Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival rates after transplantation vary considerably. There is now increasing evidence that the gut microbiome is linked to the survival of patients undergoing hematopoietic cell transplant, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1370 fecal samples from 415 liver and 672 renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes, and virulence factors. To quantify taxonomic and metabolic dysbiosis, we also analyzed 1183 age-, sex-, and body mass index–matched controls from the same population. In addition, a subset of 78 renal transplant recipients was followed longitudinally from pretransplantation to 24 months after transplantation. Our data showed that both liver and kidney transplant recipients suffered from gut dysbiosis, including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistance genes and virulence factors. These changes were found to persist up to 20 years after transplantation. Last, we demonstrated that the use of immunosuppressive drugs was associated with the observed dysbiosis and that the extent of dysbiosis was associated with increased mortality after transplantation. This study represents a step toward potential microbiome-targeted interventions that might influence the outcomes of recipients of solid organ transplantation.

More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis-expression quantitative trait loci (cis-eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis-eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis-eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis-eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD.

Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E−09) and GCM1 (rs1491489378-T, P = 3.16E−09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E−13) and FTO (P = 2.11E−09). Statistically significant genetic correlation (r_g) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (r_g = 0.5276, P = 1.45E−03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level.

Thrombosis after liver transplantation substantially impairs graft‐ and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of post‐transplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993‐2018. We determined the association between known donor thrombophilia gene variants and recipient post‐transplant thrombosis. In addition, we performed a genome‐wide association study (GWAS) and meta‐analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with post‐transplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis‐susceptible polymorphisms. By performing a meta‐GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, amongst which were AK4 (rs11208611‐T, p=4.22x10^‐05) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696‐C, p=2.62x10^‐05) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia‐related variants, are associated with increased risk of thrombosis after liver transplantation.

Background: Depressive symptoms are frequently observed in patients with primary biliary cholangitis (PBC). The role of depressive symptoms on cirrhosis has not been fully noticed in PBC. We aimed to establish a risk model for cirrhosis that took depressive symptoms into account.Methods: Depressive symptoms were assessed by the 17‐item Hamilton Depression Rating Scale (HAMD‐17). HAMD‐17 score was analyzed in relation to clinical parameters. Least absolute shrinkage and selection operator (Lasso)‐logistic regression and decision tree models were used to explore the effect of depressive symptoms on cirrhosis.Results: The rate of depressive symptom in patients with PBC (n = 162) was higher than in healthy controls (n = 180) (52.5% vs. 16.1%; p < .001). HAMD‐17 score was negatively associated with C4 levels and positively associated with levels of alkaline phosphatase (ALP), γ‐glutamyl transpeptidase (GGT), total bilirubin (TB), Immunoglobulin (Ig) G, and IgM (r = −0.162, 0.197, 0.355, 0.203, 0.182, 0.314, p < .05). In Lasso‐logistic regression analysis, HAMD‐17 score, human leukocyte antigen (HLA)‐DRB1*03:01 allele, age, ALP levels, and IgM levels (odds ratio [OR] = 1.087, 7.353, 1.075, 1.009, 1.005; p < 0.05) were independent risk factors for cirrhosis. Elevated HAMD‐17 score was also a discriminating factor for high risk of cirrhosis in patients with PBC in decision tree model.Conclusions: Depressive symptoms were associated with disease severity. Elevated HAMD‐17 score was a risk factor for cirrhosis in patients with PBC.

Background Thrombosis after liver transplantation is a leading cause of graft loss, morbidity, and mortality. Several known recipient‐ and surgery‐related characteristics have been associated with increased risk of thrombosis after transplantation. Potential donor‐related risk factors, however, remain largely undefined. Objectives We aimed to identify risk factors for early post‐transplantation thrombosis (<90 days) and to determine the impact of early postoperative thrombosis on long‐term graft and patient survival. Patients/Methods A post hoc analysis was performed of an observational cohort study including all primary, adult liver transplantations performed between 1993 and 2018. Donor‐, recipient‐, and surgery‐related characteristics were collected. Competing risk model analyses and multivariable regression analyses were performed to identify risk factors for developing early post‐transplant thrombosis and graft failure. Results From a total of 748 adult liver transplantations, 58 recipients (7.8%) developed a thrombosis after a median of 7 days. Post‐transplantation thrombotic events included 25 hepatic artery thromboses, 13 portal vein thromboses, and 22 other thrombotic complications. Donor history of smoking was independently associated with early postoperative thrombosis (odds ratio [OR] 2.42; 95% confidence interval [CI], 1.29‐4.52). Development of early post‐transplant thrombosis was independently associated with patient mortality (hazard ratio [HR] 3.61; 95% CI 1.54‐8.46) and graft failure (HR 5.80, 95% CI 3.26‐10.33), respectively. Conclusion Donor history of smoking conveys a more than two‐fold increased risk of thrombosis after liver transplantation, independent of other factors. Post‐transplant thrombosis was independently associated with decreased patient and graft survival.