Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis
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Curated by eLife
eLife assessment
Herein, Xie and colleagues use a hamster model to show that Leptospira infection leads to gut pathology, an altered gut microbiota, and increased translocation. A combined use of antibiotics and LPS neutralization prolonged survival, providing a potential new therapeutic approach. This fundamental study uses compelling methods to provide new insights into this emerging disease, which could be dissected further in future studies aimed at gaining mechanistic insight and assessing the translational relevance of these discoveries.
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- Microbiology and Infectious Disease (eLife)
Abstract
Leptospirosis is an emerging infectious disease caused by pathogenic Leptospira spp. Humans and some mammals can develop severe forms of leptospirosis accompanied by a dysregulated inflammatory response, which often results in death. The gut microbiota has been increasingly recognized as a vital element in systemic health. However, the precise role of the gut microbiota in severe leptospirosis is still unknown. Here, we aimed to explore the function and potential mechanisms of the gut microbiota in a hamster model of severe leptospirosis. Our study showed that leptospires were able to multiply in the intestine, cause pathological injury, and induce intestinal and systemic inflammatory responses. 16S rRNA gene sequencing analysis revealed that Leptospira infection changed the composition of the gut microbiota of hamsters with an expansion of Proteobacteria. In addition, gut barrier permeability was increased after infection, as reflected by a decrease in the expression of tight junctions. Translocated Proteobacteria were found in the intestinal epithelium of moribund hamsters, as determined by fluorescence in situ hybridization, with elevated LPS levels in the serum. Moreover, gut microbiota depletion reduced the survival time, increased the leptospiral load, and promoted the expression of proinflammatory cytokines after Leptospira infection. Intriguingly, fecal filtration and serum from moribund hamsters both increased the transcription of TNF-α , IL-1β , IL-10 , and TLR4 in macrophages compared with those from uninfected hamsters. These stimulating activities were inhibited by LPS neutralization using polymyxin B. Based on our findings, we identified an LPS neutralization therapy that significantly improved the survival rates in severe leptospirosis when used in combination with antibiotic therapy or polyclonal antibody therapy. In conclusion, our study not only uncovers the role of the gut microbiota in severe leptospirosis but also provides a therapeutic strategy for severe leptospirosis.
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eLife assessment
Herein, Xie and colleagues use a hamster model to show that Leptospira infection leads to gut pathology, an altered gut microbiota, and increased translocation. A combined use of antibiotics and LPS neutralization prolonged survival, providing a potential new therapeutic approach. This fundamental study uses compelling methods to provide new insights into this emerging disease, which could be dissected further in future studies aimed at gaining mechanistic insight and assessing the translational relevance of these discoveries.
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Reviewer #1 (Public Review):
Summary:
In this study, Xie and colleagues aimed to explore the function and potential mechanisms of the gut microbiota in a hamster model of severe leptospirosis. The results demonstrated that Leptospira infection was able to cause intestine damage and inflammation. Leptospira infection promoted an expansion of Proteobacteria, increased gut barrier permeability, and elevated LPS levels in the serum. Thus, they proposed an LPS-neutralization therapy which improved the survival rate of moribund hamsters combined with antibody therapy or antibiotic therapy.
Strengths:
The work is well-designed and the story is interesting to me. The gut microbiota is essential for immunity and systemic health. Many life-threatening pathogens, such as SARS-CoV-2 and other gut-damaged infection, have the potential to disrupt the …
Reviewer #1 (Public Review):
Summary:
In this study, Xie and colleagues aimed to explore the function and potential mechanisms of the gut microbiota in a hamster model of severe leptospirosis. The results demonstrated that Leptospira infection was able to cause intestine damage and inflammation. Leptospira infection promoted an expansion of Proteobacteria, increased gut barrier permeability, and elevated LPS levels in the serum. Thus, they proposed an LPS-neutralization therapy which improved the survival rate of moribund hamsters combined with antibody therapy or antibiotic therapy.
Strengths:
The work is well-designed and the story is interesting to me. The gut microbiota is essential for immunity and systemic health. Many life-threatening pathogens, such as SARS-CoV-2 and other gut-damaged infection, have the potential to disrupt the gut microbiota in the later stages of infection, causing some harmful gut microbiota-derived substances to enter the bloodstream. It is emphasized that in addition to exogenous pathogenic pathogens, harmful substances of intestinal origin should also be considered in critically ill patients.
Weaknesses:
(1) There are many serotypes of Leptospira, it is suggested to test another pathogenic serotype of Leptospira to validate the proposed therapy.
(2) Authors should explain why the infective doses of leptospires was not consistent in different study.
(3) In the discussion section, it is better to supplement the discussion of the potential link between the natural route of infection and leptospirosis.
(4) Line 231, what is the solvent of thioglycolate?
(5) Lines 962-964, there are some mistakes which are not matched to Figure 7.
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Reviewer #2 (Public Review):
Severe leptospirosis in humans and some mammals often meet death in the endpoint. In this article, authors explored the role of the gut microbiota in severe leptospirosis. They found that Leptospira infection promoted a dysbiotic gut microbiota with an expansion of Proteobacteria and LPS neutralization therapy synergized with antileptospiral therapy significantly improved the survival rates in severe leptospirosis. This study is well-organized and has potentially important clinical implications not only for severe leptospirosis but also for other gut-damaged infections.
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Reviewer #3 (Public Review):
Summary:
This is a well-prepared manuscript that presented interesting research results. The only defect is that the authors should further revise the English language.
Strengths:
The omics method produced unbiased results.
Weaknesses:
LPS neutralization is not a new method for treating leptospiral infection.
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