近年、わが国においても非アルコール性脂肪肝炎（NASH）が増加している。脂肪肝は1500万症例といわれ、NASHに進行し、さらに肝硬変や肝細胞癌などの重大なアウトカムを引き起こす公衆衛生学的にも治療および予防が重要な疾患である。また、NASHは有効な治療法が確立されていないアンメットメディカルニーズの高い疾患であり、副作用がなく有効な治療法が切実に求められている。本研究では、複数の天然物由来機能性物質のNASH（非アルコール性脂肪肝）への効果を検討し、メタボリックシンドロームの抑制を介した健康長寿促進の新規物質の発見と新規メカニズム解明を目指した。将来ヒトへの結果の還元を目指すため、よりヒトのNASHモデルに近い食事誘導性NASHモデルを用いた動物実験を行ない、複数の天然物由来機能性物質を22週間投与した。この結果、NASH予防効果として肝臓中脂質蓄積抑制や線維化抑制が見られた機能性物質を複数特定した。我々の新規仮説である腸内細菌・胆汁酸相互作用によるメカニズム解明のため、胆汁酸組成解析および腸内細菌叢解析を実施した。この結果、腸内細菌が代謝し、より毒性の強い二次胆汁酸が糞便中あるいは肝臓中に劇的に減少する機能性物質を発見した。より詳細なメカニズムの発見のため肝臓の遺伝子網羅的発現解析を胆汁酸応答遺伝子発現差異を中心に実施し、腸内細菌や胆汁酸組成解析の結果と統合的にオミクス解析を進めている。本研究では、アンメットニーズの高いNASHの予防に関して、腸内細菌叢の制御と胆汁酸組成相互作用という新規メカニズムによる予防方策を打ち出した。また、本研究で検討した複数の機能性物質は異なるメカニズムでNASHの脂肪蓄積や線維化を抑制しており、多因子疾患であるNASHの段階別あるいは個人の症状に対応し機能性物質を組み合わせる個別化医療への応用可能性も示唆している。本研究の一部の成果は海外国際学術誌にアクセプトされた。
In recent years, non-alcoholic fatty liver (NASH) has been increasing in worldwide includes Japan. Fatty liver, with 15 million cases, is a public health disease that has progressed to NASH and has serious outcomes such as cirrhosis and hepatocellular carcinoma, and is important for treatment and prevention. In addition, NASH is a disease with a high unmet medical need for which no effective treatment has been established, and an effective treatment without side effects is strongly needed. In this study, we investigated the effects of several natural functional substances on NASH, and aimed to discover novel substances that promote healthy longevity through the inhibition of metabolic syndrome and elucidate novel mechanisms. In order to reduce the results to humans in the future, we conducted animal experiments using a diet-inducible NASH model that is more similar to the human NASH model and administered several natural functional substances for 22 weeks. As a result, we identified several functional substances that prevented NASH by inhibiting lipid accumulation and fibrosis in the liver. In order to clarify our novel hypothesis of the mechanism of gut-bacteria-bile acid interaction, we conducted bile acid composition analysis and gut microbiota analysis. As a result, they found a functional substance that was metabolized by gut microbiota and dramatically reduced the more toxic secondary bile acids in the feces or in the liver. In order to discover more detailed mechanisms, we are conducting comprehensive gene expression analysis of the liver, focusing on bile acid-responsive gene expression differences, and integrated omics analysis with the results of intestinal bacteria and bile acid composition analysis. In this study, we proposed a novel mechanism for the prevention of NASH, which has a high unmet need, by regulating the gut microbiota and interacting with the bile acid composition. In addition, the multiple functional substances examined in this study suppressed fat accumulation and fibrosis of NASH by different mechanisms, suggesting the possibility of application to personalized medicine that combines functional substances in response to individual symptoms or stage of NASH, a multifactorial disease. Some of the results of this study have been accepted for publication in international academic journals.