Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

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 microbiota 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 glucuronidase,may be transformed into the inactive product.

Update on the gut microbiome in health and diseases

The Human Microbiome Project,Earth Microbiome Project,and next-generation sequencing have advanced novel genome association,host genetic linkages,and pathogen identification.The microbiome is the sum of the microbes,their genetic information,and their ecological niche.This study will describe how millions of bacteria in the gut affect the human body in health and disease.The gut microbiome changes in relation with age,with an increase in Bacteroidetes and Firmicutes.Host and environmental factors affecting the gut microbiome are diet,drugs,age,smoking,exercise,and host genetics.In addition,changes in the gut microbiome may affect the local gut immune system and systemic immune system.In this study,we discuss how the microbiome may affect the metabolism of healthy subjects or may affect the pathogenesis of metabolism-generating metabolic diseases.Due to the high number of publications on the argument,from a methodologically point of view,we decided to select the best papers published in referred journals in the last 3 years.Then we selected the previously published papers.The major goals of our study were to elucidate which microbiome and by which pathways are related to healthy and disease conditions.

Vaccine therapy for dysbiosis-related diseases

Progress in genomic analysis has resulted in the proposal that the intestinal microbiota is a crucial environmental factor in the development of multifactorial diseases,such as obesity,diabetes,rheumatoid arthritis,and inflammatory bowel diseases represented by Crohn’s disease and ulcerative colitis.Dysregulated gut microbiome contributes to the pathogenesis of such disorders;however,there are few effective treatments for controlling only disease-mediating bacteria.Here,we review current knowledge about the intestinal microbiome in health and disease,and discuss a regulatory strategy using a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides,which we have recently developed.Unlike other conventional injectable immunizations,our vaccine contributes to the induction of antigen-specific systemic and mucosal immunity.This vaccine strategy can prevent infectious diseases such as Streptococcus pneumoniae infection,and control metabolic symptoms mediated by intestinal bacteria(e.g.Clostridium ramosum)by induction of high titers of antigen-specific IgA at target mucosal sites.In the future,our vaccination approach could be an effective therapy for common infectious diseases and dysbiosis-related disorders that have been difficult to control so far.