A human microbiota-associated mouse model of early-life malnutrition reveals persistent microbiome immaturity and limited response to fecal viral transplantation

Malnutrition, a leading cause of child mortality globally, has severe, long-lasting health and socio-economic impacts. Research has shown that the gut microbiota plays a crucial role in childhood malnutrition, with microbial signatures including delayed development and an overgrowth of harmful bacteria. While dietary interventions can improve growth and development, they often fail to restore the immature microbial state after therapy.

Fecal virome transplants (FVTs) have shown promise in reshaping gut microbial communities, but their effectiveness in early life is unclear.

In this study, a diet-inducible mouse model of early-life stunting was created, where malnourished mice were 35% lighter and 25% shorter than healthy counterparts. Researchers developed a predictive model to assess gut bacteriome development, finding that Enterococcus and Clostridium were key factors in healthy maturation. The model demonstrated that the malnourished HMA mouse gut remained significantly immature and disconnected from the mouse's chronological age.

When a healthy donor's FVT was administered, it resulted in targeted changes in specific bacterial taxa, such as an increase in Enterococcus species. However, this did not improve physical growth or lead to broad community-level changes. A failed FVT from a different healthy donor revealed a significant mismatch between the donor virome and the recipient's bacteriome, indicating that niche incompatibility hampers FVT efficacy.

The research establishes a reliable human microbiota-associated mouse model for investigating early-life gut maturation, suggesting that FVT alone is insufficient for consistently reshaping the malnourished gut. The findings emphasize the need for integrated strategies that combine viral interventions with nutritional supplementation to maximize therapeutic benefits.