Background Acute kidney injury (AKI) affects a considerable proportion of patients that represents a major challenge for clinical treatment. Gut microbiota metabolites have been reported to attenuate acute kidney injury (AKI), yet their underlying mechanisms remain largely elusive. The present study aimed to explore the protective mechanisms of these metabolites against AKI using.
Methods The targets of metabolites and AKI were obtained from public databases. The PPI network is utilized to identify the core targets. GO and KEGG enrichment analysis were employed to predict significant pathway and biological functions. The Gut-Metabolites-Targets-Pathway network (G-M-T-P) network was constructed to screen the core metabolites. Furthermore, molecular docking was applied to evaluate the binding affinities between the metabolites and their candidate targets.
Results A total of 84 overlapping targets between gut microbiota metabolites and AKI were acquired. The beneficial effects of gut microbiota metabolites were associated with the regulation of inflammatory response and hypoxia. HIF-1 pathway was identified as the significant pathway mediating the effects of metabolites. STAT3, HIF1A, NFKB1, IL6 and AKT1 were identified as the core therapeutic targets of metabolites against AKI. The G-M-T-P network identified acetate, butyrate, propionate, and 3-indolepropionic acid as the core metabolites. The core metabolites exhibited strong affinity binding affinity for the core targets, suggesting their potential application in candidate drug development.
Conclusion The study highlights that the promising effects of gut microbiota metabolites in AKI treatment through modulating multi targets and pathways.
| [1] |
Abdelmageed MM, Kefaloyianni E, Arthanarisami A, Komaru Y, Atkinson JJ, Herrlich A. TNF or EGFR inhibition equally block AKI-to-CKD transition: opportunities for etanercept treatment. Nephrol Dial Transpl, 2023, 38(51139-1150
|
| [2] |
André C, Bodeau S, Kamel S, Bennis Y, Caillard P (2023) The AKI-to-CKD transition: the role of uremic toxins. Int J Mol Sci. 24(22)
|
| [3] |
Chou YT, Kan WC, Shiao CC (2022) Acute kidney injury and gut dysbiosis: a narrative review focus on pathophysiology and treatment. Int J Mol Sci. 23(7)
|
| [4] |
Corte-Iglesias V, Saiz ML, Andrade-Lopez AC, Salazar N, Bernet CR, Martin-Martin C, et al.. Propionate and butyrate counteract renal damage and progression to chronic kidney disease. Nephrol Dial Transpl, 2024, 40(1): 133-150
|
| [5] |
Deleu S, Machiels K, Raes J, Verbeke K, Vermeire S (2021) Short chain fatty acids and its producing organisms: an overlooked therapy for IBD? EBioMedicine. 66:103293
|
| [6] |
Diep TN, Liu H, Yan LJ (2025) Beneficial effects of butyrate on kidney disease. Nutrients. 17(5)
|
| [7] |
Ding H, Zhou Y, Zhu RH, Yu S, Zhang AQ, Liu H, et al.. HIF-1-mediated macrophage metabolic reprogramming promotes AKI to CKD transition. Int J Biol Sci, 2025, 21(13): 5936-5955
|
| [8] |
Dong J, Feng T, Thapa-Chhetry B, Cho BG, Shum T, Inwald DP, et al.. Machine learning model for early prediction of acute kidney injury (AKI) in pediatric critical care. Crit Care, 2021, 25(1): 288
|
| [9] |
Enescu DM, Parasca SV, Badoiu SC, Miricescu D, Ripszky Totan A, Stanescu S II et al (2022) Hypoxia-inducible factors and burn-associated acute kidney injury-A new paradigm? Int J Mol Sci. 23(5)
|
| [10] |
Favero C, Pintor-Chocano A, Sanz A, Ortiz A, Sanchez-Niño MD. Butyrate promotes kidney resilience through a coordinated kidney protective response in tubular cells. Biochem Pharmacol, 2024, 224: 116203
|
| [11] |
Gao X, Hu W, Qian D, Bai X, He H, Li L, et al.. The Mechanisms of Ferroptosis Under Hypoxia. Cell Mol Neurobiol, 2023, 43(7): 3329-3341
|
| [12] |
Guo N, Wang X, Xu M, Bai J, Yu H, Le Z. PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression. Pharmacol Res, 2024, 206: 107300
|
| [13] |
He X, Guo Y, Zhao Y (2025) Targeting gut microbiota as a promising therapy for chronic kidney disease. Integr Med Nephrol Androl. 12(3)
|
| [14] |
Hu Z, Chen D, Yan P, Zheng F, Zhu H, Yuan Z, et al.. Puerarin suppresses macrophage M1 polarization to alleviate renal inflammatory injury through antagonizing TLR4/MyD88-mediated NF-κB p65 and JNK/FoxO1 activation. Phytomedicine, 2024, 132: 155813
|
| [15] |
Huai J, Ye X. Dissecting causal relationships between gut microbiota, inflammatory factors, and acute kidney injury: A Mendelian randomization study. Clin Nephrol, 2025, 104(1): 62-71
|
| [16] |
Huang J, Meng P, Liang Y, Li X, Zhou S, Li J, et al.. Tubular CD44 plays a key role in aggravating AKI through NF-κB p65-mediated mitochondrial dysfunction. Cell Death Dis, 2025, 16(1): 119
|
| [17] |
Ji ML, Wang JN, Wu MF, Xu CH, Zhang MM, Chang WB, et al.. Targeting Stat3 with conditional knockout or PROTAC technology alleviates renal injury by Limiting pyroptosis. EBioMedicine, 2025, 116: 105739
|
| [18] |
Jin Y, Zhang SJ, Zhuang S, Li P, Miao H, Zhao YY. Microbiota-gut-kidney axis in health and renal disease. Int J Biol Sci, 2026, 22(2): 750-770
|
| [19] |
Jo SK (2021) Kidney-gut crosstalk in AKI. Kidney 2(5):886–889
|
| [20] |
Kawabata C, Hirakawa Y, Inagi R, Nangaku M. Acetate attenuates kidney fibrosis in an oxidative stress-dependent manner. Physiol Rep, 2023, 11(14): e15774
|
| [21] |
Korbecki J, Simińska D, Gąssowska-Dobrowolska M, Listos J, Gutowska I, Chlubek D, et al.. Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms. Int J Mol Sci, 2021, 22: 19
|
| [22] |
Kuwabara S, Goggins E, Okusa MD. The Pathophysiology of Sepsis-Associated AKI. Clin J Am Soc Nephrol, 2022, 17(7): 1050-1069
|
| [23] |
Lee SH, Kim KH, Lee SM, Park SJ, Lee S, Cha RH, et al.. STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation. Cell Commun Signal, 2024, 22(1): 476
|
| [24] |
Legrand M, Clark AT, Neyra JA, Ostermann M. Acute kidney injury in patients with burns. Nat Rev Nephrol, 2024, 20(3): 188-200
|
| [25] |
Li Y, Qin G-Q, Wang W-Y, Liu X, Gao X-Q, Liu J-H, et al.. Short chain fatty acids for the risk of diabetic nephropathy in type 2 diabetes patients. Acta Diabetol, 2022, 59(7): 901-909
|
| [26] |
Li B, Hong L, Luo Y, Zhang B, Yu Z, Li W et al (2022) LPS-induced liver injury of magang geese through toll-like receptor and MAPK signaling pathway. Anim (Basel). 13(1)
|
| [27] |
Liu LM, Fang HB, Wang YF, Zhang YL, Yu QQ, Zhang WY, et al.. Niaoduqing particles ameliorated tubulointerstitial fibrosis by suppressing IκB/NF-κB signalling pathway via inhibiting host- and gut microbiota-mediated tryptophan co-metabolism. Microbiol Res, 2026, 311: 128592
|
| [28] |
Liu W, Hu C, Qian X, He C, Gu R, Meng Z, et al.. TaoHeChengQi Decotion alleviate chronic renal failure via regulation of PHD2/UCP1 and RIPK3/AKT/TGF-β pathway. Phytomedicine, 2025, 141: 156548
|
| [29] |
Liu LM, Zhang YL, Zhou JT, Yu QQ, Zhang WY, Wang WF et al (2026) Ureic clearance granule ameliorates chronic kidney disease by reshaping microbial dysbiosis via modulating bile acid metabolism. Chin Med. 21(1)
|
| [30] |
Livingston MJ, Shu S, Fan Y, Li Z, Jiao Q, Yin XM, et al.. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy, 2023, 19(1): 256-277
|
| [31] |
Mali N, Mali S, Zhang L, Fu P. Interplay between gut microbiota and acute kidney injury: a review of their mutual influence and causation. Ren Fail, 2025, 47(1): 2522976
|
| [32] |
Miao H, Wang YN, Su W, Zou L, Zhuang SG, Yu XY, et al.. Sirtuin 6 protects against podocyte injury by blocking the renin-angiotensin system by inhibiting the Wnt1/β-catenin pathway. Acta Pharmacol Sin, 2024, 45(1): 137-149
|
| [33] |
Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, et al.. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev, 2022, 8(8): Cd013751
|
| [34] |
Pérez-Aizpurua X, Cabello Benavente R, Bueno Serrano G, Alcázar Peral JM, Gómez-Jordana Mañas B, Tufet IJJ, et al.. Obstructive uropathy: Overview of the pathogenesis, etiology and management of a prevalent cause of acute kidney injury. World J Nephrol, 2024, 13(2): 93322
|
| [35] |
Rossiter A, La A, Koyner JL, Forni LG. New biomarkers in acute kidney injury. Crit Rev Clin Lab Sci, 2024, 61(1): 23-44
|
| [36] |
Spencer S, Wheeler-Jones C, Elliott J. Hypoxia and chronic kidney disease: Possible mechanisms, therapeutic targets, and relevance to cats. Vet J, 2021, 274: 105714
|
| [37] |
Su L, Zhang J, Gomez H, Kellum JA, Peng Z. Mitochondria ROS and mitophagy in acute kidney injury. Autophagy, 2023, 19(2): 401-414
|
| [38] |
Sun ZH, Gong Q, Wang ZL, Li C, Wang JN, Yu JT, et al.. Microbiota-Gut-Kidney Axis and Targeted Therapeutic Strategies in Kidney Diseases. Int J Biol Sci, 2026, 22(3): 1142-1161
|
| [39] |
Tian Y, Tian R, He J, Guo Y, Yan P, Chen Y et al (2024) Toralactone alleviates cisplatin-induced acute kidney injury by modulating the gut microbiota-renal axis. Int Immunopharmacol. 142(Pt A):113115.
|
| [40] |
van Aanhold CCL, Koudijs A, Dijkstra KL, Wolterbeek R, Bruijn JA, van Kooten C et al (2022) The VEGF inhibitor soluble Fms-like tyrosine kinase 1 does not promote AKI-to-CKD transition. Int J Mol Sci. 23(17)
|
| [41] |
Wang W, Dernst A, Martin B, Lorenzi L, Cadefau-Fabregat M, Phulphagar K, et al.. Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation. Cell Rep, 2024, 43(9): 114736
|
| [42] |
Wang B, Li ZL, Zhang YL, Wen Y, Gao YM, Liu BC. Hypoxia and chronic kidney disease. EBioMedicine, 2022, 77: 103942
|
| [43] |
Wang Y, Wang X, Wang H, Bao J, Jia N, Huang H, et al.. PTEN protects kidney against acute kidney injury by alleviating apoptosis and promoting autophagy via regulating HIF1-α and mTOR through PI3K/Akt pathway. Exp Cell Res, 2021, 406(1): 112729
|
| [44] |
Winner KM, Chanderraj R, Nuppnau M, He Y, Petouhoff AM, Falkowski NR et al (2025) Anti-anaerobic antibiotics, gut microbiota, and sepsis-associated acute kidney injury. Am J Respir Crit Care Med
|
| [45] |
Xu Y, Xu J, Li J, Kong X, Mao H, Du Z, et al.. Interplay of HIF-1α, SMAD2, and VEGF signaling in hypoxic renal environments: impact on macrophage polarization and renoprotection. Ren Fail, 2025, 47(1): 2561784
|
| [46] |
Yang Z, Ni J, Sun X, Cui Q, Zhang X, Zhang M, et al.. The prevention effect of Limosilactobacillus reuteri on acute kidney injury by regulating gut microbiota. Microbiol Immunol, 2024, 68(7): 213-223
|
| [47] |
Yao W, Huo J, Liu K, Tao P. Exploring the health benefits of gut microbiota metabolites on combating ulcerative colitis via network pharmacology, bioinformatics and molecular docking. Sci Rep, 2025, 15(1): 25626
|
| [48] |
Yao W, Huo J, Liu K, Tao P. Exploring the beneficial effect of gut microbiota metabolites on diabetic nephropathy via network pharmacology study. Sci Rep, 2025, 15(1): 11027
|
| [49] |
Yao W, Huo J, Liu K, Tao P. The application of metabolites derived from gut microbiota to the treatment of chronic kidney disease: a network pharmacology study. Int J Surg, 2026, 112(2): 3090-3103
|
| [50] |
Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol, 2022, 85: 69-94
|
| [51] |
Zeng Y, Guo M, Wu Q, Tan X, Jiang C, Teng F, et al.. Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1. J Adv Res, 2025, 73: 607-630
|
| [52] |
Zhang J, Ren X, Li B, Zhao Z, Li S, Zhai W. Fecal microbiota transplantation is a promising therapy for kidney diseases. Front Med (Lausanne), 2025, 12: 1628722
|
| [53] |
Zhou S, Lan Q, Xin W, Wang Y, Zhang A, Xiong J, et al.. Targeting NINJ1-Mediated Plasma Membrane Rupture in Tubular Epithelial Cell Prevents Inflammatory Response in Acute Kidney Injury. Int J Biol Sci, 2025, 21(12): 5223-5239
|
Funding
Chinese Association of Integrative Medicine(SHGZS-202237)
Shanghai 14th Five-Year Plan TCM Characteristic Specialty Construction Project (ZYTSZK2-13)
The Seventh Cycle Key Medical Specialty Establishment Project in Jinshan District of Shanghai(JSZK2023H04)
Shanghai District-Level Comprehensive (Specialized) Hospital's Integrated Traditional Chinese and Western Medicine Specialty Capacity(QJZXYJK-202408)
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