Deciphering effects of gut microbiome repair achieved in undernourished Bangladeshi children in gnotobiotic mice
Studies have implicated perturbations in the postnatal assembly and functional maturation of the gut microbiome as a contributing factor to childhood undernutrition. Randomized controlled clinical trials of Bangladeshi children with moderate acute malnutrition have demonstrated that a microbiome-directed complementary food (MDCF-2) designed for repair their microbial communities out-performed a ready-to-use supplementary food in promoting ponderal and linear growth. Here reverse translation experiments are performed where intact fecal microbiomes collected from trial participants prior to and at the end of treatment are introduced into female gnotobiotic mice just after delivery of their pups; pups received diets reflective of the respective periods during the clinical study to recreate unrepaired and repaired gut ecosystems. Analyses of the abundances of bacterial strains (metagenome-assembled genomes), their gene expression (RNA-sequencing) and metabolism (targeted mass spectrometry), combined with assessments of ponderal growth and intestinal epithelial lineage transcriptomes (single-nucleus RNA-Seq with follow-up immunocytochemistry) disclosed effects of MDCF-2 associated microbiome repair that cannot be determined, in part because of no treatment control arms cannot be ethically incorporated into these trials. Microbiome repair produced significant increases in ponderal growth plus changes consistent with a less virulent gut ecosystem. The latter was evidenced by a reduction in virulence factors in the repaired microbiome meta-transcriptome and accompanying changes in (i) expression of components of epithelial cell junctions in the enterocytic and goblet cell lineages, (ii) pathways for synthesis and secretion of eicosanoid immune effectors in chemosensory tuft cells, and (iii) changes in goblet cell pathways involved in glycosylation and secretion of mucin. Combining experiments employing the pre- and post-treatment uncultured gut communities from clinical trial participants with experiments involving defined consortia of bacterial taxa cultured from participants, could create a virtuous cycle for formulating and testing hypotheses about microbiome repair affects host biology.