In a groundbreaking study published in Cell on September 9, 2025, researchers from the Salk Institute, in collaboration with teams from Washington University School of Medicine and the University of California San Diego, have unveiled a transformative understanding of the gut microbiome’s role in pediatric undernutrition. Undernutrition, a form of malnutrition characterized by inadequate nutrient intake or absorption, affects tens of millions of children worldwide and is a leading cause of childhood mortality and lifelong health impairments. This new investigation leverages cutting-edge long-read metagenomic sequencing and advanced meta-pangenomic analyses to map the intricate microbial communities inhabiting the intestines of Malawian toddlers—a region severely afflicted by stunted growth due to nutritional deficiencies.
Malnutrition remains a devastating public health crisis, disproportionately impacting children under the age of five. Current estimates indicate that more than 150 million children globally suffer from various manifestations of malnutrition, including undernutrition, which contributes to impaired cognitive development, poor educational achievement, and increased economic vulnerability in adulthood. The complex relationship between nutritional status and the gut microbiome—the vast ecosystem of bacteria, viruses, and other microorganisms within the gastrointestinal tract—has long been hypothesized but remained molecularly elusive due to limitations in genomic resolution and sampling methods.
The Salk-led team targeted this knowledge gap by longitudinally following eight children from Malawi, known for a staggering child stunting prevalence of roughly 35%. These young patients’ fecal samples were collected repeatedly over an 11-month period, enabling the researchers to monitor temporal shifts in the microbial genome composition with unprecedented depth. Employing a novel workflow centered around long-read sequencing technology, the team generated a comprehensive dataset that surpasses previous efforts in both scale and genomic completeness. Long-read methods overcome the historical challenges of short-read sequencing, which fragments DNA into thousands of short pieces, making the assembly of full microbial genomes akin to solving impossible puzzles. The new approach simplifies genome reassembly by producing larger contiguous DNA sequences, effectively unveiling complex microbial genomic architectures.
By reconstructing nearly one thousand individual microbial genomes—totaling 986 complete genomes, many of which are novel—the researchers established the first-ever pediatric undernutrition microbial genome catalog. This meta-pangenome catalog serves as a critical repository detailing not only species presence but also intra-species genetic variability, providing a detailed landscape of microbial gene content and functional potential linked to child growth trajectories. The magnitude and resolution of this resource mark a transformative moment, unlocking new possibilities to decipher how intricate microbial communities affect nutrient processing, immune modulation, and intestinal health.
One of the pivotal revelations of the study emerged from the analysis of microbial pangenome stability over time. The team found that children exhibiting stable genomes within key bacterial species often demonstrated improving or normal length-for-age Z-scores (LAZ), a standardized measure of physical growth in children. Conversely, those with pronounced fluctuations or instability in microbial genome collections correlated strongly with growth faltering. This association suggests that a stable microbial genomic community may be a biomarker—and potentially a causal factor—of healthy gut function and nutrient absorption, whereas instability could mirror or drive chronic gut inflammation and environmental enteric dysfunction.
At the genus level, distinct genetic differentiations in four pivotal bacterial genera—Bifidobacterium, Megasphaera, Faecalibacterium, and Prevotella—were linked to the children’s growth status. These genera are known to play essential roles in fermenting dietary fibers, producing short-chain fatty acids, and modulating immune responses. However, the study’s emphasis on genomic shifts within these genera adds a new dimension, highlighting that the genetic content and functional potential within microbial populations are dynamic factors influencing undernutrition outcomes.
This investigation further refines our understanding of undernutrition’s etiology. Undernutrition does not solely stem from insufficient nutrient intake but can derive from impaired processing caused by microbiome-derived dysfunctions. Chronic inflammation triggered by dysbiotic gut microbes can degrade intestinal barrier integrity and nutrient assimilation. The longitudinal design uniquely uncovers these progressive microbial patterns, which cross-sectional snapshots fail to capture. By tracking microbial and host growth data repeatedly over time, the researchers teased apart the complex interplay between microbial evolutionary dynamics and child health outcomes.
Beyond illuminating pediatric nutrition challenges, the study delivers a scalable, cost-effective, and highly accurate methodological advance through its optimized long-read sequencing workflow. This pipeline offers a blueprint for future studies not only in human health but also in environmental microbiology, agriculture, and biodiversity monitoring. The adaptability of this method allows for high-throughput, culture-independent meta-pangenomics that can be applied in remote or resource-limited settings, drastically expanding the reach of high-resolution genomic science.
The significance of these findings extends into the realm of public health interventions. By providing an extensive catalog of microbial genomes and tying genome stability to growth outcomes, this research lays the foundation for developing diagnostic tools that assess gut microbiome health in real-time. Tailored therapeutics, possibly including bacteriotherapies or microbiome-targeted nutritional supplements designed to establish or maintain microbial genomic stability, are tangible possibilities on the horizon. Such innovations could revolutionize the management and prevention of undernutrition, particularly in vulnerable populations with limited access to conventional medical resources.
Historically, the causal link between gut microbiota and malnutrition was supported by landmark studies, such as the 2013 experiment where microbiota transplantation from malnourished children into germ-free mice led to weight loss phenotypes reflective of the donor condition. This Salk Institute study builds upon this conceptual framework but incorporates unprecedented genomic depth and temporal insight, essentially translating microbiome science from correlative to potentially predictive and mechanistic.
The interdisciplinary nature of the project highlights the power of collaboration, blending expertise in genomics, bioinformatics, pediatrics, and global health. Co-corresponding authors Todd Michael and Mark Manary emphasize that the granularity achieved unveils precise microbial genomic shifts as opposed to broad compositional changes, framing new hypotheses about microbial contributions to nutrient absorption and inflammation. Meanwhile, Kevin Stephenson notes the importance of longitudinal sampling as a means to capture dynamic biological processes otherwise obscured by single time-point analyses.
Financially supported by diverse institutions including the NOMIS Foundation, National Science Foundation, and USAID, this study epitomizes how advanced genomic technology can be harnessed to tackle enduring public health problems. Its technological, clinical, and ecological implications underscore the growing role genomics plays beyond traditional laboratory settings, extending into fields as varied as pandemic surveillance and conservation biology.
The monumental microbial genome catalog generated here paves the way for future large-scale metagenomic investigations of pediatric populations affected by undernutrition globally. It affirms that solutions to global malnutrition crises demand not only socioeconomic and nutritional interventions but also a deep molecular understanding of host-microbiome interactions. Ultimately, such insights hold promise for reducing the burden of malnutrition and transforming the life course of millions of children worldwide.
Subject of Research: Pediatric undernutrition and gut microbiome genomics
Article Title: Culture-independent meta-pangenomics enabled by long-read metagenomics reveals associations with pediatric undernutrition
News Publication Date: September 9, 2025
Web References: https://www.cell.com/cell/fulltext/S0092-8674(25)00975-4
References: DOI: 10.1016/j.cell.2025.08.020
Image Credits: Salk Institute
Keywords: Life sciences, Health and medicine, Human health, Public health, Dietetics, Computational biology, Bioinformatics, Genetics, Genomics, Genome sequencing, Bacterial genomes, Metagenomics, Omics, Proteomics, Diseases and disorders, Nutrition disorders, Malnutrition, Undernutrition, Microbiology, Microorganisms, Microbiota, Gut microbiota, Human gut microbiota
