Maternal Diet Alters Trained Immunity in the Pathogenesis of Pediatric NAFLD.

Karen R. Jonscher ,Jesse Abrams,Jacob E. Friedman

doi:10.33696/immunology.2.061

Abstract

Pediatric nonalcoholic fatty liver disease (NAFLD) affects 1 in 10 children in the US, increases risk of cirrhosis and transplantation in early adulthood, and shortens lifespan, even after transplantation. Exposure to maternal obesity and/or a diet high in fat, sugar and cholesterol is strongly associated with development of NAFLD in offspring. However, mechanisms by which “priming” of the immune system in early life increases susceptibility to NAFLD are poorly understood. Recent studies have focused on the role “non-reparative” macrophages play in accelerating inflammatory signals promoting fibrogenesis. In this Commentary, we review evidence that the pioneering gut bacteria colonizing the infant intestinal tract remodel the naïve immune system in the offspring. Epigenetic changes in hematopoietic stem and progenitor cells, induced by exposure to an obesogenic diet in utero, may skew lineage commitment of myeloid cells during gestation. Further, microbial dysbiosis in neonatal life contributes to training innate immune cell responsiveness in the gut, bone marrow, and liver, leading to developmental programming of pediatric NAFLD. Comprehensive understanding of how different gut bacteria and their byproducts shape development of the early innate immune system and microbiome will uncover early interventions to prevent NAFLD pathophysiology.

Highlights

Nonalcoholic fatty liver disease (NAFLD), a spectrum of pathologies ranging from simple steatosis to fibrosis and cirrhosis, is the most common cause of chronic liver disease, affecting over 80% of adults with obesity [1], one third of obese children ages 3-18 in North America [2] and ~10% of the general pediatric population [2]
Half of children presenting with NAFLD have already progressed to the more serious form of nonalcoholic steatohepatitis (NASH) at time of diagnosis [2,8,9] and their survival, even after transplantation, is shortened when compared with the general population [5]
Later-life consequences of this early adaptation can be observed in adult WDfed mice, where hematopoietic stem and progenitor cells (HSPCs) are biased toward the myeloid lineage and generate a large pool of pro-inflammatory cells [115]

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), a spectrum of pathologies ranging from simple steatosis to fibrosis and cirrhosis, is the most common cause of chronic liver disease, affecting over 80% of adults with obesity [1], one third of obese children ages 3-18 in North America [2] and ~10% of the general pediatric population [2]. A major limitation in this field is the lack of fundamental understanding as to how maternal diet and/or obesity sets liver physiology and development of the immune system, beginning early in life, on a course toward NAFLD.

Results

Conclusion