# Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $705,223

## Abstract

PROJECT SUMMARY
Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis. Late-onset sepsis
(LOS) is a leading cause of morbidity and mortality in premature infants and is thought to be caused by the
systemic spread of commensal microbes. Perturbation in the developing intestinal microbiome (dysbiosis) is far
more common in premature infants than in full-term infants and is thought to underlie their heightened
susceptibility to LOS, although the mechanisms that predispose to this are not well understood. We recently
developed a new murine model of neonatal LOS, which has confirmed the long-held clinical suspicion of a direct
link between dysbiosis and LOS. We discovered that, by altering the developing microbiome to prevent dysbiosis,
we were able to prevent LOS. This protection correlated with the abundance of endogenous Ligilactobacillus
(formerly Lactobacuillus) murinus, some isolates of which proved to be effective in preventing LOS when
administered as probiotics. Remarkably, however, even closely-related L. murinus isolates differed considerably
in their probiotic efficacy, as did other strains of Lactobacilli—including a number of strains that are components
of commercial probiotics. Moreover, we have found that probiotic strains of L. murinus that prevented dysbiosis
and LOS altered the oxygen status of the intestinal epithelium, suggesting that these strains may modulate
intestinal redox status to prevent the outgrowth of facultative anaerobes that can respire oxygen or other
respiratory terminal electron acceptors. Although a major mechanism driving dysbiosis in adults is increased
availability of substrates of bacterial respiration that allows facultative anaerobes to outcompete the obligate
anaerobes that predominate in a healthy microbiome, our preliminary studies indicate that mechanisms that
predispose the adult intestine to dysbiosis under conditions of inflammation or infection are at least partially
disparate with those in the immature neonatal intestine. We therefore posit that the neonatal intestine is
susceptible to dysbiosis via mechanisms distinct from those previously characterized in adults, reflecting
developmental immaturity of the intestines and early instability of the developing intestinal microbiome. Here, we
will take a team science approach to elucidate both host and microbial determinants of neonatal dysbiosis that
predispose to LOS, marrying the efforts of two labs with complementary expertise in intestinal biology and
immunity (Weaver), and microbial genetics and bacterial respiration (Gray) with collaborators who are leaders
in microbial genomics (Julie Segre), inflammation-associated gut dysbiosis (Sebastian Winter) and neonatology
(Namasivayan Ambalavanan). Through the identification of mechanisms of dysbiosis unique to the developing
intestines and microbiome we will provide a foundation for more rational design of probiotics and prebiotics for
therapeutic interventions that prev...

## Key facts

- **NIH application ID:** 10458103
- **Project number:** 5R01AI164712-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Michael Jeffrey Gray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $705,223
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458103

## Citation

> US National Institutes of Health, RePORTER application 10458103, Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis (5R01AI164712-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10458103. Licensed CC0.

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