Kidney diseases, spanning a broad spectrum of etiologies, are a growing health concern worldwide (1). Beyond traditional risk factors, gut microbial dysbiosis has been increasingly implicated in their pathophysiology (2, 3). Alterations in gut microbial composition and related metabolite profiles have been reported in chronic kidney disease (CKD) and in specific glomerular diseases (4–6), with associations to systemic consequences such as cardiorenal syndrome and mineral bone disorder (7, 8). The crosstalk between the gut microbiota and the kidney, dubbed the gut-kidney axis, involves multiple mediators including microbe-derived uremic toxins and other amino acid derivatives (9–11), whose causal associations to glomerular diseases were demonstrated by recent Mendelian randomization studies (11, 12). Together, a growing body of evidence indicates a key role of intestinal dysbiosis and metabolite imbalance across kidney diseases.

Immunoglobulin A (IgA) nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, is closely connected to the gut microbiota in its immune-mediated pathophysiology. Central to its pathogenesis is the overproduction of galactose deficient-IgA1 (Gd-IgA1) and associated immune complexes (13, 14). Given the established role of IgA in mucosal immunity, host-microbiota interactions in mucosa-associated lymphoid tissues have been proposed as a key driver of Gd-IgA1 production (13). Supporting this concept, genome-wide association studies have also suggested genetic associations between IgAN and mucosal immune pathways including those related to microbial sensing and response (15, 16). These findings have motivated the introduction of tonsillectomy and enteric budesonide as therapeutic options (17, 18), and efforts are underway to utilize microbiota-modulating therapies including probiotics and fecal microbiota transplantation (19).

Nevertheless, the development of IgAN requires additional components, as described by the “multi-hit” model (14, 20). Mesangial cells actively contribute by binding IgA1 and driving proliferative signals (21). B cells play a pivotal role in producing Gd-IgA1 as well as autoantibodies against Gd-IgA1, although relatively little is known about their activation and potential interactions with the kidney glomeruli in IgAN (22). Unraveling the crosstalk among the gut microbiota, mucosal and systemic immune systems, and the kidney as a target organ is therefore critical for developing additional therapeutic strategies.

Data-driven, multi-omics approaches have the potential to yield novel insights into the complex pathophysiology of IgAN. Advances in high-throughput sequencing techniques have enabled comparative analyses of tonsillar or gut microbiome in patients with IgAN versus healthy or disease controls (21, 23–25). However, reported taxonomic differences varied among studies, and their functional relevance remains largely unclear. Spatial transcriptomics represent another key advancement, allowing for substructure-specific profiling of gene expression in elaborately organized structures like the nephron (26). We previously explored human IgAN-specific glomerular transcriptomic changes to uncover proinflammatory signals associated with mesangial proliferation preceding overt morphologic changes (27).

In this study, we performed 16S rRNA-based gut microbiome profiling integrated with Nanostring GeoMx-based glomerular spatial transcriptomics to characterize the molecular signature of IgAN. Comparisons with healthy controls and other glomerular disease patients enabled identification of specific changes in both the gut microbiome and the glomerular transcriptome. Specifically, IgAN showed gut microbial alterations in short-chain fatty acid (SCFA) metabolism, particularly acetate, along with glomerular transcriptional changes in SCFA transporters and G protein-coupled receptors (GPCRs). Together, these findings suggest a previously underappreciated axis of gut microbial metabolites and impaired renal sensing via GPCR downregulation, offering a potential channel for the gut-kidney interaction in IgAN.

In this study, we integrated gut microbiome profiling and glomerular spatial transcriptomics to characterize the microbial and transcriptomic changes in IgAN that potentially modulate the gut-kidney axis. The gut microbiome in IgAN showed an enrichment of major acetate-producing taxa and the methanogenesis from acetate pathway, accompanied by elevated serum acetate levels. At the same time, the glomerular transcriptome of IgAN demonstrated a downregulation of SCFA transporters and SCFA-sensing GPCRs, suggesting a mismatch between systemic metabolite availability and kidney sensing capacity.

Mounting evidence suggests acetate plays a key role in regulating immunity and inflammation, including in kidney diseases. Primarily generated through gut bacterial fermentation, acetate is the predominant SCFA, constituting 60-75% of total gut SCFAs (41, 42) and over 90% of those in serum (43). As both an energy source and a signaling molecule, it supports maintenance of the intestinal epithelial barrier while suppressing proinflammatory mediators (41). In vivo, acetate prevented acute kidney injury in an ischemia-reperfusion injury model and reduced kidney fibrosis in an unilateral ureteral obstruction model (44, 45), and it also attenuated clinical manifestations in a mouse model of IgAN (46). Hence, acetate may have renoprotective effects specific to IgAN as well as across kidney disease more broadly.

Our gut microbial analysis suggests that acetate production and consumption in the gut are both modulated in IgAN. Functional analysis indicated an increase in predicted enzymatic activities attributable to acetate consumption by methanogens. While methanogens have been associated with several diseases including inflammatory bowel disease (47), research on their role in the human gut is relatively sparse. Since methanogens were not identified in our taxonomic annotations, possibly because archaea comprise only 0.1% of reads in non-targeted sequencing (48), the observed metabolic activities may also reflect contributions from other acetate utilizers. As for acetate production, a previous study reported significantly decreased fecal SCFA levels in IgAN, with correlations to gut microbiota composition and clinical parameters, suggesting that disruption of SCFA levels could be relevant to IgAN (49). However, we did not observe differences in fecal acetate levels, and the relative increase in major acetate-producing genera in IgAN suggests that acetate production may not be compromised in IgAN. Our results are therefore most consistent with a simultaneous increase in the consumption and production of gut acetate in IgAN.

In addition, the glomerular transcriptome of IgAN shows potential evidence of altered acetate signaling in the kidney. Acetate in circulation can signal across diverse tissues through specific GPCRs (GPR41, GPR43, Olfr78) (50), which were downregulated in the glomerular transcriptome of IgAN: GPR41 was undetectable, and GPR43 and Olfr78 had significantly lower expression compared to MCD and MN. As GPR41 expression was also undetected in some of the healthy controls, the observed lack of GPR41 expression in IgAN likely reflects its low baseline expression below the detection threshold. We also observed a downregulation of SCFA transmembrane transporters, namely SMCT (SLC5A8), OAT4 (SLC22A9), OAT5 (SLC22A10), and UST5 (SLC22A25). These transporters are mainly associated with renal tubules rather than the glomerulus, but they are also part of the organic anion transporter family, whose members can mediate interorgan communication by modulating metabolite levels (51). The downregulation of olfactory receptor activity in IgAN could also reflect decreased SCFA signaling, as some renal olfactory receptors have physiological functions. Olfr78, as a prime example, localizes to the juxtaglomerular apparatus and modulates renin homeostasis through acetate and propionate signaling (52). Other downregulated orphan olfactory receptors may similarly localize to the glomerulus and contribute to acetate signaling. While these findings may indicate compensatory responses to elevated acetate levels, negative feedback is not universal. Indeed, a recent study showed that acetate exposure upregulated, rather than downregulated, GPR43 expression in kidney tubular cells (53). Hence, the glomerular downregulation of SCFA-related genes in IgAN may reflect pathologic suppression of acetate signaling, which would leave the kidney vulnerable to inflammation and oxidative stress.

Collectively, our analyses present a nuanced picture of acetate biology in IgAN that involves potential changes from synthesis in the gut to signaling in the glomerulus. While serum acetate levels were elevated in IgAN, this may be a reactive change rather than a pathological mechanism. Elevations in circulating acetate levels have been observed in acute stress conditions such as bacterial infections, where acetate facilitates memory T cell activity (54). Thus, the absolute increase in serum acetate levels in IgAN may not meet physiologic needs in acute inflammatory conditions, exacerbated by the downregulation of potential SCFA sensors in the glomerulus. The lack of correlation between fecal and serum acetate levels further demonstrates the complexity of acetate dynamics in IgAN. Previous studies in healthy individuals also did not report clear correlations between the two measurements despite rapid absorption of fecal acetate (43, 55).

In the kidney, acetate signaling may modulate diverse molecular pathways, with potential links to pathophysiologic processes underlying glomerular diseases. One possibly relevant mechanism is the nuclear transcription factor kappa B (NF-κB) pathway, a key regulator of inflammation across glomerular diseases and CKD (56–58). SCFA-activated GPR43 inhibits the NF-κB pathway and oxidative stress in DN, suggesting protective actions of acetate (59). At the same time, SCFAs can also amplify signaling from aryl hydrocarbon receptors, which can stimulate NF-κB-driven inflammation and suppress Nrf2 antioxidant pathways (60, 61). Acetate may also affect the kidney by modulating the renin-angiotensin system. Given the increased circulating acetate levels in IgAN, Olfr78 in the juxtaglomerular apparatus could be highly activated, promoting renin secretion and leading to glomerular hypertension. Indeed, a study of early DN identified elevated serum acetate levels in a rat model and suggested that excess acetate may promote kidney injury through the renin-angiotensin system (62). Also downstream of the renin-angiotensin system is the Wnt/β-catenin pathway, whose persistent activation can lead to kidney fibrosis in glomerular diseases and CKD (63, 64). Conversely, the counterbalancing effects of GPR41 on blood pressure, together with the downregulation of Olfr78, could blunt or even reverse these effects on the regulation of renin (65). As such, renal acetate signaling in IgAN may affect multiple molecular mechanisms, whose contributions to pathophysiology are likely context dependent.

Beyond its effects on glomerular inflammation, acetate may also contribute to the pathophysiology of IgAN through signaling in other cell populations. Although not directly addressed by the current analysis, earlier in vivo studies have suggested that acetate can regulate gut mucosal immune cells. Specifically, acetate supplementation induced gut IgA production and regulated IgA reactivity to microbes through stimulation of dendritic cells, which promote IgA class switching and gut homing in B cells (66). In certain contexts, acetate can also induce dendritic cells to produce B-cell activating factor (BAFF) (66, 67), an emerging therapeutic target whose levels are elevated in IgAN (14). In addition, acetate stimulates CD4⁺CCR6⁺ T follicular helper-like cells by promoting CCL20 production in colonic epithelial cells, regulating T cell-dependent IgA production in germinal centers by modulating Toll-like receptor (TLR) signaling (68). This may also be relevant to IgAN pathogenesis, as a recent study found that transplanting gut microbiota from IgAN patients into mice activates TLR4 signaling and induces the disease phenotype, while TLR4 inhibition suppresses Gd-IgA1 production (69). In all, acetate can modulate IgA biology through its interactions with gut immune cells, such as dendritic cells and helper T cells, which may have potential relevance to the pathogenesis of IgAN.

Recent studies associate gut dysbiosis and metabolite dysregulation with kidney injury across glomerular diseases. Uremic toxin generation and impaired SCFA production, along with intestinal barrier dysfunction, have been identified as major pathways whereby gut dysbiosis contribute to CKD (70). The gut microbiome in MN shows reductions in Lactobacillus, whose tryptophan-derived metabolites can attenuate kidney damage by inhibition of aryl hydrocarbon receptor signaling (71). Significant gut dysbiosis was also observed in MCD that includes decreased abundance of the butyrate producer Faecalibacterium (72). As for DN, the gut microbiome is associated with multiple potentially pathogenic mechanisms including increased endotoxin levels, decreased SCFA levels, and dysregulated bile acid metabolism (73). As such, SCFAs are associated with multiple kidney diseases, typically showing reduced production, but their mechanistic roles remain incompletely defined.

SCFAs, in particular acetate, may therefore play a disease-specific role in IgAN. Our analysis suggests an overall increased activity of acetate metabolism in the gut, where it can boost IgA production and reactivity as previously discussed. At the same time, downregulation of genes responsible for SCFA transport and sensing in the glomerulus would limit acetate uptake and signaling, which can contribute to glomerular injury through impaired regulation of anti-inflammatory pathways, disruption of renin signaling, and promotion of local metabolic stress. The observed elevation in serum acetate may represent both a systemic response to inflammation and a compensatory adaptation to defective acetate signaling in the kidney.

Human studies demonstrate the clinical relevance of gut dysbiosis in IgAN, but the contribution of SCFAs such as acetate remains to be established. Gut microbiota profile could predict treatment response in IgAN (74), and a pilot trial suggested fecal microbiota transplantation (FMT) may serve as an adjunctive treatment (75). Nonetheless, despite several reports of decreased serum and fecal acetate levels in IgAN and in broader CKD (49, 76), SCFAs were not among the intestinal metabolites altered by FMT in IgAN in the pilot study. Adding to this complexity, our glomerular transcriptomic data indicated that acetate signaling in the kidney may depend on systemic availability as well as renal sensing capacity, highlighting the need to assess associated receptor functions when interpreting SCFA biology in kidney disease.

The current study has several limitations. First, the 16S rRNA data had limited resolution. Taxonomic annotation was restricted to the genus level, and certain taxa may not have been detected, particularly archaeal species for which the primer designs and taxonomic databases are less optimized. Functional annotation was also performed indirectly through PICRUSt2, which first derives the predicted metagenome from the 16S data and then algorithmically infers pathway composition. Further validation through metagenomic sequencing and functional assays is needed to verify the observed genus- and pathway-level associations. Second, due to the relatively low number of reads in our spatial transcriptomics data, we could not reliably localize gene expression patterns within the glomerulus, and some genes with low expression levels may have not been detected, as was likely the case for GPR41. Third, while efforts were made to select representative cases, our study may not reflect the entire spectrum of IgAN. The cases included in this study are all relatively young Koreans, which may not fully capture the nature of the disease in other ethnicities, especially given the known differences in clinical severity and gender distributions in Asian-Pacific populations (14). The low number of samples subject to glomerular transcriptomics also limits the generalizability of our findings. Finally, because this is a data-driven, observational study, the contributions of metabolites, glomerular genes, and gut microbial functions to IgAN pathophysiology remain to be established by experimental studies. Other SCFAs may also signal through the involved GPCRs and contribute to the postulated mechanisms, and additional confounding factors, such as dietary patterns, could influence gut microbial composition as well as SCFA levels. There may also be important transcriptional and microbial characteristics not captured by our analysis due to the limited sample size and the study design, which compared IgAN with four different control groups separately to minimize false positive results.

In conclusion, we have identified elevations in gut microbial acetate production and consumption activities as well as glomerular downregulation of GPCR, SCFA transport, and galactosylation functions in IgAN. Our results suggest that acetate may contribute to the pathophysiology of IgAN by mediating the gut-kidney interaction through GPCR signaling.