The Early Origins of NAFLD in Humans and Non‐Human Primates

Abstract

Non‐Alcoholic Fatty Liver Disease (NAFLD) is now the most common liver disease worldwide in children and adults. Even more concerning is that the risk factors for NAFLD may start operating in early life. In the U.S., up to 25% of children are already overweight or obese entering kindergarten, and maternal obesity is consistently one of the most powerful predictors of pediatric obesity and its complications. NAFLD is currently estimated to occur in 25–50% of obese children with lifetime consequences, including liver NASH and hepatic carcinoma risk. Our group has spent the past decade studying developmental programming in humans, non‐human primates (NHP), and transgenic mouse models. We have shown that maternal Western‐Style Diet (WSD) in NHP mothers results in a NAFLD phenotype in the fetus, beginning in the early 3rd trimester. This phenotype persists in juveniles up to 14 months of age despite weaning to a healthy diet, and in the absence of obesity. Our compelling human data in neonates born to obese/Gestational Diabetic mothers demonstrate increased intrahepatic fat using MRI/MRS at 2 wks of life. However not everyone who is born to an obese mother develops disease, with other potential contributing factors particularly excessive maternal insulin resistance, hypoxia, and mitochondria dysfunction important in the fetal development of NAFLD. Our studies in obese NHP mothers using the anti‐oxidant resveratrol, may be able to mitigate some of these complications to prevent the early complications of maternal obesity on the developing liver. Interestingly, founding individual microbiota composition in infants reflects the maternal transfer during or immediately after birth. The intestinal microflora is different between individuals and its composition is largely dependent on a combination of genetics, diet and lifestyle choices. Although no single commensal bacteria species have been conclusively proven to provoke NAFLD, lack of certain bacterial species has been observed with human patients prone to or suffering from this disorder. In cross‐sectional studies comparing vaginally delivered, exclusively breast fed infants we have found a significant reduction in the early pioneering bacteria Gammaproteobacteria in 2 week old infants from obese mothers compared to infants born to normal weight mothers. Further, gnotobiotic transfer of stool from infants of obese mothers into germ‐free mice was associated with a significant reduction in IL‐10 producing anti‐inflammatory Treg cells, as well as CD3+CD4+ helper T‐cells and ER stress in the liver at 21 days post‐transplantation. These findings suggest that early commensal bacteria from obese human infants may be important in conditioning a developing immune system that educates inflammatory cells, leading to inflammation‐linked diseases, including NAFLD, a hypothesis we are currently exploring.Support or Funding InformationNIH‐NIDDK, ADA, and Bill Gates Foundation