本研究では, 「生体内シグナル伝達分子としての胆汁酸」を介した個別化予防・治療へのアプローチを目指し, 遺伝子的なバックグラウンドが異なる2系統のマウスの肥満・糖尿病発症の差異に関与する, 腸内細菌−胆汁酸組成経路による胆汁酸応答性の違いを検討した。高脂肪食由来肥満モデルマウスで胆汁酸を投与したところ, A系統では肥満および糖尿病を抑制したのに対し, B系統では抑制せず, 2系統による胆汁酸応答性の違いを見出した。次に, 胆汁酸代謝を検討した結果, A系統ではB系統よりも胆汁酸プール量が多く, 胆汁酸量に相違が見られることが明らかとなった。さらに胆汁酸の組成解析の結果, A系統では胆汁酸投与によりTGR5のリガンドとなるDCAの抱合型であるTDCAが肝臓内に増加していた。胆汁酸組成の違いが抗肥満・糖尿病をもたらすメカニズムには, 褐色脂肪でのエネルギー代謝亢進が関与していた。褐色脂肪はGPCRであるTGR5を介したエネルギー代謝亢進が我々の研究で確認されているが, A系統で血中に増加した胆汁酸がTGR5を介しエネルギー代謝を亢進したと考えられた。腸内細菌との相互作用を検討するため, 胆汁酸投与で肥満・糖尿病抑制効果の見られたA系統マウスに抗生物質投与した実験を行なった。胆汁酸の脱抱合・脱水酸化はグラム陽性菌の胆汁酸が行っており, その作用により胆汁酸が2次胆汁酸に変換される。腸内細菌のうちグラム陽性菌を殺菌する抗生物質を投与した群では, 胆汁酸投与による抗肥満・抗糖尿病作用が打ち消された。現在, 個別化予防・治療へのアプローチ構築を目指し, 詳細な腸内細菌叢解析と胆汁酸組成解析との相互作用分析を進めている。
In this study, we aim to approach individualized prevention and treatment via "bile acid as a signaling molecule in vivo", using two strains of mice with different genetic background and differentiate obesity/diabetes responsiveness. Bile acid was administered in diet induced obesity model mouse. In the strain A, bile acid administration suppressed diet induced obesity and diabetes, whereas it did not inhibit it in the strain B. We found differences in bile acid responsiveness between the two strains. Next, as a result of investigating bile acid metabolism, it was revealed that in the A strain, the amount of bile acid pool is larger than that of the B strain, and there is a difference in the amount of bile acid. In addition, as a result of composition analysis of bile acids, in the strain A, TDCA, which is a conjugated form of DCA as a ligand for TGR 5, increased in the liver by administration of bile acid. Enhanced energy metabolism in brown adipose has been involved in the mechanism by which the difference in bile acid composition may prevent diet induced obesity and diabetes. Previously we found that bile acids are ligands for G-protein-coupled receptor TGR5. In the strain A, increased bile acids in blood may promote energy metabolism in brown adipose tissue via TGR5. In order to investigate the interaction between microbiota and bile acids, experiments were conducted in which antibiotics were administered to the strain A mice. Bile acids are deconjugated and dehydroxylated by gram-positive microbiota, and bile acids are converted into secondary bile acids. The group which administered antibiotics reduced gram positive bacteria counteracted the anti-obesity/antidiabetic effect by administration of bile acid. Currently, we are advancing analysis of interaction between microbiota and bile acid composition analysis with the aim of constructing approaches to individualization prevention and treatment.