Background Recent evidence suggests that the increased incidence in Crohn’s disease (CD) is associated with a Westernization of diet including an increase in dietary fatty acid intake. In previous projects, we revealed that feeding a Western diet (WD) enriched with polyunsaturated fatty acids (PUFA) induces CD-like enteritis in mice lacking one allele of Gpx4 in their intestinal epithelial cells (IEC). Accordingly, ω6- and ω3-PUFA were shown to induce TLR2-dependent enteritis in mice and PUFA intake positively correlates with clinical disease activity in CD patients. Perturbation of Paneth cell (PC) homeostasis is known to induce intestinal inflammation. In this study we investigated the role of Paneth cells as sensors and transmitters of GPX4-restricted and PUFA-induced metabolic enteritis.
Metabolic dysfunction–associated fatty liver disease (MAFLD) has appeared as the leading liver disease worldwide. Whereas the terminology nonalcoholic fatty liver disease (NAFLD) mainly reflected a negative selection and exclusion of alcohol-related liver disease (ALD), the new definition made its focus on the association of MAFLD with overweight/obesity, type 2 diabetes and metabolic risk factors especially also in normal weight/lean subjects. Several studies from the past 2 years have now used the new definition and have provided substantial information that this new definition might be accurate. Studies from the past 2 years have provided evidence that the new definition might be especially advantageous in the characterization and identification of patients with significant fibrosis. This has also been demonstrated in the well-known Rotterdam study in which the MAFLD-only group showed a higher rate of fibrosis and liver stiffness. MAFLD might also be able to predict all-cause mortality as demonstrated in the Third National Health and Nutrition Examination Survey. Furthermore, MAFLD might improve characterization of the cardiovascular risk of this patient population. As the term MAFLD has not yet been accepted universally, it remains important to coordinate efforts globally to adapt to this new definition and especially involve all specialities dealing with metabolic disorders such as diabetologists to further improve its definition and to prepare the medical community for its future use. The aim of this review is to summarize and critically address evidence emerging over the past 2 years that usage of the term MAFLD could be helpful in daily clinical practice.
Nonalcoholic fatty liver disease (NAFLD) particularly affects patients with type 2 diabetes and obesity. The incidence of NAFLD has increased significantly over the last decades and is now pandemically across the globe. It is a complex systemic disease comprising hepatic lipid accumulation, inflammation, lipotoxicity, gut dysbiosis, and insulin resistance as main features and with the potential to progress to cirrhosis and hepatocellular carcinoma (HCC). In numerous animal and human studies the gut microbiota plays a key role in the pathogenesis of NAFLD, NAFLD-cirrhosis and NAFLD-associated HCC. Lipotoxicity is the driver of inflammation, insulin resistance, and liver injury. Likewise, western diet, obesity, and metabolic disorders may alter the gut microbiota, which activates innate and adaptive immune responses and fuels hereby hepatic and systemic inflammation. Indigestible carbohydrates are fermented by the gut microbiota to produce important metabolites, such as short-chain fatty acids and succinate. Numerous animal and human studies suggested a pivotal role of these metabolites in the progression of NAFLD and its comorbidities. Though, modification of the gut microbiota and/or the metabolites could even be beneficial in patients with NAFLD, NAFLD-cirrhosis, and NAFLD-associated HCC. In this review we collect the evidence that exogenous and endogenous hits drive liver injury in NAFLD and propel liver fibrosis and the progressing to advanced disease stages. NAFLD can be seen as the product of a complex interplay between gut microbiota, the immune response and metabolism. Thus, the challenge will be to understand its pathogenesis and to develop new therapeutic strategies.
Abstract Background & Aims Alcohol‐related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl‐fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. Methods Dimethyl‐fumarate or vehicle was orally administered to wild‐type mice receiving a Lieber‐DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical‐ and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol‐induced intestinal barrier disruption. Results Dimethyl‐fumarate protected against ethanol‐induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines ( Tnf‐α, Il‐1β, Cxcl1 ) and reduced abundance of neutrophils and macrophages in ethanol‐fed and DMF‐treated mice when compared to vehicle. DMF protected against ethanol‐induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS‐induced cytokine responses of KCs. Conclusions Dimethyl‐fumarate counteracts ethanol‐induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.
Background & Aims: Obesity and related co-morbidities such as non-alcoholic fatty liver disease (NAFLD) are increasing dramatically worldwide. Genetic variations in the gene encoding Patatin-like phospholipase domain-containing protein 3 (PNPLA3) which is also known as adiponutrin (ADPN) have been associated with NAFLD affecting hepatic fat content and liver inflammation yet the underlying molecular mechanisms remain unknown. The aim of our study was to investigate whether weight loss affects both hepatic and adipose PNPLA3 expression in severely obese patients before and after laparoscopic gastric banding (LAGB).
Introduction Genetically associated risk for Crohn’s disease (CD) has been well characterised in last decades, and a pathophysiological concept of inflammatory bowel diseases indicates that specific cellular stress pathways control gut inflammation in a susceptible host. Mechanistic insights into epithelial stress cross-talk affected by genetic variation in CD remains scarce. Here, we investigated the biological interaction between two stress pathways that were implicated in CD by genetic studies. Specifically, we studied if and how genetically controlled epithelial stress links to the development of intestinal inflammation.
Introduction Metabolic-associated liver diseases have emerged pandemically across the globe and are clinically related to metabolic disorders such as obesity and type 2 diabetes. The new nomenclature and definition (i.e. metabolic dysfunction-associated steatotic liver disease – MASLD; metabolic dysfunction-associated steatohepatitis – MASH) reflect the nature of these complex systemic disorders, which are characterized by inflammation, gut dysbiosis and metabolic dysregulation. In this review, we summarize recent advantages in understanding the pathophysiology of MASLD, which we parallel to emerging therapeutic concepts.
