Development of non-alcoholic steatohepatitis is associated with gut microbiota but not with oxysterol enzymes CH25H, EBI2, or CYP7B1 in mice.

Liver steatosis is the most frequent liver disorder and its advanced stage, non-alcoholic steatohepatitis (NASH), will soon become the main reason for liver fibrosis and cirrhosis. The "multiple hits hypothesis" suggests that progression from simple steatosis to NASH is triggered by multiple factors including the gut microbiota composition. The Epstein Barr virus induced gene 2 (EBI2) is a receptor for the oxysterol 7a, 25-dihydroxycholesterol synthesized by the enzymes CH25H and CYP7B1. EBI2 and its ligand control activation of immune cells in secondary lymphoid organs and the gut. Here we show a concurrent study of the microbial dysregulation and perturbation of the EBI2 axis in a mice model of NASH.We used mice with wildtype, or littermates with CH25H-/-, EBI2-/-, or CYP7B1-/- genotypes fed with a high-fat diet (HFD) containing high amounts of fat, cholesterol, and fructose for 20 weeks to induce liver steatosis and NASH. Fecal and small intestinal microbiota samples were collected, and microbiota signatures were compared according to genotype and NASH disease state.We found pronounced differences in microbiota composition of mice with HFD developing NASH compared to mice did not developing NASH. In mice with NASH, we identified significantly increased 33 taxa mainly belonging to the Clostridiales order and/ or the family, and significantly decreased 17 taxa. Using an Elastic Net algorithm, we suggest a microbiota signature that predicts NASH in animals with a HFD from the microbiota composition with moderate accuracy (area under the receiver operator characteristics curve = 0.64). In contrast, no microbiota differences regarding the studied genotypes (wildtype vs knock-out CH25H-/-, EBI2-/-, or CYP7B1-/-) were observed.In conclusion, our data confirm previous studies identifying the intestinal microbiota composition as a relevant marker for NASH pathogenesis. Further, no link of the EBI2 - oxysterol axis to the intestinal microbiota was detectable in the current study.

Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7α,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2-/- mice and mice with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7α-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.

The social insectivore: Peer and expert influence affect consumer evaluations of insects as food.

As conventional animal production is a significant contributor to anthropogenic climate change, eating of insects in Western markets has been primarily discussed from an environmental perspective. Following advances in food technology and regulation, edible insects are an emerging research topic not only in environmental sciences, but also in consumer research. To contribute to this rising interest, the present research presents consumer psychological drivers to promote insect consumption based on research on social influence. Two experiments that assessed the influence of peer (Study 1) as well as expert influence (Study 2) on acceptance indicators suggest that both types of influence are significantly associated with acceptance of insects as foods. Study 2 further reveals that the proposed effect of expert influence on acceptance of insects is moderated by insect-based disgust sensitivity in a way that expert influence is stronger for consumers low in insect-based disgust sensitivity. Taken together, our research shows that managing expectations via social influence can be an important driver to increase the adoption of insects in Western markets.

Neuroscientific approaches to study prosociality.

Prosociality is a core feature of human functioning and has been a topic of interest across disciplinary boundaries for decades. In this review, we highlight different neuroscientific approaches that have enriched traditional psychological methods for studying prosocial behavior among individuals and groups. First, we outline findings from task-based neuroimaging studies that provide correlational evidence for the involvement of different neural mechanisms in prosocial behavior. Next, we present different brain stimulation studies that show several brain areas to be causally related to prosocial behavior. Furthermore, we outline the task-independent neural trait approach that quantifies temporally stable brain-based characteristics in an effort to uncover sources of interindividual differences in prosocial preferences. We discuss how the findings from these approaches have contributed to our understanding of prosocial behavior and suggest directions for future research.

Large but diminishing effects of climate action nudges under rising costs.

Behavioural public policy has received broad research attention, particularly in the domain of motivating pro-environmental behaviours. We investigate how far the efficacy of arguably one the most popular behavioural policy tools (green 'default change' nudges) depends on the associated cost. On the basis of a field study involving carbon offsets for over 30,000 flights booked by more than 11,000 airline customers, we show that green defaults have a large effect on voluntary climate action, even when several hundreds of Euros are at stake. The effect fully vanishes only as costs approach approximately €800.

Mentalizing with the future: Electrical stimulation of the right TPJ increases sustainable decision-making.

While many people acknowledge the urgency to drastically change our consumption patterns to mitigate climate change, most people fail to live sustainably. We hypothesized that a lack of sustainability stems from insufficient intergenerational mentalizing (i.e., taking the perspective of people in the future). To causally test our hypothesis, we applied high-definition transcranial direct current stimulation (HD-tDCS) to the temporo-parietal junction (TPJ). We tested participants twice (receiving stimulation at the TPJ or the vertex as control), while they engaged in a behavioral economic paradigm measuring sustainable decision-making, even if sustainability was costly. Indeed, excitatory anodal HD-tDCS increased sustainable decision-making, while inhibitory cathodal HD-tDCS had no effect. These finding cannot be explained by changes in participants' fairness norms or their estimation of how other people would behave. Shedding light on the neural basis of sustainability, our results could inspire targeted interventions tackling the TPJ and give neuroscientific support to theories on how to construct public campaigns addressing sustainability issues.

The oxysterol receptor GPR183 in inflammatory bowel diseases.

Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The oxysterol receptor GPR183 and its ligands, dihydroxylated oxysterols, can mediate positioning of immune cells including innate lymphoid cells. GPR183 has been mapped to an IBD risk locus, however another gene, Ubac2 is encoded on the reverse strand and associated with Behçet's disease, therefore the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are up-regulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in group 3 innate lymphoid cells-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis.

The gene encoding for Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied. We found increased mRNA expression of EBI2 and oxysterol-synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2-/- mice in the IL-10 colitis model. The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2-/- mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures. In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis.

When Utilitarian Claims Backfire: Advertising Content and the Uptake of Insects as Food.

A key challenge for climate change mitigation on the consumer side is to break habits that excessively lead to carbon emission. One of the culturally most robust human routines is the heavy reliance of the Western societies on conventional meat sources such as beef, pork, and poultry, which were recently accused of causing particularly high climate costs. In this light, the UN (FAO) has suggested the increasing use of insects as an alternative source of animal protein intended for human diets. Yet, insects have not reached the mainstream of Western cuisine. Currently, a frequent promotion strategy of insects is to highlight the Utilitarian benefits associated with their consumption (e.g., with respect to the environment or one's health). The present research addresses the efficacy of such claims in a consumer research study involving 180 participants recruited from the general population in Germany. Arguing based on social-cognitive research in the area of moral and environmental psychology, we hypothesized and found that a focus on beneficial, but temporally distant motives (e.g., health)-counterintuitively-decreases consumption in comparison to immediate, hedonic advertisements (e.g., tasty). Furthermore, our study provides process evidence suggesting pretrial expectations induced by a particular claim mediate the relationship between claims and consumption. Thus, the present research not only refutes a state-of-the-art approach in the promotion of insects as food, but also provides an alternative approach and process evidence by integrating psychological factors.

DNA methylation dynamics in the hepatic CYP3A4 gene promoter.

The CYP3A4 gene, encoding the major drug metabolizing enzyme in humans, exhibits a high interindividual variation in hepatic expression that can lead to interindividual differences in drug metabolism and associated adverse drug effects. Much of the interindividual variability in CYP3A4 remains unexplained. In the present study we investigated the role of DNA methylation in influencing the interindividual CYP3A4 expression. Individual CpG methylation within the ∼12 kb CYP3A4 regulatory region was investigated in 72 adult as well as in 7 fetal human livers using bisulfite sequencing. We identified highly variable CpG methylation sites in adult livers, which correspond to important CYP3A4 transcription factor binding sites including the proximal promoter, XREM and CLEM4 as well as in separate C/EBP and HNF4α binding regions. CpG hypermethylation within these regulatory regions was observed in fetal livers when compared to adult livers. This data suggests that dynamic DNA methylation elements are likely associated with key regulatory CYP3A4 promoter regions and may potentially contribute to the commonly observed interindividual expression of CYP3A4 as well as the hepatic developmental shift in its expression. The findings provide novel insight to CYP3A4 regulation with possible implications for understanding interindividual differences in drug response.