Targeted phage blocks gut–kidney migration of EAEC and alleviates renal injury in diabetic kidney disease

Diabetic kidney disease (DKD) affects a substantial proportion of people with diabetes and remains a leading cause of end-stage renal disease. Although kidney-protective therapies have improved outcomes, many patients continue to experience progressive renal injury. Meanwhile, bacterial infections are more common and often more severe in people with diabetes. These observations raise an important question: can bacteria that normally reside in the intestine cross the intestinal barrier, reach the kidneys, and exacerbate renal injury in DKD?

A research team led by Hongwei Liu at the Institute of Microbiology, Chinese Academy of Sciences, found evidence supporting this possibility in a susceptible diabetic setting. Analysis of fecal samples from 20 patients with DKD and 20 matched healthy controls revealed that the relative abundance of Escherichia-Shigella in the gut microbiota was markedly higher in patients with DKD, increasing from 1.29% in healthy controls to 11.40% in patients. This finding was consistent with data from a public cohort comprising 223 patients with end-stage renal disease and 69 controls. In addition, culture-based experiments frequently recovered E. coli from fecal samples of patients with DKD.

“Most studies of the gut–kidney axis have focused on microbial communities or the metabolites they produce. Our findings suggest that, under DKD conditions, viable gut bacteria can also cross an impaired intestinal barrier, reach the kidneys, and exacerbate renal injury,” said Hongwei Liu, the corresponding author. “This opens up an opportunity to target a specific disease-aggravating bacterium rather than broadly disrupting the gut microbiota.”

In db/db mice, viable enteroaggregative Escherichia coli (EAEC) was detected in kidney tissue using culture, transmission electron microscopy, fluorescence in situ hybridization, and full-length 16S rRNA sequencing. Following oral administration of GFP-labelled EAEC, the bacteria were subsequently detected and re-isolated from the kidneys, providing direct evidence of gut-to-kidney translocation in this model. EAEC was not merely associated with DKD: oral administration of mouse-derived EAEC increased renal bacterial burden and exacerbated inflammation and fibrosis in db/db mice, whereas comparable renal injury was not observed in non-diabetic BKS control mice. Representative EAEC isolates from patients with DKD produced similar effects.

The team then isolated an EAEC-specific lytic bacteriophage, EAWsc9. Its genome contained no known virulence or antimicrobial resistance genes, and the phage efficiently inhibited EAEC growth in vitro. After three weeks of oral treatment with EAWsc9, without exogenous EAEC administration, db/db mice showed a reduction in endogenous renal EAEC burden and improvements in renal pathology. Serum creatinine, blood urea nitrogen, indoxyl sulfate, lipopolysaccharide, and IL-6 levels were also reduced, along with renal fibrosis and macrophage infiltration. No detectable adverse effects on body weight, glucose homeostasis, or liver function were observed during treatment.

These findings extend the gut–kidney axis beyond microbial community composition and metabolites to encompass viable bacterial translocation and renal colonization. They also suggest a selective, microbiota-directed antibacterial strategy for DKD associated with pathobiont expansion and infection-related renal inflammation. The researchers caution that EAEC should be considered a factor that can aggravate established DKD rather than an initiating cause. Further studies involving larger clinical cohorts, longer-term safety assessments, monitoring for phage resistance, and evaluation of personalized phage cocktails will be needed before clinical translation.

This study involved researchers from the Institute of Microbiology, Chinese Academy of Sciences; West China Hospital, Sichuan University; Inner Mongolia University; the First Affiliated Hospital of Nanjing Medical University; Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Henan Provincial People’s Hospital; and the Affiliated Hospital of Zunyi Medical University. The research was supported by the National Key Research and Development Program of China (2025YFA1309200), the National Natural Science Foundation of China (32400041), and the China Postdoctoral Science Foundation Postdoctoral Fellowship Program (GZC20232928).

About Author

Hongwei Liu is the corresponding author of this work and is affiliated with the State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, and the Medical School, University of Chinese Academy of Sciences. Professor Hongwei Liu’s research focuses on gut microbiota–host interactions, microbiome-related chemical biology, microbial metabolites, and the development of microbiota-based therapeutic products. His team has led more than 10 major research programs, including the National Key R&D Program of China and the National Basic Research Program (973 Program), and has been awarded four science and technology prizes at the provincial or national level. Professor Liu currently serves as Director of the Microecology Research Laboratory at the Institute of Microbiology, Chinese Academy of Sciences (IMCAS). He also chairs the Microbiome Committee of the Chinese Society for Microbiology and the Fungal Chemistry Committee of the Mycological Society of China. For more information, please pay attention to his research homepage https://www.im.cas.cn/rcdw/jcqn/202601/t20260109_8101287.html .

DOI Link:

https://doi.org/10.1016/j.hlife.2026.09.001