Short-chain fatty acids, the molecules that gut bacteria brew from dietary fiber, may hold a key to how the kidney defends itself against disease, according to a new review published in Frontiers in Nutrition. The review, led by Chujin Cao and Rui Zeng of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, argues that these metabolites, chiefly acetate, propionate, and butyrate, act as chemical messengers traveling along what researchers call the gut-kidney axis, shaping immune responses both in the bloodstream and inside the kidney itself. The authors suggest that when kidney disease strikes, the gut microbiota shifts in ways that deplete these protective molecules, potentially creating a vicious cycle that accelerates renal decline.

The review synthesizes evidence from a literature search of the PubMed database conducted from 2011 through 2026, using the keywords “short-chain fatty acids,” “kidney diseases,” and “immunity.” The authors screened original research articles and reviews according to PRISMA guidelines. Their central thesis is that short-chain fatty acids are not merely passive byproducts of digestion but active immunoregulatory agents that influence the differentiation, migration, and cytokine secretion of immune cells, while simultaneously acting on the kidney’s own resident cells to alter the local inflammatory environment.

At the molecular level, short-chain fatty acids exert their effects largely through G protein-coupled receptors. Three receptors dominate the picture: GPR41 and GPR43, also known as free fatty acid receptors 3 and 2, and GPR109A, or hydroxycarboxylic acid receptor 2. GPR41 and GPR43 respond to all three main short-chain fatty acids, while GPR109A is activated only by butyrate. These receptors are widely distributed across immune cell types. GPR43 appears on nearly every immune cell involved in kidney disease, including neutrophils, macrophages, dendritic cells, T cells, and B cells. GPR41 sits on macrophages, and GPR109A on dendritic cells. Crucially, the review documents that these same receptors are also present on renal resident cells, including tubular epithelial cells, podocytes, and vascular endothelial cells, meaning short-chain fatty acids can directly influence the kidney’s structural and functional units, not just the immune cells that infiltrate it.

The distribution of these receptors is not uniform. GPR41 is found throughout the renal tubule, spanning proximal tubules, distal tubules, and the medullary loop, whereas GPR43 appears only on proximal tubules. This segment-specific patterning suggests that different parts of the nephron may respond differently to circulating short-chain fatty acids. The review also notes that transporters such as SLC26A3, MCT1, MCT4, and SLC4A1/2 shuttle these molecules across cell membranes in the colon, but their presence in the kidney remains understudied. The authors’ own prior work identified expression of the short-chain fatty acid transporters Slc18a1 and Slc5a8 on tubular epithelial cells in injured kidneys, with SLC5A8 reduced in injured tissue compared with healthy controls, providing direct evidence that these metabolites act on renal parenchymal cells.

Among immune cells, the review highlights neutrophils as a key target. Neutrophil extracellular traps, web-like structures released by activated neutrophils, contribute to tissue damage and inflammatory infiltration in acute kidney injury and chronic kidney disease through their cytotoxicity, thrombogenicity, and autoantigenicity. Propionate supplementation was shown in preclinical work to inhibit the release of these traps and restore neutrophil apoptosis by blocking histone deacetylases 1, 2, 3, and 6 and enhancing histone H4 acetylation. However, the evidence is not entirely one-directional: other studies found that short-chain fatty acids did not stimulate trap release from human polymorphonuclear neutrophils or affect their viability, leaving the clinical significance of this mechanism uncertain.

Macrophages represent another critical node. The authors cite their own previous study showing that short-chain fatty acids slowed chronic kidney disease progression by preventing pro-inflammatory macrophage infiltration, offering what they describe as strong evidence for benefits in the transition from acute kidney injury to chronic kidney disease through inhibition of macrophage-driven inflammation. In animal models of transplantation, supplemental acetate protected allograft mice from rejection and induced donor-specific tolerance by expanding regulatory T cells in a GPR43-dependent manner rather than through histone deacetylase inhibition, pointing to a receptor-specific pathway for immune tolerance.

The review also examines how short-chain fatty acids interact with the kidney’s intrinsic cells, with particular attention to diabetic nephropathy. Butyrate directly exerted anti-inflammatory responses in podocytes and tubular epithelial cells by binding GPR109A. Acetate’s role proved more controversial. In vitro work showed that acetate promoted lipid accumulation in HK-2 cells by activating GPR43 and upregulating proteins involved in cholesterol uptake and synthesis, producing a profibrotic effect, and was also positively correlated with intrarenal angiotensin II protein expression, promoting renin-angiotensin system activation. Yet other studies reported that acetate has anti-inflammatory effects and alleviates glomerular hypertrophy, hypercellularity, and interstitial fibrosis. In hypertensive nephropathy, short-chain fatty acid levels were decreased in patients, and GPR43 was the major receptor downregulated in the kidney; butyrate ameliorated renal dysfunction and inflammation via GPR43 signaling and histone deacetylase inhibition, suppressing NF-κB signaling. Propionate prevented maternal chronic kidney disease-induced offspring hypertension in early life by increasing renal GPR43 expression.

Beyond individual cell types, the review describes how short-chain fatty acids shape the broader renal inflammatory microenvironment. By inhibiting HDAC2, they enriched the binding of ULK1 promoter sequences to H3K27Ac, enhancing autophagy and decreasing renal fibrosis in diabetic mice. Butyrate also reversed microRNA-mediated suppression of P311 expression, inhibiting transforming growth factor-β1 translation and alleviating diabetic nephropathy-induced fibrosis. In models of cisplatin-induced kidney injury, butyrate modulated the inflammatory response, decreasing pro-inflammatory factor expression and increasing anti-inflammatory factor expression, while attenuating cellular senescence markers including p21, p16, β-galactosidase activity, and reactive oxygen species production. The authors emphasize that most of this mechanistic evidence comes from preclinical experiments rather than human trials.

Clinical data, though limited, offer tantalizing correlations. Fecal propionate and butyrate levels in chronic kidney disease patients gradually decreased with disease progression and were closely associated with serum creatinine, blood urea nitrogen, and estimated glomerular filtration rate. Mechanistically, these metabolites downregulated tumor necrosis factor-α-triggered expression of genes related to inflammatory processes and immune system activation in tubular epithelial cells. Dietary intervention studies showed that chronic kidney disease patients on a low-protein diet had a marked decrease in butyrate-producing bacteria and reduced serum short-chain fatty acid levels compared with those on a normal-protein diet, while supplementation with a fermentable high-fiber diet reduced serum creatinine in maintenance hemodialysis patients in association with increased short-chain fatty acids. Probiotic treatment with Clostridium butyricum increased fecal and urinary short-chain fatty acid levels and was associated with decreased inflammation in children with primary nephrotic syndrome.

Despite the promise, the review is candid about the obstacles separating laboratory findings from clinical practice. The authors note that the selection of which short-chain fatty acid to use remains confusing because their roles vary among acetate, propionate, and butyrate, and it is unclear whether a single molecule or a mixture would be superior. Dosage and timing matter enormously, and increased concentrations in serum or stool do not necessarily reflect increased concentrations in the kidney. Exogenous short-chain fatty acids have difficulty reaching the kidney specifically without distributing to other organs through the circulation, which diminishes their benefit. Intravenous acetate, but not oral treatment, showed a renoprotective role in ischemia-reperfusion-induced renal injury in animal work, underscoring how delivery route changes outcome. There are also risks: complications such as ureteritis and hydronephrosis due to T-cell-mediated immune activation have been reported. The authors conclude that large-scale, well-designed randomized controlled trials are a top priority, and that determining the precise relationships among specific short-chain fatty acids, immune cell types, and kidney diseases will be essential before these gut-derived metabolites can become reliable therapeutic targets.

Subject of Research: The role of gut-derived short-chain fatty acids in regulating renal immune homeostasis and kidney disease progression

Article Title: Gut-kidney axis regulates renal immune homeostasis via short-chain fatty acids

Article References: Cao, C., Zeng, Z., & Zeng, R. (2026). Gut-kidney axis regulates renal immune homeostasis via short-chain fatty acids. Frontiers in Nutrition, 13, Article 1833495. https://doi.org/10.3389/fnut.2026.1833495

Image Credits: AI Generated

DOI: 10.3389/fnut.2026.1833495

Keywords: gut-kidney axis, short-chain fatty acids, kidney disease, immune regulation, GPR43, GPR109A, butyrate, propionate, acetate, renal inflammation, gut microbiota, chronic kidney disease