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

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.

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.

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.