Early Microbes Modify Immune System Development and Metabolic Homeostasis-The "Restaurant" Hypothesis Revisited

Abstract

The developing infant gut microbiome affects metabolism, maturation of the gastrointestinal tract, immune system function, and brain development. Initial seeding of the neonatal microbiota occurs through maternal and environmental contact. Maternal diet, antibiotic use, and cesarean section alter the offspring microbiota composition, at least temporarily. Nutrients are thought to regulate initial perinatal microbial colonization, a paradigm known as the "Restaurant" hypothesis. This hypothesis proposes that early nutritional stresses alter both the initial colonizing bacteria and the development of signaling pathways controlled by microbial mediators. These stresses fine-tune the immune system and metabolic homeostasis in early life, potentially setting the stage for long-term metabolic and immune health. Dysbiosis, an imbalance or a maladaptation in the microbiota, can be caused by several factors including dietary alterations and antibiotics. Dysbiosis can alter biological processes in the gut and in tissues and organs throughout the body. Misregulated development and activity of both the innate and adaptive immune systems, driven by early dysbiosis, could have long-lasting pathologic consequences such as increased autoimmunity, increased adiposity, and non-alcoholic fatty liver disease (NAFLD). This review will focus on factors during pregnancy and the neonatal period that impact a neonate's gut microbiome, as well as the mechanisms and possible links from early infancy that can drive increased risk for diseases including obesity and NAFLD. The complex pathways that connect diet, the microbiota, immune system development, and metabolism, particularly in early life, present exciting new frontiers for biomedical research.

Keywords: innate immunity; microbiome; non-alcoholic fatty liver disease; pregnancy; proteobacteria.

Figure 1

Maternal nutrition affects the fetal liver, microbiome, and offspring immunity, thereby increasing non-alcoholic fatty liver disease (NAFLD) and obesity risk. Maternal diet, mode of delivery, early offspring diet, and antibiotic exposure alter the infant’s pioneering microbiota and metabolite production. Changes in short-chain fatty acid production by the microbiota influence gut permeability, which can allow short-chain fatty acids and bacterial metabolites to directly influence adaptive and innate immune cell function and development. Altered adaptive immunity can lead to atopy, allergy, and autoimmunity. Microbes or their products alter hematopoietic stem cell (HSC) differentiation to macrophage progenitor cells in bone marrow and other tissues (17), which influences innate immunity. Altered innate immunity predisposes offspring to dysbiosis, macrophage activation, inappropriate macrophage infiltration, childhood obesity, and NAFLD, which often presents as non-alcoholic steatohepatitis (NASH) in obese youth.