Gut Microbes: Regulating uric acid

Certain strains of a bacterium found in the gut of some animals, Lactobacillus plantarum, are able to counter hyperuricemia, a condition caused by high levels of uric acid in the blood.
  1. Caihong Hu  Is a corresponding author
  1. College of Animal Sciences, Zhejiang University, China

Improvements in the quality of life have led to an increase in the incidence of hyperuricemia, a medical condition that can lead to kidney stones and gout, with cases increasingly affecting younger individuals (Johnson et al., 2018; Zhang et al., 2019). Hyperuricemia – the presence of abnormally high levels of uric acid in the blood – arises from interactions between the liver, the kidneys and the gut, which has a role in removing uric acid from the body (Dalbeth et al., 2021; Niu et al., 2018; Yun et al., 2017). Studies indicate that gut microbes are crucial to uric acid metabolism, and interventions such as probiotics, prebiotics and fecal microbiota transplants can help reduce hyperuricemia by altering the gut microbiota (Cao et al., 2022a; Wang et al., 2022; Zhao et al., 2022).

It has been shown that various strains of bacteria can alleviate hyperuricemia through two mechanisms: the direct hydrolysis of uric acid, and the hydrolase-mediated degradation of nucleosides that are the precursors of uric acid in the intestine. Limosilactobacillus fermentum JL-3 – a strain isolated from Chinese mud water – is capable of the hydrolysis of uric acid (Wu et al., 2021), whereas various strains of Lactobacillus, a well-known genus of bacteria, reduce uric acid levels through the hydrolysis of nucleosides in the intestine: these strains include L. paracasei (X11; Cao et al., 2022b) and strains of L. plantarum derived from Chinese sauerkraut (DM9218-A; Li et al., 2014) and Chinese mustard (GKM3; Hsu et al., 2019).

Recent studies have revealed that gene cloning can be used to identify specific hydrolases involved in the degradation of nucleosides for L. plantarum and L. aviarius (Li et al., 2023b; Li et al., 2023a). However, the precise mechanisms underlying the hydrolysis of the nucleoside precursors of uric acid have remained unclear. Now, in eLife, Wence Wang (South China Agricultural University), Qiang Tu (Shandong University) and colleagues – including Yang Fu as first author – report the results of in vitro studies and experiments on geese and mice that shed new light on the hydrolysis of these precursors (Fu et al., 2024).

The team isolated a strain called L. plantarum SQ001 from geese with hyperuricemia, and a genome-wide analysis revealed the presence of four genes that code for nucleoside hydrolysis-related enzymes (iunH, yxjA, rihA, rihC). In vitro experiments revealed that one of these enzymes, iunH, effectively catalyzes the hydrolysis of nucleosides, such as inosine and guanosine, converting them to nucleobases, as evidenced by metabolomics analysis. The hydrolysis mechanism was further validated through experiments that involved knocking out the gene for iunH in L. plantarum SQ001, and expressing it in E. coli. Although nucleosides are hydrolyzed to produce nucleobases, the direct link between this process and the reduction of uric acid remains unclear, possibly due to the transport of nucleosides and nucleobases in the gut. It may be that the lower uptake of these substances reduces the synthesis and accumulation of uric acid.

The team validated the functionality of L. plantarum SQ001 by establishing models of hyperuricemia in both geese and mice (Figure 1), and showed that this particular strain significantly enhanced the abundance of Lactobacillus in the gut of the host, which alleviated the symptoms of hyperuricemia by reducing the synthesis of uric acid and increasing its excretion. The fact that hyperuricemia was alleviated in mice may help with efforts to develop new ways to treat hyperuricemia and gout in humans.

Lactobacillus plantarum reduces uric acid synthesis through the hydrolysis of nucleosides.

A strain of the bacterium L. plantarum was isolated from the large intestine of geese with hyperuricemia, a condition caused by the presence of abnormally high levels of uric acid in the blood (top left). In vitro experiments showed that the presence of the bacteria led to an increase in the degradation of nucleosides that are precursors of uric acid. Administering the bacteria to healthy geese and mice (top right) also led to a reduction in the levels of uric acid in the blood. Other experiments showed that L. plantarum absorbed the nucleosides, and that an enzyme called iunH broke down the nucleosides to produce nucleobases (bottom).

Figure created with figdraw.com.

References

Article and author information

Author details

  1. Caihong Hu

    Caihong Hu is in the College of Animal Sciences, Zhejiang University, China

    For correspondence
    chhu@zju.edu.cn
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5445-4532

Publication history

  1. Version of Record published:

Copyright

© 2024, Hu

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 360
    views
  • 30
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Caihong Hu
(2024)
Gut Microbes: Regulating uric acid
eLife 13:e104493.
https://doi.org/10.7554/eLife.104493

Further reading

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease
    Amanda Mixon Blackwell, Yasaman Jami-Alahmadi ... Paul A Sigala
    Research Article

    Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum parasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest that Plasmodium repurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.

    1. Ecology
    2. Microbiology and Infectious Disease
    Benedikt M Mortzfeld, Shakti K Bhattarai, Vanni Bucci
    Short Report

    Interspecies interactions involving direct competition via bacteriocin production play a vital role in shaping ecological dynamics within microbial ecosystems. For instance, the ribosomally produced siderophore bacteriocins, known as class IIb microcins, affect the colonization of host-associated pathogenic Enterobacteriaceae species. Notably, to date, only five of these antimicrobials have been identified, all derived from specific Escherichia coli and Klebsiella pneumoniae strains. We hypothesized that class IIb microcin production extends beyond these specific compounds and organisms. With a customized informatics-driven approach, screening bacterial genomes in public databases with BLAST and manual curation, we have discovered 12 previously unknown class IIb microcins in seven additional Enterobacteriaceae species, encompassing phytopathogens and environmental isolates. We introduce three novel clades of microcins (MccW, MccX, and MccZ), while also identifying eight new variants of the five known class IIb microcins. To validate their antimicrobial potential, we heterologously expressed these microcins in E. coli and demonstrated efficacy against a variety of bacterial isolates, including plant pathogens from the genera Brenneria, Gibbsiella, and Rahnella. Two newly discovered microcins exhibit activity against Gram-negative ESKAPE pathogens, i.e., Acinetobacter baumannii or Pseudomonas aeruginosa, providing the first evidence that class IIb microcins can target bacteria outside of the Enterobacteriaceae family. This study underscores that class IIb microcin genes are more prevalent in the microbial world than previously recognized and that synthetic hybrid microcins can be a viable tool to target clinically relevant drug-resistant pathogens. Our findings hold significant promise for the development of innovative engineered live biotherapeutic products tailored to combat these resilient bacteria.