The small intestinal microbiota in undernourished women and undernourished children in Bangladesh: identifying causal mechanisms and therapeutic targets

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PROJECT SUMMARY/ABSTRACT Childhood undernutrition is a global health challenge manifested by impaired ponderal growth (wasting/acute malnutrition), impaired linear growth (stunting), immune and metabolic dysfunctions, altered CNS development plus other abnormalities. >30M children worldwide suffer from moderate acute malnutrition (MAM) with prevalence anticipated to worsen significantly with the COVID-19 pandemic. Globally, 159M children are stunted. Current treatments have limited effectiveness. By analyzing serially collected fecal samples from healthy members of Bangladeshi birth cohorts and those with MAM, we found that MAM is associated with impaired microbiota development (microbiota immaturity). We have developed a microbiota-directed formulation of complementary foods that repairs their microbiota, resulting in significantly greater improvements in ponderal growth compared to an existing nutritional intervention, and revealing mechanisms by which microbiota members are linked to host mediators of healthy growth. The role of the small intestinal (SI) microbiota in childhood undernutrition remains enigmatic in part because of the difficulty in obtaining samples. Associations between altered SI absorptive function, asymptomatic enteropathogen infection and stunting, have led to the hypothesis that subclinical enteric dysfunction contributes to growth faltering. Environmental enteric dysfunction (EED) is a SI enteropathy of unknown etiology first described in adult Peace Corps volunteers, returning from areas of high fecal-oral contamination, with diarrhea, intestinal malabsorption, reduced villus height/number and gut barrier function disruption. Studies of EED have relied on non-validated fecal or plasma biomarkers making its contribution to childhood undernutrition ill-defined. Our Bangladesh Environmental Enteric Dysfunction (BEED) study involved endoscopy of stunted children who failed a nutritional intervention, which revealed a group of SI bacterial taxa whose absolute abundances negatively correlate with linear growth; a cultured consortium of these duodenal taxa produced SI enteropathy in recipient gnotobiotic mice. We now propose to test the hypothesis that the SI microbiota contributes to SI enteropathy and malnutrition (low-BMI) in women of childbearing age and, via transmission to their children, to perpetuate intergenerational undernutrition. Our 4 specific aims will compare the SI microbiota plus the duodenal mucosal and plasma proteomes of malnourished Bangladeshi women (BMI<18.5kg/m2) of child-bearing age with histopathologic evidence of enteropathy versus those with normal BMIs (20-24.9kg/m2) and no histopathologic evidence of enteropathy, determine whether their SI microbiota transmits SI enteropathy and impaired growth to gnotobiotic mice, ascertain whether these phenotypes are prevented/rescued by SI microbial community members from normal-BMI Bangladeshi women without enteropathy, and screen biochemically-diverse plant polysaccharides in our mouse models for their effects on enteropathy/growth, with leads advanced to gnotobiotic piglets.