villi length and villi length-crypt depth ratio than HFD group. In conclusion, L. rhamnosus GG plays an important role in modulating serum leptin levels and giving rise to the enhancement of leptin sensitivity and intestinal health in diet-induced obesity.