UBC Theses and Dissertations
The intestinal microbiota in early life undernutrition Huus, Kelsey Elizabeth
Child undernutrition is a global health issue that is exacerbated by poor sanitation and infectious disease; however, the microbial and immune contributions to child growth remain poorly understood. To understand how nutrition impacts immune-microbe interactions, I assessed interactions between intestinal bacteria and immunoglobulin A (IgA), the antibody responsible for mucosal homeostasis, in mouse and human undernutrition. In contrast to healthy control mice, undernourished mice failed to develop IgA recognition of commensal Lactobacillus. Glycan-mediated interactions between Lactobacillus and IgA were lost in undernourished mice; this was driven by bacterial adaptation to the nutritional environment, independently of host antibody, and was associated with bacterial mutations in carbohydrate processing genes. Together these data indicate that diet-driven bacterial adaptations shape IgA recognition in the gut, which may have implications for the use of probiotics and oral vaccines in undernutrition. To extend these findings to human populations, I measured IgA-microbiota interactions in the fecal microbiota of 200 children with or without linear growth stunting from Madagascar and the Central African Republic. Stunted children had increased abundance of several pathobionts; two of these, Haemophilus and Campylobacter, were strongly recognized by IgA regardless of nutritional status, while Lactobacillus was broadly IgA-negative. Stunted children also had a greater number of IgA-positive fecal bacteria overall, a phenotype previously seen in inflammatory bowel disease patients. Together, IgA-binding patterns in mice and humans suggest that undernutrition alters intestinal homeostasis. To understand how pathobiotic communities respond to nutrient limitation, I further examined metabolic interactions between human Bacteroidales and E. coli, strains which exacerbate inflammation and growth stunting in undernourished mice. These bacteria experienced a mutual growth advantage which was enhanced by protein-limited, carbohydrate-rich conditions, and which led to outgrowth of B. fragilis and E. coli at the expense of other strains. Thus, cross-feeding between pathobionts might contribute to community dysbiosis in the undernourished gut. Taken together, I show that undernutrition drives not only the composition of the intestinal microbiota but also its metabolic and immune functionality. A better understanding of intestinal microbial function in undernutrition may lead to improved intervention strategies.
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