# Role of the Gut Microbiota in Shaping Severity of Malaria

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $768,686

## Abstract

ABSTRACT
Recent studies in humans and mice have identified previously unknown interactions between the host gut
microbiome and Plasmodium that dictate susceptibility to severe malaria. Yet, the specific members of gut
microbiota and their functions responsible for differential malaria outcomes remain unknown. The objective of
this application is to determine the gut bacteria function that shapes host immunity to Plasmodium and
susceptibility to severe malaria. We have demonstrated that gut microbiota in mice affects the magnitude of
parasite burden and severity of malaria by modulating Plasmodium-induced humoral immune responses in the
spleen, the secondary lymphoid organ required for immune-mediated clearance of Plasmodium. Our data
demonstrate that gut bacteria do not confer resistance to hyperparasitemia. Rather, specific bacteria confer
susceptibility to hyperparasitemia. Specifically, gut Bacteroides species function within a microbial consortium
to cause susceptibility to hyperparasitemia in mice. Of note, Ugandan children with severe malarial anemia
have increased abundances of several Bacteroides species compared to children with asymptomatic
Plasmodium falciparum infections. Importantly, colonizing hyperparasitemia-resistant mice with these human-
associated Bacteroides species caused susceptibility to hyperparasitemia. These data strongly support the
relevance and translational potential of our ongoing efforts using murine malaria to identify mechanisms by
which gut bacteria cause susceptibility to severe malaria and investigate gut microbiome-based therapeutics to
prevent severe malaria. Our data show that mice susceptible to hyperparasitemia have increased regulatory T
cells (Tregs) in both intestinal tissue and the spleen before and during Plasmodium infection. Tregs have been
shown in mice to inhibit humoral immunity to Plasmodium. Bacteroides are among the primary producers of the
short-chain fatty acid (SCFA) propionate that induces Tregs. We have also published that mice susceptible to
hyperparasitemia have increased amounts of propionate compared to hyperparasitemia-resistant mice.
Intriguingly, we have published that treating hyperparasitemia-susceptible mice orally with the antibiotics
metronidazole or vancomycin reduces the severity of malaria. Oral treatment with metronidazole decreases
intestinal propionate levels, while oral treatment with vancomycin decreases colonic Tregs. These novel
findings support the central hypothesis that propionate production by gut bacteria induces Tregs that dampen
humoral immunity to Plasmodium, causing susceptibility to severe malaria. This hypothesis will be tested
through the following aims: Aim 1. Determine if propionate-producing bacteria cause susceptibility to severe
malaria by inducing Tregs that dampen humoral immunity. Aim 2. Determine if stool propionate levels and
Tregs correlate with malaria disease severity in diverse groups of African children and mice.

## Key facts

- **NIH application ID:** 10904308
- **Project number:** 1R01AI183911-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Nathan Schmidt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $768,686
- **Award type:** 1
- **Project period:** 2024-05-03 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904308

## Citation

> US National Institutes of Health, RePORTER application 10904308, Role of the Gut Microbiota in Shaping Severity of Malaria (1R01AI183911-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10904308. Licensed CC0.

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