Gut microbiota-associated metabolite N-acetyl-D-glucosamine alleviates systemic inflammatory responses induced by acute Toxoplasma gondii infection

TL;DR

A gut microbiota-produced molecule, GlcNAc, reduces inflammation and parasite burden in mice infected with Toxoplasma gondii, suggesting new treatment strategies for parasitic diseases.

Contribution

First demonstration of GlcNAc's role in modulating inflammation during T. gondii infection through gut microbiota.

Findings

GlcNAc significantly downregulates pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, and IL-12 in infected mice.

Exogenous GlcNAc reduces parasite burden and prevents weight loss in T. gondii-infected mice.

GlcNAc upregulates anti-inflammatory cytokines IL-10 and TGF-β during infection.

Abstract

Toxoplasma gondii (T. gondii) is an opportunistic protozoan parasite capable of infecting nearly all warm-blooded animals, including humans. Infection with T. gondii often triggers potent inflammatory responses that can lead to severe and potentially life-threatening tissue damage. Based on the mechanistic relationship between the gut microbiota and the host immune system, this study explores the metabolic regulatory network orchestrated by the gut microbiota during T. gondii infection. Using intraperitoneal infection models with both a wild-type ME49 strain and an attenuated ME49Δα-amy strain, we report for the first time a pivotal role for N-acetyl-D-glucosamine (GlcNAc) in modulating parasite-induced inflammation. Integrated analysis of 16S rRNA sequencing and metabolomic profiling revealed that GlcNAc, a gut microbiota-associated metabolite, was significantly enriched in mice infected with the ME49Δα-amy strain. Exogenous administration of GlcNAc to T. gondii-infected mice resulted in the marked downregulation of key pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12, and a significant upregulation of the anti-inflammatory cytokines IL-10 and TGF-β. Moreover, GlcNAc treatment substantially reduced parasite burden and alleviated infection-associated weight loss. These findings not only elucidate the immunomodulatory function of microbiota-related metabolites in the context of zoonotic parasitic infections but also provide a novel theoretical foundation for the development of microbiota-targeted therapeutic strategies against toxoplasmosis. Collectively, our work offers important insights that may inform public health interventions aimed at controlling and preventing zoonotic parasitic diseases.

Toxoplasma gondii is a widespread parasite that infects humans and animals, often through contaminated food or water. Infection can cause severe inflammation and tissue damage. In this study, we investigated how gut bacteria influence the body’s response to this parasite. We discovered that a molecule produced by gut microbiota, named N-acetyl-D-glucosamine (GlcNAc), plays a key role in reducing harmful inflammation during infection. When we gave GlcNAc to infected mice, it lowered inflammation, reduced the number of parasites, and prevented weight loss. These findings help explain how our body’s natural microbes can fight infectious diseases. More broadly, this work suggests that targeting gut metabolites like GlcNAc could lead to new treatments for infections caused by parasites and other inflammatory diseases, benefiting both human and animal health.

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