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Nephrolithiasis is a medical condition characterized by the existence or development of calculi, commonly referred to as stones within the renal system, and poses significant health challenges. Calcium phosphate and calcium oxalate are the predominant constituents of renal calculi and are introduced into the human body primarily via dietary sources. The presence of oxalates can become particularly problematic when the delicate balance of the normal flora residing within the gastrointestinal tract is disrupted. Within the human gut, species of Oxalobacter, Lactobacillus, and Bifidobacterium coexist in a symbiotic relationship. They play a pivotal role in mitigating the risk of stone formation by modulating certain biochemical pathways and producing specific enzymes that can facilitate the breakdown and degradation of oxalate salts. The probiotic potential exhibited by these bacteria is noteworthy, as it underscores their possible utility in the prevention of nephrolithiasis. Investigating the mechanisms by which these beneficial microorganisms exert their effects could lead to novel therapeutic strategies aimed at reducing the incidence of kidney stones. The implications of utilizing probiotics as a preventive measure against kidney stone formation represent an intriguing frontier in both nephrology and microbiome research, meriting further investigation to unlock their full potential. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that intestinal and urinary tract flora are closely related to the formation of kidney stones. The removal of probiotics represented by lactic acid bacteria and the colonization of pathogenic bacteria can directly or indirectly promote the occurrence of kidney stones. However, currently existing natural probiotics have limitations. Synthetic biology is an emerging discipline in which cells or living organisms are genetically designed and modified to have biological functions that meet human needs, or even create new biological systems, and has now become a research hotspot in various fields. Using synthetic biology approaches of microbial engineering and biological redesign to enable probiotic bacteria to acquire new phenotypes or heterologous protein expression capabilities is an important part of synthetic biology research. Synthetic biology modification of microorganisms in the gut and urinary tract can effectively inhibit the development of kidney stones by a range of means, including direct degradation of metabolites that promote stone production or indirect regulation of flora homeostasis. This article reviews the research status of engineered microorganisms in the prevention and treatment of kidney stones, to provide a new and effective idea for the prevention and treatment of kidney stones.

Nephrolithiasis is a medical condition characterized by the existence or development of calculi, commonly referred to as stones within the renal system, and poses significant health challenges. Calcium phosphate and calcium oxalate are the predominant constituents of renal calculi and are introduced into the human body primarily via dietary sources. The presence of oxalates can become particularly problematic when the delicate balance of the normal flora residing within the gastrointestinal tract is disrupted. Within the human gut, species of Oxalobacter, Lactobacillus, and Bifidobacterium coexist in a symbiotic relationship. They play a pivotal role in mitigating the risk of stone formation by modulating certain biochemical pathways and producing specific enzymes that can facilitate the breakdown and degradation of oxalate salts. The probiotic potential exhibited by these bacteria is noteworthy, as it underscores their possible utility in the prevention of nephrolithiasis. Investigating the mechanisms by which these beneficial microorganisms exert their effects could lead to novel therapeutic strategies aimed at reducing the incidence of kidney stones. The implications of utilizing probiotics as a preventive measure against kidney stone formation represent an intriguing frontier in both nephrology and microbiome research, meriting further investigation to unlock their full potential.

Individuals with urinary stone disease (USD) exhibit dysbiosis in the urinary tract and the loss of Lactobacillus that promote urinary tract health. However, the microbial metabolic functions that differentiate individuals with USD from healthy individuals are unknown. The objective of the current study was to determine the microbial functions across prokaryotic, viral, fungal, and protozoan domains that are associated with calcium oxalate (CaOx) stone formers through comparative shotgun metagenomics of midstream, voided urine samples for a small number of patients (n = 5 CaOx stone formers, n = 5 healthy controls). Results revealed that CaOx stone formers had reduced levels of genes associated with oxalate metabolism, as well as transmembrane transport, proteolysis, and oxidation-reduction processes. From 17 draft genomes extracted from the data and > 42,000 full length reference genomes, genes enriched in the Control group mapped overwhelming to Lactobacillus crispatus and those associated with CaOx mapped to Pseudomonas aeruginosa and Burkholderia sp. The microbial functions that differentiated the clinical cohorts are associated with known mechanisms of stone formation. While the prokaryotes most differentiated the CaOx and Control groups, a diverse, trans-domain microbiome was apparent. While our sample numbers were small, results corroborate previous studies and suggest specific microbial metabolic pathways in the urinary tract that modulate stone formation. Future studies that target these metabolic pathways as well as the influence of viruses, fungi, and protozoa on urinary tract physiology is warranted.

The solute-linked carrier 26 (SLC26) protein family is comprised of multifunctional transporters of substrates that include oxalate, sulphate, and chloride. Disorders of oxalate homeostasis cause hyperoxalemia and hyperoxaluria, leading to urinary calcium oxalate precipitation and urolithogenesis. SLC26 proteins are aberrantly expressed during kidney stone formation, and consequently may present therapeutic targets. SLC26 protein inhibitors are in preclinical development. In this review, we integrate the findings of recent reports with clinical data to highlight the role of SLC26 proteins in oxalate metabolism during urolithogenesis, and discuss limitations of current studies and potential directions for future research. [ABSTRACT FROM AUTHOR]

Biohydrogen is mainly produced by anaerobic bacteria, anaerobic fungi, and algae under anaerobic conditions. In higher eukaryotes, it is thought that molecular hydrogen (H2) functions as a signaling molecule for physiological processes such as stress responses. Here, it is demonstrated that white-rot fungi produce H2 during wood decay. The white-rot fungus Trametes versicolor produces H2 from wood under aerobic conditions, and H2 production is completely suppressed under hypoxic conditions. Additionally, oxalate and formate supplementation of the wood culture increased the level of H2 evolution. RNA-seq analyses revealed that T. versicolor oxalate production from the TCA/glyoxylate cycle was down-regulated, and conversely, genes encoding oxalate and formate metabolism enzymes were up-regulated. Although the involvement in H2 production of a gene annotated as an iron hydrogenase was uncertain, the results of organic acid supplementation, gene expression, and self-recombination experiments strongly suggest that formate metabolism plays a role in the mechanism of H2 production by this fungus. It is expected that this novel finding of aerobic H2 production from wood biomass by a white-rot fungus will open new fields in biohydrogen research.

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbes can degrade oxalate using multiple ODPs and protect against its absorption. The exact oxalate-degrading taxa in the human microbiota and their ODP have not been described. We leverage multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota primarily uses the type II ODP, rather than type I. Furthermore, among the diverse ODP-encoding microbes, an oxalate autotroph, Oxalobacter formigenes, dominates this function transcriptionally. Patients with inflammatory bowel disease (IBD) frequently suffer from disrupted oxalate homeostasis and calcium oxalate nephrolithiasis. We show that the enteric oxalate level is elevated in IBD patients, with highest levels in Crohn’s disease (CD) patients with both ileal and colonic involvement consistent with known nephrolithiasis risk. We show that the microbiota ODP expression is reduced in IBD patients, which may contribute to the disrupted oxalate homeostasis. The specific changes in ODP expression by several important taxa suggest that they play distinct roles in IBD-induced nephrolithiasis risk. Lastly, we colonize mice that are maintained in the gnotobiotic facility with O. formigenes, using either a laboratory isolate or an isolate we cultured from human stools, and observed a significant reduction in host fecal and urine oxalate levels, supporting our in silico prediction of the importance of the microbiome, particularly O. formigenes in host oxalate homeostasis.

Nephrolithiasis ranks third among urological diseases in terms of prevalence, making up about 15% of cases. The continued increase in the incidence of nephrolithiasis is most probably due to changes in eating habits (high protein, sodium, and sugar diets) and lifestyle (reduced physical activity) in all developed countries. Some 80% of all kidney stones cases are oxalate urolithiasis, which is also characterized by the highest risk of recurrence. Frequent relapses of nephrolithiasis contribute to severe complications and high treatment costs. Unfortunately, there is no known effective way to prevent urolithiasis at present. In cases of diet-related urolithiasis, dietary changes may prevent recurrence. However, in some patients, the condition is unrelated to diet; in such cases, there is evidence to support the use of stone-related medications. Interestingly, a growing body of evidence indicates the potential of the microbiome to reduce the risk of developing renal colic. Previous studies have primarily focused on the use of Oxalobacterformigenes in patients with urolithiasis. Unfortunately, this bacterium is not an ideal probiotic due to its antibiotic sensitivity and low pH. Therefore, subsequent studies sought to find bacteria which are capable of oxalate degradation, focusing on well-known probiotics including Lactobacillus and Bifidobacterium strains, Eubacterium lentum, Enterococcus faecalis, and Escherichia coli.

Numerous studies have shown that intestinal and urinary tract flora are closely related to the formation of kidney stones. The removal of probiotics represented by lactic acid bacteria and the colonization of pathogenic bacteria can directly or indirectly promote the occurrence of kidney stones. However, currently existing natural probiotics have limitations. Synthetic biology is an emerging discipline in which cells or living organisms are genetically designed and modified to have biological functions that meet human needs, or even create new biological systems, and has now become a research hotspot in various fields. Using synthetic biology approaches of microbial engineering and biological redesign to enable probiotic bacteria to acquire new phenotypes or heterologous protein expression capabilities is an important part of synthetic biology research. Synthetic biology modification of microorganisms in the gut and urinary tract can effectively inhibit the development of kidney stones by a range of means, including direct degradation of metabolites that promote stone production or indirect regulation of flora homeostasis. This article reviews the research status of engineered microorganisms in the prevention and treatment of kidney stones, to provide a new and effective idea for the prevention and treatment of kidney stones., Competing Interests: All authors disclosed no relevant relationships., (© 2024 The Authors.)

Analysis of 16S ribosomal RNA (rRNA)-encoding gene sequences from gut microbial ecosystems reveals bewildering genetic diversity. Some metabolic functions, such as glucose utilisation, are fairly widespread throughout the genetic spectrum. Others, however, are not. Despite so many phylotypes being present, single species or perhaps only two or three species often carry out key functions. Among ruminal bacteria, only three species can break down highly structured cellulose, despite the prevalence and importance of cellulose in ruminant diets, and one of those species, Fibrobacter succinogenes, is distantly related to the most abundant ruminal species. Fatty acid biohydrogenation in the rumen, particularly the final step of biohydrogenation of C18 fatty acids, stearate formation, is achieved only by a small sub-group of bacteria related to Butyrivibrio fibrisolvens. Individuals who lack Oxalobacter formigenes fail to metabolise oxalate and suffer kidney stones composed of calcium oxalate. Perhaps the most celebrated example of the difference a single species can make is the ‘mimosine story’ in ruminants. Mimosine is a toxic amino acid found in the leguminous plant, Leucaena leucocephala. Mimosine can cause thyroid problems by being converted to the goitrogen, 3-hydroxy-4(1H)-pyridone, in the rumen. Observations that mimosine-containing plants were toxic to ruminants in some countries but not others led to the discovery of Synergistes jonesii, which metabolises 3-hydroxy-4(1H)-pyridone and protects animals from toxicity. Thus, despite the complexities indicated by molecular microbial ecology and genomics, it should never be forgotten that gut communities contain important metabolic niches inhabited by species with highly specific metabolic capability.

Biohydrogen is mainly produced by anaerobic bacteria, anaerobic fungi, and algae under anaerobic conditions. In higher eukaryotes, it is thought that molecular hydrogen (H 2 ) functions as a signaling molecule for physiological processes such as stress responses. Here, it is demonstrated that white-rot fungi produce H 2 during wood decay. The white-rot fungus Trametes versicolor produces H 2 from wood under aerobic conditions, and H 2 production is completely suppressed under hypoxic conditions. Additionally, oxalate and formate supplementation of the wood culture increased the level of H 2 evolution. RNA-seq analyses revealed that T. versicolor oxalate production from the TCA/glyoxylate cycle was down-regulated, and conversely, genes encoding oxalate and formate metabolism enzymes were up-regulated. Although the involvement in H 2 production of a gene annotated as an iron hydrogenase was uncertain, the results of organic acid supplementation, gene expression, and self-recombination experiments strongly suggest that formate metabolism plays a role in the mechanism of H 2 production by this fungus. It is expected that this novel finding of aerobic H 2 production from wood biomass by a white-rot fungus will open new fields in biohydrogen research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mori, Takahashi, Soga, Arimoto, Kishikawa, Yama, Dohra, Kawagishi and Hirai.)

The solute-linked carrier 26 (SLC26) protein family is comprised of multifunctional transporters of substrates that include oxalate, sulphate, and chloride. Disorders of oxalate homeostasis cause hyperoxalemia and hyperoxaluria, leading to urinary calcium oxalate precipitation and urolithogenesis. SLC26 proteins are aberrantly expressed during kidney stone formation, and consequently may present therapeutic targets. SLC26 protein inhibitors are in preclinical development. In this review, we integrate the findings of recent reports with clinical data to highlight the role of SLC26 proteins in oxalate metabolism during urolithogenesis, and discuss limitations of current studies and potential directions for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Huang, Liu, Liao, Yan and Liu.)

Background: Evidence exists reporting that Pyrrosia lingua (PL, Xinhui Pharmaceutical, Polypodiaceae) alleviates nephrolithiasis in rat models. The precipitation of calcium oxalate may result in kidney stones, and the intestinal microbiota is critical for oxalate metabolism. Therefore, we attempt to delineate the molecular mechanism underlying the effect of PL on nephrolithiasis and its association with gut microbiota.Methods: Following differential flora analysis in gutMEGA, the network relationship of PL and nephrolithiasis was analyzed based on the TCMSP, DisGeNET and STRING databases. Moreover, the kidney stone model rats were fed with different doses of PL powder and PL extract. In addition, metabolomics technology was employed to identify the active ingredients in PL extract and the microbial metabolites in rat feces.Results: The effect of PL on the nephrolithiasis was based on quercetin and kaempferol by mediating the toll-like receptor signaling pathway and regulating the expression levels of interleukin 6, tumor necrosis factor, mitogen activated protein kinase 8, and secreted phosphoprotein 1. PL significantly reduced the levels of urine oxalic acid, urine calcium, and osteopontin (OPN) levels in rat models of nephrolithiasis. Notably, PL extract decreased these two indicators to lower levels. Furthermore, contents of Oxalobacter formigenes, Bacteriodetes, Bifidobacterium and Fecalibacterium were obviously reduced after treatment with PL extract.Conclusion: PL powder and its active extracts reduce the oxalate level in urine by regulating oxalate metabolism, thus ameliorating the damage of kidney tissues and preventing kidney stone formation. This study suggests the use of PL and its extracts as an alternative source of promising agents that might directly or indirectly inhibit the progression of kidney stone diseases. [ABSTRACT FROM AUTHOR]

Nephrolithiasis ranks third among urological diseases in terms of prevalence, making up about 15% of cases. The continued increase in the incidence of nephrolithiasis is most probably due to changes in eating habits (high protein, sodium, and sugar diets) and lifestyle (reduced physical activity) in all developed countries. Some 80% of all kidney stones cases are oxalate urolithiasis, which is also characterized by the highest risk of recurrence. Frequent relapses of nephrolithiasis contribute to severe complications and high treatment costs. Unfortunately, there is no known effective way to prevent urolithiasis at present. In cases of diet-related urolithiasis, dietary changes may prevent recurrence. However, in some patients, the condition is unrelated to diet; in such cases, there is evidence to support the use of stone-related medications. Interestingly, a growing body of evidence indicates the potential of the microbiome to reduce the risk of developing renal colic. Previous studies have primarily focused on the use of Oxalobacterformigenes in patients with urolithiasis. Unfortunately, this bacterium is not an ideal probiotic due to its antibiotic sensitivity and low pH. Therefore, subsequent studies sought to find bacteria which are capable of oxalate degradation, focusing on well-known probiotics including Lactobacillus and Bifidobacterium strains, Eubacterium lentum, Enterococcus faecalis, and Escherichia coli. [ABSTRACT FROM AUTHOR]

Abstract: Primary hyperoxaluria type 1 (PH1) is an atypical peroxisomal disorder, as befits a deficiency of alanine:glyoxylate aminotransferase (AGT), which is itself an atypical peroxisomal enzyme. PH1 is characterized by excessive synthesis and excretion of the metabolic end-product oxalate and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract. Disease in many patients is caused by a unique protein trafficking defect in which AGT is mistargeted from peroxisomes to mitochondria, where it is metabolically ineffectual, despite remaining catalytically active. Although the peroxisomal import of human AGT is dependent upon the PTS1 import receptor PEX5p, its PTS1 is exquisitely specific for mammalian AGT, suggesting the presence of additional peroxisomal targeting information elsewhere in the AGT molecule. This and many other functional peculiarities of AGT are probably a consequence of its rather chequered evolutionary history, during which much of its time has been spent being a mitochondrial, rather than a peroxisomal, enzyme. Analysis of the molecular basis of AGT mistargeting in PH1 has thrown into sharp relief some of the fundamental differences between the requirements of the peroxisomal and mitochondrial protein import pathways, particularly the properties of peroxisomal and mitochondrial matrix targeting sequences and the different conformational limitations placed upon importable cargos. [Copyright &y& Elsevier]

Abstract: NAD-dependent formate dehydrogenase (FDH, EC 1.2.1.2.) was purified 34-fold with 5.8% yield as an electrophoretically homogeneous protein from the white-rot fungus Ceriporiopsis subvermispora. The native enzyme has a molecular mass of 84kDa consisting of two identical subunits as a homodimer. The K m values for formate and NAD were found to be 2.5mM and 28μM, respectively, at the optimum pH 6.5. The enzyme activity was inhibited by NADH, ADP, and ATP. The kinetic analysis indicated that the enzyme reaction proceeded by the ordered Bi Bi mechanism. Oxalate was found to be catabolized by mediations of oxalate decarboxylase (ODC, EC 4.1.1.2) and FDH during the vegetative growth of C. subvermispora, while it was oxidized by oxalate oxidase (OXO, EC 1.2.3.4) at the later stage of the cultivation. A possible role of the two-oxalate decomposing systems with ODC and OXO was discussed in relation to carbon metabolism of lignin-degrading basidiomycetes. [Copyright &y& Elsevier]

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbes can degrade oxalate using multiple ODPs and protect against its absorption. The exact oxalate-degrading taxa in the human microbiota and their ODP have not been described. We leverage multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota primarily uses the type II ODP, rather than type I. Furthermore, among the diverse ODP-encoding microbes, an oxalate autotroph, Oxalobacter formigenes , dominates this function transcriptionally. Patients with inflammatory bowel disease (IBD) frequently suffer from disrupted oxalate homeostasis and calcium oxalate nephrolithiasis. We show that the enteric oxalate level is elevated in IBD patients, with highest levels in Crohn's disease (CD) patients with both ileal and colonic involvement consistent with known nephrolithiasis risk. We show that the microbiota ODP expression is reduced in IBD patients, which may contribute to the disrupted oxalate homeostasis. The specific changes in ODP expression by several important taxa suggest that they play distinct roles in IBD-induced nephrolithiasis risk. Lastly, we colonize mice that are maintained in the gnotobiotic facility with O. formigenes , using either a laboratory isolate or an isolate we cultured from human stools, and observed a significant reduction in host fecal and urine oxalate levels, supporting our in silico prediction of the importance of the microbiome, particularly O. formigenes in host oxalate homeostasis., Competing Interests: ML, JD, JH, AV, TB, MH, PL, HL, KR, AT, MB, LN No competing interests declared, JA is an employee of Litholink, AB is an employee of Genentech, (© 2021, Liu et al.)