Fecal Microbiome Distinguishes Alcohol Consumption From Alcoholic Hepatitis But Does Not Discriminate Disease Severity.

BACKGROUND AND AIMS: The role of the intestinal microbiome in alcoholic hepatitis is not established. The aims of this study were to (1) characterize the fecal microbial ecology associated with alcoholic hepatitis, (2) relate microbiome changes to disease severity, and (3) infer the functional relevance of shifts in microbial ecology. APPROACH AND RESULTS: The fecal microbiome in patients with moderate alcoholic hepatitis (MAH) or severe alcoholic hepatitis (SAH) was compared with healthy controls (HCs) and heavy drinking controls (HDCs). Microbial taxa were identified by 16S pyrosequencing. Functional metagenomics was performed using PICRUSt. Fecal short chain fatty acids (SCFAs) were measured using a liquid chromatography-mass spectrometry platform. A total of 78 participants (HC, n = 24; HDC, n = 20; MAH, n = 10; SAH, n = 24) were studied. HDC had a distinct signature compared with HC with depletion of Bacteroidetes (46% vs. 26%; P = 0.01). Alcoholic hepatitis was associated with a distinct microbiome signature compared with HDC (area under the curve = 0.826); differential abundance of Ruminococcaceae, Veillonellaceae, Lachnospiraceae, Porphyromonadaceae, and Rikenellaceae families were the key contributors to these differences. The beta diversity was significantly different among the groups (permutational multivariate analysis of variance [PERMANOVA] P < 0.001). SAH was associated with increased Proteobacteria (SAH 14% vs. HDC 7% and SAH vs. HC 2%, P = 0.20 and 0.01, respectively). Firmicutes abundance declined from HDC to MAH to SAH (63% vs. 53% vs. 48%, respectively; P = 0.09, HDC vs. SAH). Microbial taxa did not distinguish between MAH and SAH (PERMANOVA P = 0.785). SCFAs producing bacteria (Lachnospiraceae and Ruminococcaceae) were decreased in alcoholic hepatitis, and a similar decrease was observed in fecal SCFAs among alcoholic hepatitis patients. CONCLUSIONS: There are distinct changes in fecal microbiome associated with the development, but not severity, of alcoholic hepatitis.

Obesity does not significantly impact outcomes following simultaneous liver kidney transplantation: review of the UNOS database - a retrospective study.

Simultaneous liver kidney transplantation (SLK) is the only curative option for patients with combined end stage liver and kidney disease. With the global obesity epidemic, an increasing number of obese patients are in need of SLK. However, the impact of pre-transplant obesity on outcomes after SLK is unknown. An analysis of the United States OPTN registry (Oct 1987 - June 2016) identified 7205 SLK transplants. Of these, 1677 patients were overweight/obese (OW, BMI 30-39) and 183 were morbidly obese (MO, BMI ≥40). 29% of patients had NASH in the MO group versus 16.4% and 4.7% in the OW and normal weight (NW) groups, respectively. The 1, 3 and 5 year overall patient survival, kidney and liver graft survivals were comparable between the three groups. Numerically higher rates of acute kidney rejection were reported in the MO group at 1 year [12.73%, 8.59%, and 10.05% for MO, OW and NW, respectively (P = 0.22)]. Multivariate analysis identified diagnosis of hepatitis C, donor age, diabetes mellitus, and delayed kidney transplant function but not BMI as risk factors for poor patient and both liver and kidney graft survival. Based on these findings, obesity should not be a contraindication for SLK even for patients with BMIs ≥ 40.

An Evaluation of the Collagen Fragments Related to Fibrogenesis and Fibrolysis in Nonalcoholic Steatohepatitis.

Fibrosis, resulted from the imbalance of fibrogenesis and fibrolysis, is a key readout of disease progression in nonalcoholic steatohepatitis (NASH) and reflects mortality risk. Non-invasive biomarkers capable of diagnosing fibrosis stages and monitoring fibrosis changes in NASH patients are urgently needed. This study is to evaluate collagen formation and degradation biomarkers, reflective of fibrogenesis or fibrolysis, in patients with biopsy proven NASH. Collagen formation biomarker PRO-C3 and PRO-C6 levels were significantly higher in patients with advanced fibrosis stage 3-4 than those with fibrosis stage 0-2. Elevated PRO-C3 levels were also associated with severe lobular inflammation and ballooning, but not with steatosis. Multivariate logistic regression analysis identified PRO-C3 and PRO-C6 to be independently related to fibrosis stage. PRO-C3 showed similar performance to identify patients with advanced fibrosis in discovery and validation cohorts. Furthermore, in a longitudinal study cohort with paired biopsies, mean PRO-C3 increased with worsening of fibrosis and decreased with fibrosis improvement. The results suggest that PRO-C3 may be a potentially useful biomarker in identifying patients with advanced fibrosis and active fibrogenesis, as well as in assessing changes in fibrosis over time. It is worthy of further evaluation to confirm its diagnostic value and clinical utility.

Liver transplant modulates gut microbial dysbiosis and cognitive function in cirrhosis.

Liver transplantation (LT) improves daily function and cognition in patients with cirrhosis, but a subset of patients can remain impaired. Unfavorable microbiota or dysbiosis is observed in patients with cirrhosis, but the effect of LT on microbial composition, especially with poor post-LT cognition, is unclear. The aims were to determine the effect of LT on gut microbiota and to determine whether gut microbiota are associated with cognitive dysfunction after LT. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Cognition (Psychometric Hepatic Encephalopathy score [PHES]), health-related quality of life (HRQOL), and stool microbiota (multitagged sequencing for diversity and taxa) tests were performed at both visits. Persistent cognitive impairment was defined as a stable/worsening PHES. Both pre-/post-LT data were compared with age-matched healthy controls. We enrolled 45 patients (56 ± 7 years, Model for End-Stage Liver Disease score 26 ± 8). They received LT 6 ± 3 months after enrollment and were re-evaluated 7 ± 2 months after LT with a stable course. A significantly improved HRQOL, PHES, with increase in microbial diversity, increase in autochthonous, and decrease in potentially pathogenic taxa were seen after LT compared with baseline. However, there was continued dysbiosis and HRQOL/cognitive impairment after LT compared with controls in 29% who did not improve PHES after LT. In these, Proteobacteria relative abundance was significantly higher and Firmicutes were lower after LT, whereas the reverse occurred in the group that improved. Delta PHES was negatively correlated with delta Proteobacteria and positively with delta Firmicutes. In conclusion, LT improves gut microbiota diversity and dysbiosis compared with pre-LT baseline but residual dysbiosis remains compared with controls. There is cognitive and HRQOL enhancement in general after LT, but a higher Proteobacteria relative abundance change is associated with posttransplant cognitive impairment. Liver Transplantation 23 907-914 2017 AASLD.

Dual-photon microscopy-based quantitation of fibrosis-related parameters (q-FP) to model disease progression in steatohepatitis.

There is a need for further refinement of current histological systems for assessment of hepatic fibrosis in nonalcoholic fatty liver disease (NAFLD). This study evaluated hepatic fibrosis in NAFLD using dual-photon microscopy-based quantitation of fibrosis-related parameters (q-FPs). Fifty test cohort subjects and 42 validation cohort subjects with NAFLD and the full spectrum of fibrosis were studied. q-FPs were measured in specific predefined regions of interest (general, vessel, perisinusoid, and vascular septa). Seventy q-FPs had inter- and intraobserver concordance ≥0.8 and were related to the NASH Clinical Research Network fibrosis staging. Of these, 16 q-FPs with the strongest correlations (P < 0.001 for all) were entered in a principal component analysis model (odds ratio [OR] 7.8, P < 0.001), which separated any stage of fibrosis versus no fibrosis, and cirrhosis versus earlier stages with the areas under the receiver operating characteristic curves of 0.88 and 0.93 (P ≤ 0.01 for both), respectively. In an independent multivariable analysis, four q-FPs-the number of collagen strands (OR 8.5, P = 0.004), strand length (OR 12.0, P = 0.02), strand eccentricity (OR 8.3, P = 0.004), and strand solidity (OR 8.0, P = 0.003)-were independently associated with fibrosis stages and were used to model fibrosis along a continuous linear scale using desirability functions; this linear scale of fibrosis measurement was also related to fibrosis stage (P < 0.0001). The robustness of both the multivariable model and the linear scale of measurement was confirmed in the validation cohort. CONCLUSION: The q-FP model provides an accurate reproducible method to evaluate fibrosis in NAFLD along a quantitative and continuous scale. (Hepatology 2017;65:1891-1903).