The liver communicates with the intestine via the portal vein, biliary system, and mediators in the circulation. Microbes in the intestine maintain liver homeostasis but can also serve as a source of ...pathogens and molecules that contribute to fatty liver diseases. We review changes in the gut microbiota that can promote development or progression of alcohol-associated and non-alcoholic fatty liver disease-the most common chronic liver diseases in Western countries. We discuss how microbes and their products contribute to liver disease pathogenesis, putative microbial biomarkers of disease, and potential treatment approaches based on manipulation of the gut microbiota. Increasing our understanding of interactions between the intestinal microbiome and liver might help us identify patients with specific disease subtypes and select specific microbiota-based therapies.
Non-alcoholic fatty liver DISEASE (NAFLD) is the most common chronic liver disease in Western countries and affects approximately 25% of the adult population. Since NAFLD is frequently associated ...with further metabolic comorbidities such as obesity, type 2 diabetes mellitus, or dyslipidemia, it is generally considered as the hepatic manifestation of the metabolic syndrome. In addition to its potential to cause liver-related morbidity and mortality, NAFLD is also associated with subclinical and clinical cardiovascular disease (CVD). Growing evidence indicates that patients with NAFLD are at substantial risk for the development of hypertension, coronary heart disease, cardiomyopathy, and cardiac arrhythmias, which clinically result in increased cardiovascular morbidity and mortality. The natural history of NAFLD is variable and the vast majority of patients will not progress from simple steatosis to fibrosis and end stage liver disease. However, patients with progressive forms of NAFLD, including non-alcoholic steatohepatitis (NASH) and/or advanced fibrosis, as well as NAFLD patients with concomitant types 2 diabetes are at highest risk for CVD. This review describes the underlying pathophysiological mechanisms linking NAFLD and CVD, discusses the role of NAFLD as a metabolic dysfunction associated cardiovascular risk factor, and focuses on common cardiovascular manifestations in NAFLD patients.
Alcoholic hepatitis is the most severe form of alcohol-related liver disease. While the gut microbiome is known to play a role in disease development and progression, less is known about specific ...compositional changes of the gut bacterial microbiome associated with disease severity. Therefore, the aim of our study was to correlate gut microbiota features with disease severity in alcoholic hepatitis patients.
We used 16S rRNA gene sequencing on fecal samples from 74 alcoholic hepatitis patients, which were enrolled at 9 centers in Europe, the United States, and Mexico in a multi-center observational study. The relative abundance of gut bacterial taxa on genus level, as well as the microbiome diversity, was correlated to various clinical, laboratory, and histologic parameters.
We observed a negative correlation between the model for end-stage liver disease score and Shannon diversity, independent of potentially confounding factors (P
adjust
= 0.046). Alcoholic hepatitis patients with more severe disease had significantly decreased relative abundances of Akkermansia while the relative abundance of Veillonella was increased. We observed a reduction in the Bacteroides abundance (P
adjust
= 0.048) and Shannon diversity (P
adjust
= 0.018) in antibiotic-treated patients and patients receiving steroids had an increase in Veillonella abundance (P
adjust
= 0.005), which was both independent of potentially confounding factors.
We observed distinct changes in the gut bacterial microbiome of alcoholic hepatitis patients with more severe disease. The gut bacterial microbiome might be an attractive target to prevent and treat this deadly disease.
Alcohol-associated liver disease (ALD) is an important cause of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of ALD; however, little is ...known about commensal fungi therein.
We studied the dynamic changes of the intestinal fungal microbiome, or mycobiome, in 66 patients with alcohol use disorder (AUD) and after 2 weeks of alcohol abstinence using internal transcribed spacer 2 (ITS2) amplicon sequencing of fecal samples.
Patients with AUD had significantly increased abundance of the genera
,
,
,
, and
, and of the species
and
compared with control subjects. Significantly improved liver health markers caspase-cleaved and intact cytokeratin 18 (CK18-M65) levels and controlled attenuation parameter (CAP) in AUD patients after 2 weeks of alcohol abstinence were associated with significantly lower abundance of the genera
,
,
,
,
, and the species
and
. This was mirrored by significantly higher specific anti-
immunoglobulin G (IgG) and M (IgM) serum levels in AUD patients in relation to control participants, and significantly decreased anti-
IgG levels in AUD subjects after 2 weeks of abstinence. The intestinal abundance of the genus
was significantly higher in AUD subjects with progressive liver disease compared with non-progressive liver disease.
In conclusion, improved liver health in AUD patients after alcohol abstinence was associated with lower intestinal abundances of
and
, and lower serum anti-
IgG levels. Intestinal fungi might serve as a therapeutic target to improve the outcome of patients in ALD.
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide with a reported prevalence ranging 6–33%, depending on the studied populations. It encompasses ...a spectrum of liver manifestations ranging from simple steatosis (also known as nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. NAFLD is strongly associated with the components of metabolic syndrome, mainly obesity and type 2 diabetes mellitus. NAFLD patients are at increased risk of liver‐related as well as cardiovascular mortality. Current paradigm suggests a benign course for NAFL whereas NASH is considered to be the progressive phenotype. Although previously under‐recognized accumulating evidence suggests that NAFL may also progress, suggesting a higher number of patients at risk than previously appreciated. Liver biopsy remains the gold standard for definitive diagnosis, but the majority of patients can be diagnosed accurately by noninvasive methods. Approved therapies for NAFLD are still lacking and lifestyle modifications aiming at weight loss remain the mainstay of NAFLD treatment. Intensive research could identify insulin resistance, lipotoxicity and dysbiosis of the gut microbiota as major pathophysiological mechanisms, leading to the development of promising targeted therapies which are currently investigated in clinical trials. In this review we summarized the current knowledge of NAFLD epidemiology, natural history, diagnosis, pathogenesis and treatment and considered future directions.
The fungal microbiota plays an important role in the pathogenesis of alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to compare changes of ...the fecal fungal microbiota between patients with ALD and NAFLD and to elucidate patterns in different disease stages between the two conditions. We analyzed fungal internal transcribed spacer 2 (ITS2) sequencing using fecal samples from a cohort of 48 patients with ALD, 78 patients with NAFLD, and 34 controls. The fungal microbiota differed significantly between ALD and NAFLD. The genera
,
,
, and the species
(
),
(
),
(
) were significantly increased in patients with ALD, whereas the genera
and
were significantly increased in the NAFLD cohort. We identified the fungal signature consisting of
,
,
, and
to have the highest discriminative ability to detect ALD vs NAFLD with an area under the curve (AUC) of 0.93. When stratifying the ALD and NAFLD cohorts by fibrosis severity, the fungal signature with the highest AUC of 0.92 to distinguish ALD F0-F1 vs NAFLD F0-F1 comprised
,
,
,
, and
. For more advanced fibrosis stages (F2-F4), the fungal signature composed of
,
,
, and
achieved the highest AUC of 0.99 to differentiate ALD from NAFLD. This is the first study to identify a fungal signature to differentiate two metabolic fatty liver diseases from each other, specifically ALD from NAFLD. This might have clinical utility in unclear cases and might hence help shape treatment approaches. However, larger studies are required to validate this fungal signature in other populations of ALD and NAFLD.
Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity ...is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation postnatal day 21 (P21). Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.
Alcohol use is a leading cause of chronic liver disease worldwide, and changes in the microbiome associated with alcohol use contribute to patients’ risk for liver disease progression. Less is known ...about the effects of alcohol use on the intestinal viral microbiome (virome) and interactions between bacteriophages and their target bacteria. We studied changes in the intestinal virome of 62 clinically well‐characterized patients with alcohol use disorder (AUD) during active alcohol use and after 2 weeks of alcohol abstinence, by extracting virus‐like particles and performing metagenomic sequencing. We observed decreased abundance of Propionibacterium, Lactobacillus, and Leuconostoc phages in patients with active AUD when compared with controls, whereas after 2 weeks of alcohol abstinence, patients with AUD demonstrated an increase in the abundance of Propionibacterium, Lactobacillus, and Leuconostoc phages. The intestinal virome signature was also significantly different in patients with AUD with progressive liver disease, with increased abundance of phages targeting Enterobacteria and Lactococcus species phages compared with patients with AUD with nonprogressive liver disease. By performing moderation analyses, we found that progressive liver disease is associated with changes in interactions between some bacteriophages and their respective target bacteria. In summary, active alcohol use and alcohol‐associated progressive liver disease are associated with changes in the fecal virome, some of which are partially reversible after a short period of abstinence. Progression of alcohol‐associated liver disease is associated with changes in bacteriophage–bacteria interactions.
The intestinal virome of patients with alcohol use disorder (AUD) is significantly different from controls. Abstinence from alcohol in patients with AUD is also associated with significant differences in the intestinal virome, trending toward that of controls. Patients with progressive liver disease as determined by liver stiffness measurement and serum caspase‐cleaved and intact cytokeratin 18 (CK18‐M65) have a different intestinal virome signature than those with nonprogressive disease, which may be in part due to changes in bacteriophage–bacteria correlations with liver disease progression.
Excessive alcohol consumption is associated with hepatic steatosis and dysregulation of the gut microbiota in patients with alcohol use disorder (AUD). However, how gut microbiota responds when ...patients stop drinking has not been well studied. In this study, we use shotgun metagenomic sequencing to elucidate the alterations in the functional capacity of gut microbiota in patients with AUD when they stop drinking for 2-weeks. Sensitive microbial pathways to alcohol abstinence were identified in AUD patients. Further, we found the functional microbial responses to alcohol abstinence were different in AUD patients with different degree of hepatic steatosis. Our results provide insights into the link between functional alterations of the gut microbiota and steatosis associated with alcohol consumption.
Notch is an intercellular signaling pathway related mainly to sprouting neo-angiogenesis. The objective of our study was to evaluate the angiogenic mechanisms involved in the vascular augmentation ...(sprouting/intussusception) after Notch inhibition within perfused vascular beds using the chick area vasculosa and MxCreNotch1(lox/lox) mice. In vivo monitoring combined with morphological investigations demonstrated that inhibition of Notch signaling within perfused vascular beds remarkably induced intussusceptive angiogenesis (IA) with resultant dense immature capillary plexuses. The latter were characterized by 40 % increase in vascular density, pericyte detachment, enhanced vessel permeability, as well as recruitment and extravasation of mononuclear cells into the incipient transluminal pillars (quintessence of IA). Combination of Notch inhibition with injection of bone marrow-derived mononuclear cells dramatically enhanced IA with 80 % increase in vascular density and pillar number augmentation by 420 %. Additionally, there was down-regulation of ephrinB2 mRNA levels consequent to Notch inhibition. Inhibition of ephrinB2 or EphB4 signaling induced some pericyte detachment and resulted in up-regulation of VEGFRs but with neither an angiogenic response nor recruitment of mononuclear cells. Notably, Tie-2 receptor was down-regulated, and the chemotactic factors SDF-1/CXCR4 were up-regulated only due to the Notch inhibition. Disruption of Notch signaling at the fronts of developing vessels generally results in massive sprouting. On the contrary, in the already existing vascular beds, down-regulation of Notch signaling triggered rapid augmentation of the vasculature predominantly by IA. Notch inhibition disturbed vessel stability and led to pericyte detachment followed by extravasation of mononuclear cells. The mononuclear cells contributed to formation of transluminal pillars with sustained IA resulting in a dense vascular plexus without concomitant vascular remodeling and maturation.
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