The gut-lung-kidney axis is pivotal in immune-related kidney diseases, with gut dysbiosis potentially exacerbating the severity of Coronavirus disease 2019 (COVID-19) in recipients of kidney transplant. This study aimed to characterize the gut microbiome and metabolome in renal transplant recipients with COVID-19 pneumonia over a one-year follow-up period.

A total of 30 renal transplant recipients were enrolled, comprising 17 with COVID-19 pneumonia, six with mild COVID-19, and seven without COVID-19. Fecal samples were collected at the onset of infection for gut microbiome and metabolome analysis. Generalized Estimating Equations (GEE) model and Latent Class Growth Mixed Model (LCGMM) were employed to dissect the relationships among clinical characteristics, laboratory tests, and gut microbiota and metabolites.

Four microbial phyla (Deferribacteres, TM7, Fusobacteria, and Gemmatimonadetes) and 13 genera were significantly enriched across three recipients groups, correlating with baseline inflammatory response and allograft function. Additionally, 52 differentially expressed metabolites were identified, with seven significantly correlating with eight altered microbiota genera. LCGMM revealed two distinct classes of recipients, with those suffering from COVID-19 pneumonia exhibiting significantly elevated serum creatinine (Scr) trajectories over the one-year period. GEE further identified 12 genera and 181 metabolites closely associated with these trajectories; a multivariable model incorporating gut metabolites of 1-Caffeoylquinic Acid and PMK was found to effectively predict one-year allograft function.

Our study indicates a possible interaction between the composition of the gut microbiota and metabolites community and COVID-19 in renal transplant recipients, particularly in relation to disease severity and the prediction of one-year allograft function.

Diarrhea is a common complication after pediatric kidney transplantation. While mycophenolate mofetil is an important and common cause of post-transplant diarrhea, diarrhea can result from infectious and other non-infectious causes. Many complications can result from severe diarrhea including acute kidney injury from dehydration. Other unique complications in transplant recipients include tacrolimus toxicity and acute rejection (from changes in immunosuppressive pharmacokinetics or dosing in response to the diarrhea). Therefore, a thorough evaluation is recommended for all pediatric patients with severe diarrhea to ensure that appropriate interventions are instituted, and risks of complications minimized. Our review describes the scope of the morbidity of diarrheal illness after transplantation, common causes, and newer insights in the management of diarrhea, both supportive and targeted to the underlying cause.

Many kidney transplant recipients continue to experience high symptom burden despite restoration of kidney function. High symptom burden is a significant driver of quality of life. In the post-transplant setting, high symptom burden has been linked to negative outcomes including medication non-adherence, allograft rejection, graft loss, and even mortality. Symbiotic bacteria (microbiota) in the human gastrointestinal tract critically interact with the immune, endocrine, and neurological systems to maintain homeostasis of the host. The gut microbiome has been proposed as an underlying mechanism mediating symptoms in several chronic medical conditions including irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia, and psychoneurological disorders via the gut-brain-microbiota axis, a bidirectional signaling pathway between the enteric and central nervous system. Post-transplant exposure to antibiotics, antivirals, and immunosuppressant medications results in significant alterations in gut microbiota community composition and function, which in turn alter these commensal microorganisms' protective effects. This overview will discuss the current state of the science on the effects of the gut microbiome on symptom burden in kidney transplantation and future directions to guide this field of study.

The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high.

Kidney transplantation is an effective way to improve the condition of patients with end-stage renal disease. However, maintaining long-term graft function and improving patient survival remain a key challenge after kidney transplantation. Dysbiosis of intestinal flora has been reported to be associated with complications in renal transplant recipients. The commensal microbiota plays an important role in the immunomodulation of the transplant recipient responses. However, several processes, such as the use of perioperative antibiotics and high-dose immunosuppressants in renal transplant recipients, can lead to gut dysbiosis and disrupt the interaction between the microbiota and the host immune responses, which in turn can lead to complications such as infection and rejection in organ recipients. In this review, we summarize and discuss the changes in intestinal flora and their influencing factors in patients after renal transplantation as well as the evidence related to the impact of intestinal dysbiosis on the prognosis of renal transplantation from in vivo and clinical studies, and conclude with a discussion of the use of microbial therapy in the transplant population. Hopefully, a deeper understanding of the function and composition of the microbiota in patients after renal transplantation may assist in the development of clinical strategies to restore a normal microbiota and facilitate the clinical management of grafts in the future.

Gut microbiota is often modified after kidney transplantation. This principally happens in the first period after transplantation. Antibiotics and, most of all, immunosuppressive drugs are the main responsible. The relationship between immunosuppressive drugs and the gut microbiota is bilateral. From one side immunosuppressive drugs modify the gut microbiota, often generating dysbiosis; from the other side microbiota may interfere with the immunosuppressant pharmacokinetics, producing products more or less active with respect to the original drug. These phenomena have influence over the graft outcomes and clinical consequences as rejections, infections, diarrhea may be caused by the dysbiotic condition. Corticosteroids, calcineurin inhibitors such as tacrolimus and cyclosporine, mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known. In contrast is well known how the gut microbiota may interfere with glucocorticoids, which may be transformed into androgens. Tacrolimus may be transformed by micro biota into a product called M1 that is 15-fold less active with respect to tacrolimus. The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glu curonidase, may be transformed into the inactive product.

Kidney graft rejection still represents the major cause of graft loss in kidney transplant recipients. Of growing interest is the bidirectional relationship between gut microbiome and immune system suggesting that gut microbiota can affect allograft outcome.

In this cross-sectional case-control study, we characterized the gut microbial profile of adult renal transplant recipients with and without graft rejection to define a cohort-specific microbial fingerprint through 16S ribosomal RNA gene sequencing. We used very strict inclusion and exclusion criteria to address confounder of microbiota composition.

Different relative abundances in several gut microbial taxa were detectable in control patients compared with patients with kidney allograft rejection. Alpha diversity was lower in the rejection group and beta diversity revealed dissimilarity between patients with and without kidney graft rejection (P < 0.01). When the rejection group was stratified according to different types of allograft rejection, major changes were identified between patients with chronic T-cellular-mediated rejection and controls. Changes in alpha diversity within the gut microbiome were related to the probability of chronic T-cellular-mediated rejection (P < 0.05). Kidney transplant patients without rejection showed significant enrichment of rather anti-inflammatory taxa whereas in the rejection group bacteria well known for their role in chronic inflammation were increased. For example, amplicon sequence variant (ASV) 362 belonging to the genus Bacteroides and ASV 312 belonging to Tannerellaceae were enriched in no rejection (P < 0.001 and P < 0.01), whereas ASV 365 was enriched in patients with allograft rejection (P = 0.04). Looking at metagenomic functions, a higher abundance of genes coding for enzymes involved in bacterial multidrug resistance and processing of short-chain fatty acids was found in patients without rejection but an increase in enzymes involved in nicotinamide adenine dinucleotide phosphate production was seen in patients with allograft rejection.

A distinct microbial fingerprint of patients with allograft rejection might serve as noninvasive biomarker in the future.

Intrinsic metabolism shapes the immune environment associated with immune suppression and tolerance in settings such as organ transplantation and cancer. However, little is known about the metabolic activities in an immunosuppressive environment. In this study, we employed metagenomic, metabolomic, and immunological approaches to profile the early effects of the immunosuppressant drug tacrolimus, antibiotics, or both in gut lumen and circulation using a murine model. Tacrolimus induced rapid and profound alterations in metabolic activities within two days of treatment, prior to alterations in gut microbiota composition and structure. The metabolic profile and gut microbiome after seven days of treatment was distinct from that after two days of treatment, indicating continuous drug effects on both gut microbial ecosystem and host metabolism. The most affected taxonomic groups are Clostriales and Verrucomicrobiae (i.e., Akkermansia muciniphila), and the most affected metabolic pathways included a group of interconnected amino acids, bile acid conjugation, glucose homeostasis, and energy production. Highly correlated metabolic changes were observed between lumen and serum metabolism, supporting their significant interactions. Despite a small sample size, this study explored the largely uncharacterized microbial and metabolic events in an immunosuppressed environment and demonstrated that early changes in metabolic activities can have significant implications that may serve as antecedent biomarkers of immune activation or quiescence. To understand the intricate relationships among gut microbiome, metabolic activities, and immune cells in an immune suppressed environment is a prerequisite for developing strategies to monitor and optimize alloimmune responses that determine transplant outcomes.

Intrinsic metabolism shapes the immune environment associated with immune suppression and tolerance in settings such as organ transplantation and cancer. However, little is known about the metabolic activities in an immunosuppressive environment. In this study, we employed metagenomic, metabolomic, and immunological approaches to profile the early effects of the immunosuppressant drug tacrolimus, antibiotics, or both in gut lumen and circulation using a murine model. Tacrolimus induced rapid and profound alterations in metabolic activities within two days of treatment, prior to alterations in gut microbiota composition and structure. The metabolic profile and gut microbiome after seven days of treatment was distinct from that after two days of treatment, indicating continuous drug effects on both gut microbial ecosystem and host metabolism. The most affected taxonomic groups are Clostriales and Verrucomicrobiae (i.e., Akkermansia muciniphila), and the most affected metabolic pathways included a group of interconnected amino acids, bile acid conjugation, glucose homeostasis, and energy production. Highly correlated metabolic changes were observed between lumen and serum metabolism, supporting their significant interactions. Despite a small sample size, this study explored the largely uncharacterized microbial and metabolic events in an immunosuppressed environment and demonstrated that early changes in metabolic activities can have significant implications that may serve as antecedent biomarkers of immune activation or quiescence. To understand the intricate relationships among gut microbiome, metabolic activities, and immune cells in an immune suppressed environment is a prerequisite for developing strategies to monitor and optimize alloimmune responses that determine transplant outcomes.

The clinical response to classical immunosuppressant drugs (cIMDs) is highly variable among individuals. We performed a systematic review of published evidence supporting the hypothesis that gut microorganisms may contribute to this variability by affecting cIMD pharmacokinetics, efficacy or tolerability. The evidence that these drugs affect the composition of intestinal microbiota was also reviewed. The PubMed and Scopus databases were searched using specific keywords without limits of species (human or animal) or time from publication. One thousand and fifty five published papers were retrieved in the initial database search. After screening, 50 papers were selected to be reviewed. Potential effects on cIMD pharmacokinetics, efficacy or tolerability were observed in 17/20 papers evaluating this issue, in particular with tacrolimus, cyclosporine, mycophenolic acid and corticosteroids, whereas evidence was missing for everolimus and sirolimus. Only one of the papers investigating the effect of cIMDs on the gut microbiota reported negative results while all the others showed significant changes in the relative abundance of specific intestinal bacteria. However, no unique pattern of microbiota modification was observed across the different studies. In conclusion, the available evidence supports the hypothesis that intestinal microbiota could contribute to the variability in the response to some cIMDs, whereas data are still missing for others.

Kidney transplantation is an effective method to improve the condition of patients with end-stage renal disease. The gut microbiota significantly affects the immune system and can be used as an influencing factor to change the prognoses of patients who have undergone kidney transplantation. Recipients after kidney transplantation showed a lower abundance of Firmicutes and Faecalibacterium prausnitzii and a higher proportion of Bacteroidetes and Proteobacteria. After using prebiotics, synbiotics, and fecal microbiota transplantation to regulate the microbial community, the prognoses of patients who underwent kidney transplantation evidently improved. We aimed to determine the relationship between gut microbiota and various postoperative complications inpatients who have undergone kidney transplantation in recent years and to explore how gut microecology affects post-transplant complications. An in-depth understanding of the specific functions of gut microbiota and identification of the actual pathogenic flora during complications in patients undergoing kidney transplantation can help physicians develop strategies to restore the normal intestinal microbiome of transplant patients to maximize their survival and improve their quality of life.

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. 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.

Gut microbiome research has been a surge of interest in many branches of medicine in the last decade. Our main aim is to show ability of microbes to infuence the functions of human body, especially in the immune system, and on the other hand to clarify changes in composition of gut microbiome in the post-transplantation period and their function for the long-term survival of the graft and the patient in the context of the occurrence of a wide range of complications. Kidney transplantation with the subsequent use of immunosuppressants and antibiotics affects the composition of gut microbiome. The subsequent development of dysbiosis significantly increases the risk of acute rejection, interstitial fibrosis and tubular atrophy of the graft, post-transplant diarrhoea, organ´s infections and metabolic complications such as post-transplant diabetes mellitus. Also important is the influence of the microorganisms of the gut microbiome on metabolism of immunosuppressants with the production of less effective components and the subsequent necessity of modifying their levels with a higher risk of underdosing and the occurrence of graft rejection. Support of the composition of the gut microbiome in the post-transplantation period in favor of bacteria producing short chain fatty acids (SCFA) is possible by changing of diet with predominance of fiber, the application of probiotics, prebiotics. According to available studies, it can lead to benefits in term of metabolic compensation, to the induction of donor-specific tolerance and many others, with an overall improvement in the quality of patient and graft survival.

The search for novel heterocyclic compounds with a natural product skeleton as potent enzyme inhibitors against clinical hits is our prime concern in this study. Here, a simple and facile two-step strategy has been designed to synthesize a series of novel coumarin-based dihydropyranochromenes (12a-12m) in a basic moiety. The synthesized compounds were thus characterized through spectroscopic techniques and screened for inhibition potency against the cytosolic hCA II isoform and β-glucuronidase. Few of these compounds were potent inhibitors of hCA II and β-glucuronidase with varying IC₅₀ values ranging from 4.55 ± 0.22 to 21.77 ± 3.32 μM and 440.1 ± 1.17 to 971.3 ± 0.05 μM, respectively. Among the stream of synthesized compounds, 12e and 12i were the most potent inhibitors of β-glucuronidase, while 12h, 12i, and 12j showed greater potency against hCA II. In silico docking studies illustrated the significance of substituted groups on the pyranochromene skeleton and binding pattern of these highly potent compounds inside enzyme pockets.

The intestinal microbiota produces β-glucuronidase that plays an essential role in the metabolism of the immunosuppressant mycophenolate mofetil (MMF). This drug is commonly used in organ and hematopoietic cell transplantation (HCT), with variations in dosing across transplant types. We hypothesized that β-glucuronidase activity differs between transplant types, which may account for differences in dosing requirements. We evaluated fecal β-glucuronidase activity in patients receiving MMF post-allogeneic HCT and post-kidney transplant. Kidney transplant patients had significantly greater β-glucuronidase activity (8.48 ± 6.21 nmol/hr/g) than HCT patients (3.50 ± 3.29 nmol/hr/g; P = .001). Microbially mediated β-glucuronidase activity may be a critical determinant in the amount of mycophenolate entering the systemic circulation and an important factor to consider for precision dosing of MMF.

Mycophenolate mofetil (MMF) is an important immunosuppressant used after allogeneic hematopoietic cell transplant (HCT). MMF has a narrow therapeutic index and blood concentrations of mycophenolic acid (MPA), the active component of MMF, are highly variable. Low MPA concentrations are associated with risk of graft vs host disease (GvHD) while high concentrations are associated with toxicity. Reasons for variability are not well known and may be due, at least in part, to the presence of β-glucuronidase producing bacteria in the gastrointestinal tract which enhance MPA enterohepatic recirculation (EHR) by transforming MPA metabolites formed in the liver back to MPA.

To determine if individuals with high MPA EHR have a greater abundance of β-glucuronidase producing bacteria in their stool and higher MPA concentrations relative to those with low EHR.

We conducted a pharmacomicrobiomics study in 20 adult HCT recipients receiving a myeloablative or reduced intensity preparative regimen. Participants received MMF 1g IV every 8 hours with tacrolimus. Intensive pharmacokinetic sampling of mycophenolate was conducted before hospital discharge. Total MPA, MPA glucuronide (MPAG) and acylMPAG were measured. EHR was defined as a ratio of MPA area under the concentration-versus-time curve (AUC)_4-8 to MPA AUC_0-8. Differences in stool microbiome diversity and composition, determined by shotgun metagenomic sequencing, were compared above and below the median EHR (22%, range 5-44%).

Median EHR was 12% and 29% in the low and high EHR groups, respectively. MPA troughs, MPA AUC_4-8 and acylMPAG AUC_4-8/AUC_0-8, were greater in the high EHR group vs low EHR group [1.53 vs 0.28 mcg/mL, p = 0.0001], [7.33 vs 1.79 hr*mcg/mL, p = 0.0003] and [0.33 vs 0.24 hr*mcg/mL, p = 0.0007], respectively. MPA AUC_0-8 was greater in the high EHR than the low EHR group and trended towards significance [22.8 vs. 15.3 hr*mcg/mL, p=0.06]. Bacteroides vulgatus, stercoris and thetaiotaomicron were 1.2-2.4 times more abundant (p=0.039, 0.024, 0.046, respectively) in the high EHR group. MPA EHR was positively correlated with B. vulgatus (⍴=0.58, p≤0.01) and B. thetaiotaomicron (⍴=0.46, p<0.05) and negatively correlated with Blautia hydrogenotrophica (⍴=-0.53, p<0.05). Therapeutic MPA troughs were achieved in 80% of patients in the high EHR group and 0% in the low EHR. There was a trend towards differences in MPA AUC_0-8 and MPA C_ss mcg/mL in high vs. low EHR groups (p=0.06).

MPA EHR was variable. Patients with high MPA EHR had greater abundance of Bacteroides species in stool and higher MPA exposure than patients with low MPA EHR. Bacteroides may therefore be protective from poor outcomes such as graft vs host disease but in others it may increase the risk of MPA adverse effects. These data need to be confirmed and studied after oral MMF.

Research in the past decade has revealed important implications for the microbiome in human health. Studies have defined a distinct gut microbiota in kidney transplant recipients and have recently linked the microbiota to infectious complications, similar to the allogeneic stem cell transplant population.

In this review, we focus on the metabolism of immunosuppressive medications by the gut microbiota and on the urinary microbiome in the setting of infectious and immunological complications. We highlight seminal studies showing the role of specific gut microbiota in the direct metabolism of tacrolimus into a lesser effective immunosuppressant as well as the role of the gut microbiota in the metabolism of mycophenolic acid (MPA) glucuronide. We describe distinct urinary microbiota patterns in kidney transplant recipients with interstitial fibrosis tubular atrophy, chronic allograft nephropathy, tolerance, and bacterial and viral complications.

The microbiota has important implications for immunosuppressive medications and immunological outcomes in kidney transplant recipients. Further research is needed to better delineate the impact of the metabolism of tacrolimus and MPA by gut bacteria and the role of the urine microbiota in the development of immunological and infectious complications.