Use of antibiotics as a therapeutic approach to prevent AKI-to-CKD progression

The microbiota plays important roles in the health and diseases of its host. Gharaie et al. demonstrated that antibiotic treatment, especially amoxicillin, facilitated the repair process from ischemic acute kidney injury despite postinjury administration through microbiota modulation. This commentary discusses the implications and limitations of the study's findings for utilizing gut microbiota modification with antibiotics as a novel therapeutic approach to prevent acute kidney injury–to–chronic kidney disease progression. The microbiota plays important roles in the health and diseases of its host. Gharaie et al. demonstrated that antibiotic treatment, especially amoxicillin, facilitated the repair process from ischemic acute kidney injury despite postinjury administration through microbiota modulation. This commentary discusses the implications and limitations of the study's findings for utilizing gut microbiota modification with antibiotics as a novel therapeutic approach to prevent acute kidney injury–to–chronic kidney disease progression. A growing body of evidence has unveiled microbiota's pivotal roles in its host's health and diseases. Microbiota interacts with the host's organs, including the kidneys, via metabolic and immune pathways. Recently, a novel theory, namely the "gut-kidney axis," has been proposed to explain the interaction between the gut microbiota and the kidney.1Inagi R. The gut-kidney connection in advanced chronic kidney disease.Kidney Res Clin Pract. 2015; 34: 191-193Crossref PubMed Scopus (6) Google Scholar The gut-kidney axis is bidirectional. Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), are associated with gut dysbiosis, which refers to an imbalance in gut microbiota. By contrast, gut dysbiosis contributes to the progression of AKI and CKD. An alteration in the gut microbiota occurs as early as 1 day after AKI.2Yang J. Kim C.J. Go Y.S. et al.Intestinal microbiota control acute kidney injury severity by immune modulation.Kidney Int. 2020; 98: 932-946Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar This gut dysbiosis is associated with reduced levels of short-chain fatty acids (SCFAs), intestinal inflammation, and increased intestinal permeability, also known as leaky gut. Conversely, gut dysbiosis itself leads to the exacerbation of tissue damage in AKI, as demonstrated by fecal microbiota transplantation (FMT).2Yang J. Kim C.J. Go Y.S. et al.Intestinal microbiota control acute kidney injury severity by immune modulation.Kidney Int. 2020; 98: 932-946Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The uremic milieu also alters the composition of the gut microbiota. In patients with CKD, increased urea and uric acid levels lead to the expansion of microbial families possessing urease or uricase enzymes, which metabolize these excess substances. Conversely, uremic toxins, such as p-cresyl sulfate and indoxyl sulfate, are produced by the gut microbiota and associated with systemic inflammation, leading to further progression of CKD. Despite increasing recognition of the gut-kidney axis as a promising therapeutic target, there remains limited evidence regarding the specific alterations in the microbiota that are linked to the pathogenesis of kidney diseases, as well as which interventions may hold therapeutic promise. In their work, Gharaie et al. have provided new insight into the role of microbiota in the pathophysiology of AKI-to-CKD transition (Figure 1).3Gharaie S. Lee K. Newman-Rivera A.M. et al.Microbiome modulation after severe acute kidney injury accelerates functional recovery and decreases kidney fibrosis.Kidney Int. 2023; 104: 470-491Google Scholar They demonstrated the therapeutic potential of gut microbiome modification with antibiotic treatment, especially amoxicillin, in repair after ischemic AKI. Amoxicillin treatment following unilateral ischemic reperfusion injury (IRI) improved the recovery of glomerular filtration rate and mitigated kidney fibrosis. The protective effects of amoxicillin were not observed in germ-free mice. In addition, FMT from amoxicillin-treated mice to germ-free mice suppressed kidney medullary fibrosis after IRI. On the basis of these findings, the authors argued that the effects of amoxicillin were mediated by the altered gut microbiota. However, this inhibition of fibrosis with amoxicillin-modified microbiota was demonstrated in comparison with the control group that did not receive FMT, and no significant difference was identified compared with mice receiving FMT from normal mice that were not subjected to amoxicillin. Furthermore, there was no significant improvement in glomerular filtration rate recovery in mice with FMT from amoxicillin-treated mice compared with mice without FMT or mice with FMT from normal mice. Therefore, it is difficult to conclude from these results whether only the altered gut microbiota induced by amoxicillin treatment contributed to its renoprotective effects. Gut microbiome analysis using 16S rRNA sequencing revealed that α diversity, a term used to describe species diversity within an individual sample, increased 1 week after amoxicillin treatment compared with baseline and other antibiotic groups (metronidazole and a combination of antibiotics). The authors also investigated changes in microbial metabolites. SCFAs, produced by bacterial fermentation of dietary fiber, are known to have anti-inflammatory properties. To examine the possibility that SCFAs mediate the acceleration of the repair process, Gharaie et al. measured plasma levels of SCFAs. Only the levels of acetic acid were decreased after amoxicillin treatment, whereas the levels of other SCFAs were unchanged. Considering the prior report that acetate supplementation mitigated kidney injury following IRI,4Andrade-Oliveira V. Amano M.T. Correa-Costa M. et al.Gut bacteria products prevent AKI induced by ischemia-reperfusion.J Am Soc Nephrol. 2015; 26: 1877-1888Crossref PubMed Scopus (331) Google Scholar it is unlikely that the alteration in acetic acid levels contributed to the protective effect of amoxicillin treatment. Given that microbiota changes may affect immune responses, Gharaie et al. examined T-lymphocyte populations in the kidney. Amoxicillin treatment decreased interleukin-17+ CD4+ T cells and increased programmed cell death protein 1 (PD-1)+ CD8+ T cells in the kidneys. Interleukin-17 is a proinflammatory cytokine and is associated with tissue damage. PD-1 is an immune checkpoint molecule that is expressed in T cells. PD-1 signaling plays an important role in regulating T-cell effector functions. To explore whether CD4+ or CD8+ T cells were implicated in the renoprotective effects of amoxicillin, Gharaie et al. conducted experiments using CD4–/– or CD8–/– mice. Intriguingly, the acceleration of glomerular filtration rate recovery after IRI in response to amoxicillin administration was not seen in CD8–/– mice, but was seen in CD4–/– mice. Furthermore, amoxicillin treatment did not suppress kidney fibrosis following IRI in CD8–/– mice, indicating the potential involvement of PD-1+ CD8 T cells. The authors did not conduct histopathologic analysis to evaluate kidney fibrosis in CD4–/– mice and only presented data regarding the expression of fibrosis-related genes. Therefore, the provided data were insufficient to discuss the contribution of CD4 T cells in the development of fibrosis. PD-1 ligand 1 (PD-L1), a ligand of PD-1, is expressed in kidney tubular epithelial cells. An in vitro study revealed that the interaction of kidney tubular PD-L1 and PD-1 on CD8+ T cells dampened cytokine production.5Starke A. Lindenmeyer M.T. Segerer S. et al.Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses.Kidney Int. 2010; 78: 38-47Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar In addition, a recent clinical trial has shown the efficacy of PD-1 receptor stimulation with a humanized monoclonal antibody in the treatment of rheumatoid arthritis, suggesting the role of PD-1 signaling in suppressing inflammation.6Tuttle J. Drescher E. Simon-Campos J.A. et al.A phase 2 trial of peresolimab for adults with rheumatoid arthritis.N Engl J Med. 2023; 388: 1853-1862Crossref PubMed Scopus (6) Google Scholar Hence, the increased count of PD-1+ CD8+ T cells in the kidney may underlie the protective effects of amoxicillin. This study provides an encouraging outlook for utilizing gut microbiota modification with antibiotics as a novel therapeutic approach to prevent AKI-to-CKD progression. There are no efficacious therapeutic interventions for established AKI, making prevention the main strategy. Therefore, the effectiveness of amoxicillin, despite being administered after onset AKI, offers a promising prospect for its clinical implementation. However, there are several limitations and challenges to the practical application of gut microbiome modification as a therapeutic option. First, the gut microbiome is dynamic and variable across and within individuals. The impact of antibiotics on the gut microbiome can be highly variable. In the study by Gharaie et al., the increase in α diversity after amoxicillin treatment was detected. Loss of microbial diversity is associated with various acute and chronic diseases.7Pickard J.M. Zeng M.Y. Caruso R. et al.Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease.Immunol Rev. 2017; 279: 70-89Crossref PubMed Scopus (795) Google Scholar Therefore, the enhanced α diversity by amoxicillin administration may have contributed to the observed beneficial effects on kidney tissue repair. However, another study demonstrated a reduction in α diversity of the gut microbiome following amoxicillin treatment,8Lekang K. Shekhar S. Berild D. et al.Effects of different amoxicillin treatment durations on microbiome diversity and composition in the gut.PLoS One. 2022; 17e0275737Crossref Scopus (6) Google Scholar which is in contrast to the findings of the study by Gharaie et al. This discordance may be attributed to the difference in the dosage of amoxicillin and/or environmental factors. Additional research is required to determine the specific types, dosages, and durations of antibiotics that can induce beneficial alterations in the gut microbiota. Second, there is concern about the generalizability. In their study, Gharaie et al. investigated the renoprotective potential of amoxicillin premedication. They identified that pretreatment with amoxicillin mitigated kidney injury in a model of bilateral IRI, but not in a cisplatin-induced AKI model. This suggests that the efficacy of amoxicillin on AKI is context dependent and may not be applicable to other types of kidney diseases. Third, antibiotic treatment has some undesirable consequences, including the selection of antibiotic-resistant strains and the possibility of inducing allergic reactions. A recent report showed that the administration of a probiotic Lactobacillus casei attenuated kidney damage after IRI.9Zhu H. Cao C. Wu Z. et al.The probiotic L. casei Zhang slows the progression of acute and chronic kidney disease.Cell Metab. 2021; 33: 1926-1942.e8Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar This protective effect was also demonstrated in cisplatin-induced AKI and 5/6 nephrectomy models. Considering the potential adverse effects of antibiotics, probiotics may represent a safer and better-tolerated therapeutic option for the treatment of kidney diseases. In recent years, substantial efforts have been made to unravel the intricate interplay between the gut microbiome and the kidneys, leading to progressive advancements in our understanding of the underlying mechanisms involved. However, microbiome research still faces several challenges. Proving causality and identifying causal pathogens remain difficult because of the complex microbiome-host relationship. In addition, numerous confounders, such as diet and lifestyle, can modify the microbiome, and the lack of reproducibility across studies further complicates research in this field. Recent technological advancements, including omics-based strategies, will help us to elucidate the intricate complexity of the microbiome. Interdisciplinary approaches will be crucial to properly collect and interpret huge amounts of omics data and to fill the gap between basic science and clinical application. All the authors declared no competing interests. Microbiome modulation after severe acute kidney injury accelerates functional recovery and decreases kidney fibrosisKidney InternationalVol. 104Issue 3PreviewTargeting gut microbiota has shown promise to prevent experimental acute kidney injury (AKI). However, this has not been studied in relation to accelerating recovery and preventing fibrosis. Here, we found that modifying gut microbiota with an antibiotic administered after severe ischemic kidney injury in mice, particularly with amoxicillin, accelerated recovery. These indices of recovery included increased glomerular filtration rate, diminution of kidney fibrosis, and reduction of kidney profibrotic gene expression. Full-Text PDF