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Gut Microbiome and Metabolome Signatures in Calcium Oxalate Stone Recurrence: A Multi-Omics Study

ABSTRACT:

Background: The incidence and recurrence rate of nephrolithiasis have been increasing annually. Recent evidence highlights a close association between the composition and function of the gut microbiome and the occurrence and recurrence of kidney stones. We performed a multi-omic study to investigate changes in gut microbiota and their metabolites during nephrolithiasis development and recurrence, and to explore the underlying molecular mechanisms. Fecal samples from 37 recurrent stone patients, 38 first-episode stone patients, and 39 healthy controls were collected for 16S rDNA amplicon sequencing and liquid chromatography-mass spectrometry. Ten samples from each group were randomly selected for metagenomic sequencing.

Results: Compared to incident cases, recurrent stone patients exhibited further reduced gut microbial richness and diversity, with enrichment of Enterobacterales, Pseudomonadota, Gammaproteobacteria, Enterobacteraceae, Escherichia-Shigella, and Bacillia. In the recurrent kidney stone group, 9 metabolites were upregulated and 86 downregulated, primarily enriched in purine metabolism, and caffeine metabolism pathways. We identified 10 metabolites as recurrence biomarkers and found significant correlations between Escherichia-Shigella and Asn-Tyr, Leu-Ala-Ile, Tyrosyl-Alanine, or 3'-hydroxyhexobarbital. Additionally, gender-specific gut microbiota signatures were observed. Oxalate decarboxylase and short-chain fatty acid-related enzymes decreased during stone formation but rebounded with recurrence. Caffeine and its metabolites were significantly downregulated in recurrent patients, suggesting a potential association with stone formation and recurrence that merits further investigation.

Conclusions: Our study comprehensively characterizes the gut microbiome and metabolome signatures associated with nephrolithiasis recurrence. The findings reveal that recurrent nephrolithiasis is characterized by impaired gut microbial evenness, enrichment of specific taxa including Escherichia-Shigella, and dysregulated metabolic pathways such as purine metabolism and caffeine metabolism. The 10 identified metabolites show promise as potential recurrence biomarkers, with notable correlations between Escherichia-Shigella and key metabolites. These results highlight the critical association of the gut microbiome-metabolome axis with renal stone recurrence, providing novel microbial and metabolic targets for early prediction, with potential implications for prevention and personalized treatment that require further validation.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13960 | MetaboLights | 2026-03-03

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13960_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13960_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13960_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13960_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) can be offered to patients beyond Milan criteria. However, there are currently no molecular markers that can be used on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to identify proteins on HCC explant predictive of recurrence post-transplant, thereby guiding surveillance strategies and identifying patients beyond Milan criteria who would fare well following LT. Methods: LT recipients who had been transplanted at the University Health Network for HCC beyond Milan criteria in the context of Hepatitis B cirrhosis were identified. Snap-frozen samples from the dominant tumors of recurrent (N=7) and non-recurrent (N=4) patients were analyzed using LC-MS/MS on a Q-Exactive Plus mass spectrometer to delineate a distinctive proteomic signature. These tumors were also profiled by a Human Gene 2.0 ST microarray platform to identify a transcriptomic signature predictive of recurrence and analyzed with R packages. STRING database was used to characterize the implicated pathways. Kaplan-Meier estimator was used to generate a combined proteomic/transcriptomic signature predictive of HCC recurrence in patients with HCC beyond Milan criteria at time of LT. Significantly predictive proteins were verified and internally validated by immunoblotting or immunohistochemistry. Results: A total of 79 proteins and 636 genes were significantly differentially expressed in recurrent HCC, compared to non-recurrent (p<0.05). Among these, LGALS3, LGALS3BP, HAL, THBS1, and BLMH, were significantly increased in recurrent HCC at the protein and gene expression level. In turn, ALDH1A1 protein and gene expression were significantly decreased in recurrent HCC. Univariate survival analysis depicted ALDH1A1 (HR=0.084, 95%CI 0.01-0.68, p=0.02), LGALS3BP (HR=7.14, 95%CI 1.20-42.96, p=0.03), and LGALS3 (HR=2.89, 95%CI 1.01-8.3, p=0.049) as the key dysregulated proteins and genes in the patients with HCC recurrence versus those with non-recurrence by both proteomic and transcriptomic analysis. Decreased ALDH1A1 and significantly increased LGALS3 protein expression in recurrent HCC was verified by immunoblotting. Increased LGALS3BP protein expression in recurrent HCC was orthogonally verified and validated by immunohistochemistry in 30 independent HCC samples. Conclusion: Protein and gene expression of the cancer stem cell marker ALDH1A1 was protective against cancer recurrence in patients transplanted for HCC beyond Milan criteria. Conversely, increased expression of LGALS3 and LGALS3BP on explant was significantly predictive of post-transplant recurrence. These findings were internally validated, suggesting potential utility in identifying patients with HCC beyond Milan who would clearly benefit from transplant with limited recurrence risk and guiding post-transplant surveillance.

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Gut Microbiome and Metabolome Signatures in Calcium Oxalate Stone Recurrence: A Multi-Omics Study

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