Gut Microbiota Disruption and Gut-Derived Lipopolysaccharide Contribute to Severe Leptospirosis Pathogenesis

Основні поняття

Leptospira infection disrupts the gut microbiota composition and intestinal barrier, leading to the translocation of gut-derived lipopolysaccharide (LPS) that induces an uncontrolled inflammatory response and contributes to the pathogenesis of severe leptospirosis. Neutralizing gut-derived LPS can improve the survival rate of hamsters with severe leptospirosis when combined with antibiotic or antibody therapy.

Анотація

The study explored the role of the gut microbiota in the pathogenesis of severe leptospirosis using a hamster model. The key findings are:

Leptospira interrogans was able to proliferate in the intestine, disrupt the intestinal structure, and induce intestinal and systemic inflammatory responses.

Leptospira infection changed the composition of the gut microbiota, with an expansion of Proteobacteria and a decrease in Lactobacillus and Allobaculum. The intestinal permeability was also increased after infection.

Depletion of the gut microbiota exacerbated leptospirosis, leading to reduced survival, increased leptospiral load, and elevated proinflammatory cytokine expression.

Gut-derived lipopolysaccharide (LPS) from Leptospira-infected hamsters induced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-10, TLR4) in macrophages, which was inhibited by LPS neutralization.

Combining LPS neutralization therapy with antibiotic or antibody therapy significantly improved the survival rate of hamsters with severe leptospirosis compared to individual therapies.

The study highlights the critical role of the gut microbiota and gut-derived LPS in the pathogenesis of severe leptospirosis, and provides a potential novel therapeutic strategy by targeting gut-derived LPS.

Статистика

Leptospiral burdens in the ileums and colons of Leptospira-infected hamsters were significantly increased at the articulo mortis (AM) stage compared to uninfected controls.
The intestinal permeability of Leptospira-infected hamsters was significantly increased at the AM stage compared to uninfected and day 2 post-infection groups.
Leptospiral load in the blood was significantly higher in the antibiotic-treated group compared to the control infection group, which was partially reversed by fecal microbiota transplantation.
Leptospiral load in the blood was not reduced by LPS neutralization therapy alone, but was decreased by antibiotic therapy or antibody therapy.

Цитати

"Leptospira infection destroyed the intestinal structure, caused bleeding, and led to the infiltration of inflammatory cells."
"The species richness and diversity of the gut microbiota in the AM group were even higher than those in the D2 group. The species richness and diversity of the gut microbiota decreased first and then increased with disease progression."
"Gut-derived lipopolysaccharide (LPS) from Leptospira-infected hamsters induced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-10, TLR4) in macrophages, which was inhibited by LPS neutralization."

Ключові висновки, отримані з

Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis

by Xie,X., Chen... о www.biorxiv.org 01-18-2024

https://www.biorxiv.org/content/10.1101/2024.01.17.576119v2

Глибші Запити

How do the specific changes in gut microbiota composition during leptospirosis progression contribute to disease severity and host susceptibility?

The specific changes in gut microbiota composition during leptospirosis progression play a crucial role in disease severity and host susceptibility. In severe leptospirosis, there is a disruption in the gut microbiota, leading to dysbiosis characterized by a decrease in species richness and diversity. This dysbiosis allows for the expansion of pathogenic bacteria, such as Proteobacteria, while beneficial bacteria like Lactobacillus are reduced. The altered gut microbiota composition can weaken the intestinal barrier, increase intestinal permeability, and promote the translocation of pathogenic bacteria into the bloodstream. This translocation of bacteria, along with the release of microbial products like lipopolysaccharide (LPS), can trigger an exaggerated inflammatory response, contributing to disease severity. Additionally, the dysbiosis-induced changes in the immune system can affect the host's ability to mount an effective immune response against Leptospira infection, thereby increasing host susceptibility to the disease.

How do the potential mechanisms by which gut-derived LPS promotes the uncontrolled inflammatory response in severe leptospirosis go beyond the activation of TLR4 signaling?

Gut-derived lipopolysaccharide (LPS) plays a significant role in promoting the uncontrolled inflammatory response in severe leptospirosis through mechanisms beyond the activation of Toll-like receptor 4 (TLR4) signaling. While TLR4 is a key receptor for LPS recognition and immune activation, the effects of LPS extend beyond TLR4 activation. In severe leptospirosis, gut-derived LPS can directly interact with other pattern recognition receptors (PRRs) on immune cells, such as NOD-like receptors (NLRs) and C-type lectin receptors (CLRs), leading to the production of proinflammatory cytokines and chemokines. Additionally, LPS can induce the release of damage-associated molecular patterns (DAMPs) from damaged tissues, further exacerbating the inflammatory response. Moreover, LPS can activate the inflammasome pathway, resulting in the maturation and secretion of proinflammatory cytokines like IL-1β. These multiple pathways of LPS-induced inflammation contribute to the uncontrolled immune response observed in severe leptospirosis, going beyond the sole activation of TLR4 signaling.

Could modulating the gut microbiota composition, for example by targeted probiotic supplementation, be a viable preventive or therapeutic strategy for leptospirosis in addition to LPS neutralization?

Modulating the gut microbiota composition through targeted probiotic supplementation holds promise as a viable preventive or therapeutic strategy for leptospirosis, complementing LPS neutralization. By introducing beneficial bacteria, such as Lactobacillus species, through probiotic supplementation, it is possible to restore gut microbial balance, enhance the integrity of the intestinal barrier, and reduce the translocation of pathogenic bacteria and their products like LPS. This restoration of gut homeostasis can help in regulating the immune response, improving host resistance to Leptospira infection, and reducing disease severity. Additionally, probiotics can exert direct antimicrobial effects against pathogens, including Leptospira, and modulate immune responses to promote a balanced inflammatory reaction. Combining targeted probiotic supplementation with LPS neutralization may offer a comprehensive approach to managing leptospirosis by addressing both the dysbiosis-induced inflammation and the direct effects of LPS on immune activation.