Host-derived Lactobacillus plantarum alleviates hyperuricemia by improving gut microbial community and hydrolase-mediated degradation of purine nucleosides

  1. Yang Fu
  2. Xiao-Dan Luo
  3. Jin-Ze Li
  4. Qian-Yuan Mo
  5. Xue Wang
  6. Yue Zhao
  7. You-Ming Zhang
  8. Hao-Tong Luo
  9. Dai-Yang Xia
  10. Wei-Qing Ma
  11. Jian-Ying Chen
  12. Li-Hau Wang
  13. Qiu-Yi Deng
  14. Lukuyu Ben
  15. Muhammad Kashif Saleemi
  16. Xian-Zhi Jiang
  17. Juan Chen
  18. Kai Miao
  19. Zhen-Ping Lin
  20. Peng Zhang
  21. Hui Ye
  22. Qing-Yun Cao
  23. Yong-Wen Zhu
  24. Lin Yang
  25. Qiang Tu
  26. Wence Wang

  • Curated by eLife

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    eLife Assessment

    The landmark significance of this manuscript is based on the mechanistic description of purine metabolism by Lactobacillus plantarum, which helps to alleviate hyperuricemia, which is a phenotype that underlies multiple disease symptoms. The evidence provided for L. plantarum's involvement in reducing hyperuricemia was exceptional, combining microbiomics, whole genomics, in vitro bacterial culture, gene knock-outs, and metabolomics. Collectively, the study shows a clear link between the gut microbiota and hyperuricemia, providing a pathway for modification to help alleviate this condition.

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Abstract

The gut microbiota is implicated in the pathogenesis of hyperuricemia (HUA) and gout. However, it remains unclear whether probiotics residing in the host gut, such as Lactobacillus , can prevent HUA development. Herein, we isolated Lactobacillus plantarum SQ001 from the cecum of HUA geese and conducted in vitro assays on uric acid (UA) and nucleoside co-culture. Metabolomics and genome-wide analyses, revealed that this strain may promote nucleoside uptake and hydrolysis through its nucleoside hydrolase gene. The functional role of iunH gene was confirmed via heterologous expression and gene knockout studies. Oral administration of L. plantarum SQ001 resulted in increased abundance of Lactobacillus species and reduced serum UA levels. Furthermore, it downregulated hepatic xanthine oxidase, a key enzyme involved in UA synthesis, as well as renal reabsorption protein GLUT9, while enhancing the expression of renal excretion protein ABCG2. Our findings suggest that L. plantarum has potential to ameliorate gut microbial dysbiosis with HUA, thereby offering insights into its potential application as a probiotic therapy for individuals with HUA or gout.

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  1. Version published to 10.7554/elife.100068 on eLife
  2. eLife

    Author response:

    Reviewer #1 (Public Review):

    Lactobacillus plantarum is a beneficial bacterium renowned for its positive physiological effects and probiotic functions. Fu et al. conducted an investigation into the involvement of this bacterium in host purine metabolism. Initially, they employed microbiomics to analyze changes in L. plantarum within a hyperuricemia model, followed by isolation of the bacterium from this model. The gene map associated with purine nucleoside metabolism was determined through whole-genome analysis. Metabolic shifts in L. plantarum under nucleoside-enriched conditions were assessed using HPLC and metabolomics, while underlying mechanisms were explored through gene knockout experiments. Finally, the efficacy of L. plantarum was validated in hyperuricemia models involving goslings and mice. The authors presented their findings coherently and logically, addressing key questions using appropriate methodologies and yielding significant and innovative results. The authors demonstrated that host-derived Lactobacillus plantarum alleviates host hyperuricemia by influencing purine metabolism. However, their study primarily focused on this bacterium without delving deeper into the mechanisms underlying hyperuricemia beyond verification through two models. Nevertheless, these findings are sufficient to support their conclusion effectively. Additionally, further research is warranted to investigate the metabolites of Lactobacillus plantarum.

    We appreciate the reviewers' suggestions. We have studied Lactobacillus plantarum in detail, focusing specifically on its role in the purine nucleoside metabolism of the host, confirmed through in vitro and in vivo experiments. Our key finding demonstrates how Lactobacillus plantarum contributes to this process. We also examined the expression of hepatic uric acid synthesis proteins and renal uric acid excretion proteins related to alleviating host hyperuricaemia (Figure 9). While discussing the metabolites of Lactobacillus plantarum may fall outside the scope of this article, we plan to investigate this further. Our goal is to identify a signature metabolite via in vitro and in vivo studies and explore how it may help reduce hyperuricaemia in the host.

    Reviewer #2 (Public Review):

    Summary:

    Purine nucleoside metabolism in intestinal flora is integral to the purine nucleoside metabolism in the host. This study identified the iunH gene in Lactobacillus plantarum that regulates its purine nucleoside metabolism. Oral gavage of Lactobacillus plantarum and subsequent analysis showed it maintains homeostasis of purine nucleoside metabolism in the host.

    Strengths:

    This study presents sufficient evidence for the role of Lactobacillus plantarum in alleviating hyperuricaemia, combining microbiomics, whole genomics, in vitro bacterial culture, and metabolomics. These results suggest the iunH gene of Lactobacillus plantarum is crucial in host purine nucleoside metabolism. The experimental design is robust, and the data are of high quality. This study makes significant contributions to the fields of hyperuricaemia, purine nucleoside metabolism, and Lactobacillus plantarum investigation.

    We appreciate the reviewers' encouraging feedback.

    Weaknesses:

    A key limitation of this manuscript is the absence of an in-depth study on the alleviation metabolism of Lactobacillus plantarum. Notable questions include: What overall metabolic changes occur in a purine nucleoside-enriched environment? How do the metabolites of Lactobacillus plantarum vary? Do these metabolites influence host purine nucleoside metabolism? These areas merit further investigation.

    Thank you! The Supplementary Material link includes intracellular and extracellular metabolomics data for Lactobacillus plantarum, detailing the overall metabolic changes. We agree with the reviewer that the effect of metabolites on host purine nucleoside metabolism is worth investigating, but it has not been explored too much in this paper as it focuses more on the changes in the metabolites of the purine nucleosides themselves. We plan to explore this topic further in future research.

    Reviewer #3 (Public Review):

    Fu et al. present a multi-model study using goose and mouse that investigates the protective effects of Lactobacillus plantarum against hyperuricaemia. They highlight this strain's significance and clarify its role in responding to intestinal nucleoside levels and affecting uric acid metabolism through modulation of host signaling pathways.

    Strengths:

    (1) Fu et al. created two animal models for validation, yielding more reliable and extensive data. In addition, the in vitro tests were repeatedly tested by a multitude of methods, proving to be convincing.

    (2) This study integrates microbiomics, whole genomics, in vitro bacterial culture, and metabolomics, providing a wealth of data and valuable insights for future research.

    We thank the reviewer for their encouraging assessment.

    Weakness:

    Fu et al. clearly described the role of Lactobacillus plantarum, but it is also important to explore its other mechanisms influencing uric acid metabolism in the host. While changes in hepatic and renal uric acid metabolism were confirmed, the gut's role in this process deserves investigation, particularly regarding whether Lactobacillus plantarum or its metabolites act within the gut. The authors have effectively conveyed the story outlined in the article's title, and the remainder can be explored later. In addition, further discussion is needed to highlight how this strain of Lactobacillus plantarum differs from other Lactobacillus strains or how it innovatively functions differ from some literature reported.

    Thank you! We fully acknowledge the importance of investigating the role of gut in this process, especially whether Lactobacillus plantarum or its metabolites have an effect within the gut, which would be an interesting topic for a follow-up study. We fully agree that it is crucial to highlight how this Lactobacillus plantarum differs from other strains and those reported in the literature regarding its innovative functions, as discussed in detail in lines 343 to 376. We fully acknowledge the importance of investigating the role of gut in this process, especially whether Lactobacillus plantarum or its metabolites have an effect within the gut, which would be an interesting topic for a follow-up study. We fully agree that it is crucial to highlight how this Lactobacillus plantarum differs from other strains and those reported in the literature regarding its innovative functions, as discussed in detail in lines 343 to 376. Previous studies indicate that Lactobacillus plantarum can reduce hyperuricaemia, but its specific uric acid-lowering mechanism and the process of nucleoside degradation remain unclear. We investigated the nucleoside hydrolysis function of Lactobacillus plantarum, identified key genes, and validated by gene knockout. Our findings suggest that host-derived Lactobacillus plantarum plays an antagonistic role against hyperuricaemia.

  3. eLife

    eLife Assessment

    The landmark significance of this manuscript is based on the mechanistic description of purine metabolism by Lactobacillus plantarum, which helps to alleviate hyperuricemia, which is a phenotype that underlies multiple disease symptoms. The evidence provided for L. plantarum's involvement in reducing hyperuricemia was exceptional, combining microbiomics, whole genomics, in vitro bacterial culture, gene knock-outs, and metabolomics. Collectively, the study shows a clear link between the gut microbiota and hyperuricemia, providing a pathway for modification to help alleviate this condition.

  4. eLife

    Reviewer #1 (Public Review):

    Lactobacillus plantarum is a beneficial bacterium renowned for its positive physiological effects and probiotic functions. Fu et al. conducted an investigation into the involvement of this bacterium in host purine metabolism. Initially, they employed microbiomics to analyze changes in L. plantarum within a hyperuricemia model, followed by isolation of the bacterium from this model. The gene map associated with purine nucleoside metabolism was determined through whole-genome analysis. Metabolic shifts in L. plantarum under nucleoside-enriched conditions were assessed using HPLC and metabolomics, while underlying mechanisms were explored through gene knockout experiments. Finally, the efficacy of L. plantarum was validated in hyperuricemia models involving goslings and mice. The authors presented their findings coherently and logically, addressing key questions using appropriate methodologies and yielding significant and innovative results. The authors demonstrated that host-derived Lactobacillus plantarum alleviates host hyperuricemia by influencing purine metabolism. However, their study primarily focused on this bacterium without delving deeper into the mechanisms underlying hyperuricemia beyond verification through two models. Nevertheless, these findings are sufficient to support their conclusion effectively. Additionally, further research is warranted to investigate the metabolites of Lactobacillus plantarum.

  5. eLife

    Reviewer #2 (Public Review):

    Summary:
    Purine nucleoside metabolism in intestinal flora is integral to the purine nucleoside metabolism in the host. This study identified the iunH gene in Lactobacillus plantarum that regulates its purine nucleoside metabolism. Oral gavage of Lactobacillus plantarum and subsequent analysis showed it maintains homeostasis of purine nucleoside metabolism in the host.

    Strengths:
    This study presents sufficient evidence for the role of Lactobacillus plantarum in alleviating hyperuricaemia, combining microbiomics, whole genomics, in vitro bacterial culture, and metabolomics. These results suggest the iunH gene of Lactobacillus plantarum is crucial in host purine nucleoside metabolism. The experimental design is robust, and the data are of high quality. This study makes significant contributions to the fields of hyperuricaemia, purine nucleoside metabolism, and Lactobacillus plantarum investigation.

    Weaknesses:
    A key limitation of this manuscript is the absence of an in-depth study on the alleviation metabolism of Lactobacillus plantarum. Notable questions include: What overall metabolic changes occur in a purine nucleoside-enriched environment? How do the metabolites of Lactobacillus plantarum vary? Do these metabolites influence host purine nucleoside metabolism? These areas merit further investigation.

  6. eLife

    Reviewer #3 (Public Review):

    Fu et al. present a multi-model study using goose and mouse that investigates the protective effects of Lactobacillus plantarum against hyperuricaemia. They highlight this strain's significance and clarify its role in responding to intestinal nucleoside levels and affecting uric acid metabolism through modulation of host signaling pathways.

    Strengths:
    (1) Fu et al. created two animal models for validation, yielding more reliable and extensive data. In addition, the in vitro tests were repeatedly tested by a multitude of methods, proving to be convincing.
    (2) This study integrates microbiomics, whole genomics, in vitro bacterial culture, and metabolomics, providing a wealth of data and valuable insights for future research.

    Weakness:
    Fu et al. clearly described the role of Lactobacillus plantarum, but it is also important to explore its other mechanisms influencing uric acid metabolism in the host. While changes in hepatic and renal uric acid metabolism were confirmed, the gut's role in this process deserves investigation, particularly regarding whether Lactobacillus plantarum or its metabolites act within the gut. The authors have effectively conveyed the story outlined in the article's title, and the remainder can be explored later. In addition, further discussion is needed to highlight how this strain of Lactobacillus plantarum differs from other Lactobacillus strains or how it innovatively functions differ from some literature reported.

  7. Version published to 10.1101/2024.08.01.606206v1 on bioRxiv