Reduced butyrate-producing bacteria and altered metabolic pathways in the gut microbiome of immunoglobulin A nephropathy patients

Abstract

Gut-associated lymphoid tissue is central to the production of galactose-deficient IgA1 (Gd-IgA1), a key factor in immunoglobulin A nephropathy (IgAN). Although no major differences in gut microbiome diversity have been reported across IgAN cohorts, functional alterations in microbial composition may contribute to disease pathogenesis. The study was designed as a cross-sectional study with an embedded prospective cohort component. Forty-eight adults with biopsy-confirmed IgAN-categorized as progressors (eGFR decline > 5 ml/min/1.73 m²/year, n = 23) or nonprogressors (n = 23)-and 23 healthy controls (HC) were recruited. Stool samples underwent metagenomic and functional profiling. Alpha diversity did not differ significantly between IgAN patients and HC. However, butyrate-producing bacteria (Butyrococcus, Agathobacter rectalis) were less abundant in IgAN patients. The sulfoquinovose degradation I pathway, associated with these bacteria, was also reduced. Nucleotide- and nucleoside-biosynthesis pathways were elevated in IgAN. Gd-IgA1 levels correlated with variations in metabolic pathways. Progressors demonstrated enhanced activity in isopropanol biosynthesis, biotin biosynthesis II, and phospholipid biosynthesis pathways. IgAN patients show reduced butyrate-producing bacteria and distinct functional changes in the gut microbiome suggestive of immune activation and inflammation. Progressors exhibit additional metabolic shifts linked to bacterial membrane stabilization.

Keywords: Butyrate-producing bacteria; Gut microbiome; Immunoglobulin a nephropathy; Progressors.

Fig. 1

Study group flow chart.

Fig. 2

Alterations in the gut microbiome in IgA nephropathy patients and healthy individuals. A Taxonomy bar plot depicting 20 of the most representative species of every individual stratified by study group. B Relative abundance of Eubacterium R sp000433975 in control subjects (blue) and IgAN patients (red). Boxplots show the median, 25th, and 75th percentiles and outliers. C Volcano plot representing the differential abundance effect size (logFC) and FDR relationship between control subjects and IgAN patients. Labeled values represent the top 20 Species based on FDR. A positive coefficient (brown) represents taxa with increased abundance in the IgAN patients, and a negative coefficient (blue) represents taxa in the control patients. Model adjusted for BMI. D Volcano plot of MetaCyc metabolic differentially abundant pathways. Labeled values represent the top 20 metabolic pathways based on FDR. The effect size is expressed as a coefficient with positive values for pathways enriched in IgAN patients, while negative values correspond to pathways enriched in control subjects. Model adjusted for Gd-IgA1, eGFR and BMI. C and D FDR values of 0 were replaced with the smallest non-zero normalized floating-point number in the R statistical programming language (2.225074e-308), to allow for logarithmic transformation and visualization. Covariates included in the models were selected based on association with microbiome variation as determined by PERMANOVA analysis.

Fig. 3

Differences in microbiome composition between IgAN progressors and nonprogressors. A Taxonomy bar plot depicting the 20 most representative species for each individual, stratified by study group. B Volcano plot representing the relationship between the effect size (Maaslin2 coefficient) and FDR between IgAN progressors and nonprogressors. Labeled values represent the top 20 species based on FDR. A positive coefficient (brown) represents taxa with increased abundance in the progressor group, and a negative coefficient (blue) represents taxa with increased abundance in the nonprogressor group. Model adjusted for BMI. C Volcano plot of MetaCyc metabolic differential pathways. The effect size is expressed as a coefficient with positive values for pathways enriched in IgAN progressors and negative values for nonprogressor-related pathways. Labels show top 20 enriched pathways based on FDR. Model adjusted for Gd-IgA1 and BMI. D Venn diagram depicting the overlapping species identified from the differential abundance analyses of the case–control and progressor–nonprogressor comparisons. C and D FDR values of 0 were replaced with the smallest non-zero normalized floating-point number in the R statistical programming language (2.225074e-308), to allow for logarithmic transformation and visualization. Covariates included in the models were selected based on association with microbiome variation as determined by PERMANOVA analysis.