Maternal Diet Alters Trained Immunity in the Pathogenesis of Pediatric NAFLD

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.

Keywords: Epigenetic reprogramming; Hematopoietic stem cells; Microbiome; Pediatric NAFLD; Pioneering bacteria; Trained immunity.

Figure 1:

Early pioneering bacteria induce metabolic reprogramming of innate immunity and increase susceptibility to pediatric NAFLD in offspring. Maternal Western-style diet, high in fat, sugar, and cholesterol, alters initial bacterial colonization in infants. By reshaping the ratio of dominant bacterial species in the gut during early life, the composition of the lipopolysaccharide (LPS) pool, bacterial metabolites, short-chain fatty acids (SCFA), microbe-associated molecular patterns (MAMPs) and pathogen-associated molecular patterns (PAMPs) are also varied. These altered microbial signals induce expansion of hematopoietic stem and progenitor cells, myeloid lineage skewing, and inflammatory polarization of monocyte/macrophages recruited to the steatotic liver. Therefore, a shifted ratio of Enterobacteriaceae to acidophilic commensals, such as Bacteroides or Bifidobacterium, may mediate susceptibility to NAFLD in childhood and accelerate disease progression through “training” of innate immune cells. This figure was generated with the assistance of BioRender (www.biorender.com).