Introduction
Kidney transplantation improves quality of life, morbidity, and mortality of patients with kidney failure. However, integrated immunosuppressive therapy required to preserve graft function is associated with the development of post-transplant complications, including infections, altered immunosuppressive metabolism, gastrointestinal toxicity, and diarrhea. The gut microbiota has emerged as a potential therapeutic target for personalizing immunosuppressive therapy and managing post-transplant complications. Gut microbial dysbiosis has been reported following KT. It is generally characterized by a loss of microbial diversity and an increase in the relative abundance of Proteobacteria compared to healthy individuals. The impact appears to be bidirectional, as the gut microbiota is increasingly recognized to influence alloimmunity, drug metabolism, and post-transplant complications in kidney transplant recipients (KTRs). Specific microbial signatures have been associated with graft rejection, mycophenolate mofetil and tacrolimus metabolism, and the development of new-onset diabetes after transplantation. In addition, the abundance of gut enterobacteria has been linked to the development of urinary tract infections, while other microbial populations have a protective role in urinary and respiratory tract infections. This review reports current evidence on gut microbial dysbiosis in kidney transplant recipients, alterations in their gut microbiota associated with kidney transplantation outcomes, and the application of gut microbiota intervention therapies in treating post-transplant complications.
Review Strategy
Cohort studies, single-case reports, and reviews published in English studying the gut microbiota alterations in KTRs older than 18 years, post-transplant complications, immunosuppressants metabolism, uremic toxicity, and the gut microbiota as a therapeutic target were selected. Relevant abstracts were selected for full-text review. Details regarding the study population, design, microbiome composition in KTRs, and transplantation outcome were extracted per article chosen. Out of 184 records identi ed, 121 abstracts were screened, 64 full texts were retrieved and assessed for eligibility, and 56 were included in the review. Of those, 23 studies reported a potential role of gut microbiota in KT. The selection process is illustrated in Figure 1.
Gut Microbial Dysbiosis in Kidney Transplant Recipients
Several transplantation-related factors can alter the gut microbiota of KTRs, such as discontinued dialysis and drugs used in ESKD, dietary changes, induction therapy, surgery, maintenance immunosuppressive therapy, and antimicrobial prophylaxis. Guirong et al. showed an increased abundance of Bacteroides and Enterobacteriaceae in KTRs compared with healthy individuals. Post-transplant microbiota was also characterized by decreased abundance of the short-chain-fay-acid-producing bacteria Ruminococcaceae, Lachnospira, and Faecalibacterium. Proteobacteria increased shortly after transplantation and continued to increase up to 22 years post-transplantation, while the gut microbiota in the long post-graft period was characterized by a higher abundance of Rikenellaceae RC9, Dialister, Parabacteroides, Suerella, Escher. This imbalance could contribute to the high rate of post-transplant infections in KTRs, as Proteobacteria include numerous infectious pathogens. Decreased Bacteroidetes abundance could negatively impact immune regulation, as Bacteroides fragilis mediates the conversion of CD4+ T cells into IL10-producing Foxp3+ Treg cells through the capsular polysaccharide A in a toll-like receptor-2-dependent mechanism. Yu et al. reported a reduction in microbial richness and an increase in Roseburia intestinalis and F. prausnitzii following transplantation, which may be related to the application of different sequencing and data analysis methods and the use of KTRs’ pre-transplant specimens as the control group. Nephrectomy had no impact on gut microbial richness or diversity. KTRs have been found to have lower richness and diversity, increased abundance of Proteobacteria, and depletion in several SCFA-producing species following transplantation. However, identifying a unique profile associated with KT remains challenging due to the confounding effect of immunosuppressants, antimicrobial treatment, and dietary habits. CKD is associated with lower intestinal Bi dobacteriaceae, Lactobacillaceae, Bacteroidaceae, and Prevotellaceae, and ESKD patients have a higher abundance of Proteobacteria and depletion in SCFAs. Taking these similarities into account, it can be challenging to discern the gut microbial community of CKD patients from that in KTRs.
The Impact of Gut Microbiota on Kidney Transplantation
Uremic Retention Solutes
Gut-derived uremic toxins have been identified to play a role in inflammation, metabolic function, cardiovascular disease, and fibrosis in CKD patients. TMAO plasma concentrations have been associated with an increased risk of graft failure and proposed as a potential biomarker of graft function in KTRs. Treatment with a synbiotic, mainly containing Lactobacillus and Bi dobacterium spp., decreased plasma p-cresol a er 15 and 30 days of administration. Liabeuf et al. reported no association between serum IxS levels and adverse outcomes post-transplantation, including graft loss, cardiovascular events, and mortality.
Allograft Function
Delayed graft function can increase the risk of gut dysfunction, systemic inflammation, and allograft rejection, but a similar pre-transplantation microbial structure between donors and KTRs could compensate for genetic disparity and reduce the risk of infections.
Allograft Rejection
Immune tolerance is essential to ensure graft function and survival of transplant recipients. T-lymphocyte peripheral tolerance is the primary mode of tolerance to transplanted organs, and members of the gut microbiota have been found to modulate Tregs differentiation. The gut microbiota and derived metabolites can also modulate host inflammatory response through microbiota- cytokine interactions. Schirmer et al. found that interindividual variation in cytokine response to various microbial stimulations was linked to specific commensal bacteria and microbial functions in healthy individuals. These results suggest that modulating cytokine expression by microbial interventions may have therapeutic value in allograft rejection. Lee et al. reported alterations in the gut microbiota of KTRs associated with acute rejection (AR) during the first three months post-transplantation, with a lower abundance of Clostridiales, Bacteroidales, Eubacterium dolichum, and Ruminococcus, and a higher abundance of Lactobacillales, Enterococcus, Anaero lum, and Clostridium tertium compared to those who did not develop AR. This suggests that immunosuppressive therapy could have contributed to the alterations observed. However, further studies are needed to validate the potential of gut microbial taxa as biomarkers of rejection events.
Immunosuppressants Metabolism
Recent data suggest the impact of the gut microbiota on the most prescribed immunosuppressive medications: MMF and TAC. MMF is converted to its active form, mycophenolic acid (MPA), by plasma and tissue esterases & inactivated by hepatic glucuronidation to MPA glucuronide. TAC is a macrolide of the calcineurin inhibitor family that binds to the FK506-binding protein and blocks T-cell activation. Management strategies include MMF dose reduction or discontinuation, which can lead to increased risk of allograft rejection. TAC has been associated with gastrointestinal symptoms in KTRs, but its antimicrobial activity can disrupt the gut microbial community. Lee et al. found that F. prausnitzii and other commensal bacteria metabolize TAC into a less effective immunosuppressive metabolite (M1). M1 was detected within the rst four hours of administration, with concentrations reduced by at least five-fold compared to parent TAC. These results could explain the interpatient variability in TAC therapeutic level requirements and suggest that changes in the gut microbiota might impact TAC trough variability.
Post-Transplant Infection
Urinary tract infections are among the most frequent complications affecting post-transplant patients, and a pilot study reported an increased fecal abundance of Enterococcus correlated with the development of enterococcus UTI in KTRs. Fricke et al. found alterations in the rectal microbiota of KTRs associated with urinary and upper respiratory tract infections during the first six months after transplantation. Another study found that 1% Escherichia gut abundance and 1% Enterococcus gut abundance were associated with the future development of infection, independent of gender, antimicrobial treatment, and immune maintenance therapy. A phylogenetic analysis showed a close relationship between the same subject’s urine and fecal strains of E. coli. The authors found that an overgrowth of enteropathogenic bacteria could influence UTI development in KTRs. A follow-up study found that a high abundance of Faecalibacterium and Romboutsia was associatedS with a lower risk of developing Enterobacteriaceae bacteriuria, while increased Lactobacillus abundance was associated with an increased risk. This suggests a possible protective role of butyrate-producing bacteria in developing respiratory viral infections. Butyrate has important roles in immunomodulation, maintenance of the intestinal barrier, and protection against bacterial and viral infections.
Post-Transplant Diarrhea
Post-transplant diarrhea is a common complication that increases the risk of graft failure, death-censored graft survival, and patient death. Recent data suggest alterations in the gut microbiome of KTRs as a potential non-infectious etiology. Lee et al. observed a lower gut microbial diversity and a decrease in the relative abundance of Bacteroides, Ruminococcus, Coprococcus, and Dorea to be associated with the development of diarrhea within the first-month post-transplantation. Two KTRs with a history of CDI underwent fecal microbial transplantation (FMT) and the resolution of diarrhea correlated with an overall increase in the abundance of the taxa previously identi ed as significantly lower in diarrheal specimens. These results indicate that restoring the gut microbial community imbalance could successfully manage post-transport diarrhea.
New Onset Diabetes (NODAT)
NODAT develops in approximately 20% of KTRs in the first year after transplantation and has been identified as an adverse effect of immunosuppressive treatment. Lecronier et al. observed alterations in the gut microbiota associated with NODAT after KT, suggesting a potential role for these taxa in the future development of NODAT. Additional studies should validate the possible role of gut microbiota in NODAT development in KTRs.
Gut-Microbiota-Based Therapies in Kidney Transplantation
The plasticity of the gut microbiome allows the development of therapeutic interventions to prevent and treat health disorders. Diet intervention and FMT are approaches to reshape the entire gut microbiome, while prebiotics, probiotics, and bacteriophages are more targeted manipulations. Prophylaxis with the probiotic Lactobacillus plantarum 299v (LP299v) decreased CDI incidence in immunosuppressed patients receiving antibiotics therapy, and was associated with reduced diarrhea events and lower serum C-reactive protein concentrations. e administration of probiotics has also shown immunomodulatory effects. The application of gut microbiota- based therapies has not been widely explored in KT, but recent data suggest the efficacy of these therapies for treating and preventing infectious complications. FMT has been reported to reduce Enterococcus abundance and the resolution of C. dicile and vancomycin- resistant Enterococcus infections up to one year of follow-up. Successful FMT was also reported for a KTR with recurrent UTI caused by ESBL-producing Klebsiella pneumoniae (ESBL-K. pneumoniae). Despite the promise of FMT to treat post-transplant infections and diarrhea in KTRs, this therapy should be used cautiously to avoid adverse events. Future application of FMT may involve the development of defined microbial mixtures to prevent unfavorable clinical outcomes.
Conclusions
The gut microbiota is increasingly recognized as influencing kidney post-transplant outcomes, with KT having lower gut microbial richness and diversity than the healthy population. Specific taxa have been associated with the development of infections and diarrhea complications, allograft rejection, and the ability to metabolize immunosuppressants essential for preserving graft function. Microbiota intervention therapies such as FMT have successfully resolved infection and diarrhea complications in KTRs, suggesting the potential role of gut microbiota in graft survival. More studies are needed to define the community structures representative of a healthy microbiome in transplant patients early after transplantation and longitudinally, as well as the role of gut-microbiome-modulating alloimmunity.
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