Wesolowski Stephanie R, Kasmi Karim C El, Jonscher Karen R, Friedman Jacob E
Department of Pediatrics, Section of Neonatology, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, MS 8106, Aurora, Colorado 80045, USA.
Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, MS 8106, Aurora, Colorado 80045, USA.
Nat Rev Gastroenterol Hepatol. 2017 Feb;14(2):81-96. doi: 10.1038/nrgastro.2016.160. Epub 2016 Oct 26.
Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.
母体环境的变化导致子宫内环境改变，可能会对胎儿造成细微损害，增加其一生的疾病风险和/或在儿童期及以后加速疾病发展。特别令人担忧的是，非酒精性脂肪性肝病（NAFLD）在儿童和成人中的患病率正在迅速上升，且被诊断出的年龄越来越小，这表明其起源于生命早期。大量针对人类和非人类灵长类动物的证据表明，母体营养会影响胎盘和胎儿组织，导致肝脏代谢、线粒体功能、肠道微生物群、肝脏巨噬细胞激活以及出生后对非酒精性脂肪性肝炎（NASH）的易感性发生持续变化。子宫内的有害暴露包括胎儿缺氧、营养供应增加、炎症以及肠道微生物群改变，这些可能产生代谢线索，包括脂肪酸、代谢物、内毒素、胆汁酸和细胞因子，它们会持续使婴儿肝脏易患NAFLD，并增加对NASH的易感性。与早期疾病途径的机制联系可能涉及脂质代谢改变、线粒体功能障碍、肠道微生物拓殖、巨噬细胞编程以及表观遗传变化，这些变化会改变肝脏微环境，增加肝脏损伤风险。在本综述中，我们讨论了母体、胎儿、新生儿和婴儿期的暴露如何提供发育线索和机制，以帮助解释NAFLD的加速发展和疾病患病率的增加。临床和临床前模型中确定的机制为预防和干预提供了重要机会，可能会减缓下一代中NAFLD流行趋势的增长。
