Imbalance in gut microbes from babies born to obese mothers increases gut permeability and myeloid cell adaptations that provoke obesity and NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease affecting nearly 40% of obese youth and up to 10% of the general pediatric population. A key aspect of NAFLD pathogenesis is proinflammatory hepatic macrophage activation and hepatic recruitment of circulating monocytes, which originate from the bone marrow. In neonates, the activation and polarization of myeloid immune cells are normally shaped in part by systemic factors derived from intestinal microbiota during the first 1000 days of life. Perturbations of the gut microbiome, and in turn the metabolites and bacterial products released systemically, can affect the functional phenotype of these immune cells. Evidence in germ-free mice has shown that fecal microbial transfer from obese mice or obese human donors promotes obesity and inflammation in the recipients, suggesting a direct role for the gut microbiome in promoting obesity and possibly NAFLD. Indeed, patients suffering from NAFLD show evidence for dysbiosis, increased gut permeability, and changes in bile acids that drive the progression of hepatic inflammation toward non-alcoholic steatohepatitis (NASH), the more severe form of the disease. Compared with infants born to normal-weight mothers, we previously showed that the gut microbiome from neonates born to obese mothers is compositionally distinct. However, whether this alteration in early gut microbiota in infants born to obese mothers can cause inflammatory processes that initiate development of NAFLD or obesity is unknown. How these alterations contribute to long-term immune cell mediated liver inflammation and progression of NAFLD needs to be determined. Our recently published work (Soderborg et al., Nat Commun 9:4462) demonstrates a causative role of early life microbiome dysbiosis in infants born to mothers with obesity in novel pathways that promote developmental programming of NAFLD.

Figure 1. FIGURE 1: Proposed mechanism by which dysbiosis in infants of obese mothers predisposes offspring to non-alcoholic fatty liver disease (NAFLD) and obesity.

Altered gut microbes in the infant of an obese mother cause altered bile acid metabolism, increased short-chain fatty acid production and a leaky gut with bacterial translocation. In the bone, infant dysbiosis results in poorly functioning recruited macrophages. In the liver, the inflammation caused by translocated bacteria remains unresolved due to hyporesponsive recruited macrophages. Exposure to a secondary hit, such as a Western-style diet, results in hepatic steatosis and obesity.

Figure 2. FIGURE 2: Representative photomicrographs of picrosirius red staining in the livers from mice colonized with stool from 2-week-old infants born to (A) normal-weight and (B) obese mothers.

Black arrows indicate bile ducts. BD, bile duct; PV, portal vein. Sections of liver were collected and fixed in 10% formaldehyde and transferred to 70% ethanol until embedded in paraffin and processed on slides for picrosirius red staining. All staining was completed by the University of Colorado Cancer Center Research Histology Shared Resource. Images were captured on an Olympus BX53 microscope using cellSens software and DP27 camera (Olympus). All animal studies were approved by University of Colorado Institutional Animal Care and Use Committee (protocol number 00309).