Longitudinal Analysis of the Intestinal Microbiota in Liver Transplantation

Abstract

BackgroundIncreasing evidence suggests that the intestinal microbiota plays an important role in liver diseases. However, the dynamics of the intestinal microbiota during liver transplantation (LT) and its potential role in clinical course remain unknown.MethodsWe prospectively analyzed the intestinal microbiota of 38 patients who underwent LT in Kyoto University Hospital. We characterized the microbial compositions of fecal specimens from LT patients using a metagenomics approach by an Illumina MiSeq platform. We analyzed the diversity of microbiota sequentially from pretransplantation until 2 months after LT and also compared the microbiota during an episode of acute cellular rejection (ACR) and bloodstream infections (BSI) to the microbial composition of time-matched fecal specimens obtained from patients who did not experience ACR or BSI, respectively.ResultsThree hundred twenty fecal specimens were analyzed. Dynamic changes were observed in the microbial composition of LT recipients during the perioperative period. Over the course of LT, the mean diversity index decreased during the first 3 weeks after LT and gradually increased during our observation period. The loss of intestinal microbiota diversity was associated with high Child-Pugh scores, high model for end-stage liver disease scores, ACR, and BSI. At the family level, Bacteroides, Enterobacteriaceae, Streptococcaceae, and Bifidobacteriaceae were increased whereas Enterococcaceae, Lactobacillaceae, Clostridiaceae, Ruminococcaceae, and Peptostreptococcaceae were decreased in ACR patients.ConclusionsThe microbiota of LT patients was associated with the severity of liver diseases and the presence of ACR and BSI. These results lay the groundwork for more comprehensive investigations of microbiota characteristics to identify diagnostic markers for transplant health and to guide intervention strategies to improve transplant outcomes.

Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far?

“…Concerning with the relation of gut microbiome before LT and the post-LT complication, cirrhotic patients with decreased microbial diversity before LT were more likely to develop postoperative infections than those with stable microbiota consisting of slight microbial dysbiosis [229,230]. Other clinical and experimental studies have also demonstrated that the gut microbiota disturbance, especially loss of diversity, can be associated with infection and rejection risk after LT. [226,231,232].…”

Transplant associated infections—The role of the gastrointestinal microbiota and potential therapeutic options

“…A number of studies have evaluated changes in the gastrointestinal microbiota as a consequence of transplantation (Table ) . We conducted searches in MEDLINE, Embase and CINAHL from database inception to May 2019.…”

“…A number of studies have evaluated changes in the gastrointestinal microbiota as a consequence of transplantation (Table 1). [36][37][38][39][40][41][42][43][44][45][46] We conducted searches in MEDLINE, Embase and CINAHL from database inception to May 2019. A MEDLINE search strategy for obtaining studies evaluating changes in the gastrointestinal microbiota in transplant recipients are provided in Supplementary Table S1.…”

Antibiotic pretreatment alleviates liver transplant damage in mice and humans

“…To determine whether RFX treatment is an independent predictor of EAD in liver transplant patients, we conducted multivariate analysis based on a step-wise logistic regression model by screening "pre-OLT Abx-free or RFX <10 days" simultaneously with donor Abx use; recipient age, sex, and BMI; MELD score; disease etiology; concomitant HCC; cold/warm ischemia time; blood transfusions; donor age, sex, BMI, and race; DCD; donor laboratory data (AST, ALT, T-bil); Abx use during surgery; as well as post-OLT Abx and basiliximab therapy. Notably, "pre-OLT Abx-free or RFX <10 days" was identified as one of the predictive factors of EAD (OR = 2.530, 95% CI: 1.031-6.210, P = 0.043), along with donor BMI (kg/m 2 , OR = 1.077, 95% CI: 1.009-1.150, P = 0.026); liver pathophysiology has emerged as an attractive research field, recent studies have documented putative associations between intestinal microbial characteristics and liver graft status in both animals (42) and humans (43). The loss of intestinal microbiota diversity was accompanied by high Child-Pugh and MELD scores, as well as an increased incidence of rejection episodes and bloodstream infections in liver transplant patients.…”

“…The loss of intestinal microbiota diversity was accompanied by high Child-Pugh and MELD scores, as well as an increased incidence of rejection episodes and bloodstream infections in liver transplant patients. Indeed, the frequencies of Bacteroides, Enterobacteriaceae, Streptococcaceae, and Bifidobacteriaceae were increased, whereas those of Enterococcaceae, Lactobacillaceae, Clostridiaceae, Ruminococcaceae, and Peptostreptococcaceae were decreased in OLT patients experiencing acute rejection (43). On the other hand, the potential of gut microbiota modifications to affect IRI pathology and underlying mechanisms remain largely unknown (44).…”