Comorbidities, mortality and metabolic profile in individuals with primary biliary cholangitis-A Phenome-Wide-Association-Study.

BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease that can lead to fibrosis and cirrhosis. In this cohort study, we aimed to investigate morbidity and mortality in conjunction with metabolomic changes of PBC in a UK population-based cohort. METHODS: 454 participants with PBC and 908 propensity score (age, sex, BMI, ethnicity) matched controls without liver disease were included in the study. A subset of participants with PBC and controls were analysed for their metabolomic profile. Further, PBC-associated comorbidities were investigated by PheWAS analysis. Lastly, we assessed causes of death in individuals with PBC using a Fine and Grey competing-risks regression model. RESULTS: Compared to the control group, various pathways associated with the metabolism of amino acids, lipids, and liver biochemistry were significantly enriched in individuals with PBC. We found reduced levels of S-HDL-cholesterol and Glycoprotein Acetyls in individuals with PBC as well as an association with diseases of the circulatory system. Notably, PBC individuals had a higher prevalence of digestive diseases, autoimmune diseases, cardiovascular diseases, anaemias, mental disorders, and urinary tract infections compared to the control group. Strikingly, the overall mortality was almost three times higher in the PBC group compared to the control group, with diseases of the digestive system accounting for a significant elevation of the death rate. A subsequent analysis, enhanced by propensity score matching that included the APRI score, demonstrated that the observed morbidity could not be exclusively attributed to advanced hepatic disease. CONCLUSIONS: Our study provides a detailed perspective on the morbidity of individuals with PBC. The exploration of potential effects of disease state on morbidity suggest that early detection and early treatment of PBC could enhance patient prognosis and prevent the onset of comorbid diseases. Finally, the metabolomic alterations could represent a link between the pathophysiological processes underlying PBC development, progression, and associated morbidity.

Fear and food: Anxiety-like behavior and the susceptibility to weight loss in an activity-based anorexia rat model.

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by energy restriction, low body weight, a fear of gaining weight, and often excessive physical activity. Anxiety disorders appear to constitute a major risk factor for developing AN and are the most frequent comorbidity. Here, the influence of anxiety-like behavior prior to food restriction on increased physical activity, leading to greater susceptibility to weight loss, was tested in rats. Furthermore, the possible anxiolytic effect of starvation itself was analyzed. A chronic starvation model activity-based anorexia (ABA) was applied to mimic physiological and behavioral characteristics of AN. During the induction of starvation and acute starvation, food intake was reduced by 70% and the rats lost 25% of their body weight, which was kept stable to imitate chronic starvation. Anxiety-like behavior was quantified before and after chronic starvation using the elevated plus maze, based on rodents' aversion to open spaces. Anxiety-related behavior before food restriction was associated with increased running-wheel activity during habituation and during the induction of starvation, and predicted faster weight loss in ABA rats. Additionally, food-restricted animals showed less anxiety-like behavior after chronic starvation. Animals showing more anxiety-like behavior appear to be more susceptible to weight loss, partially mediated by increased physical activity. Anxiety-related behavior was associated with increased physical activity, which in turn was associated with more rapid weight loss. Our data let us assume that food restriction has an anxiolytic effect. These findings demonstrate the importance of considering anxiety disorders in patients with AN.

Gut microbiota and brain alterations in a translational anorexia nervosa rat model.

Anorexia nervosa (AN) is an eating disorder that leads to brain volume reduction and is difficult to treat since the underlying pathophysiology is poorly understood. The human gut microbiota is known to be involved in host metabolism, appetite- and bodyweight regulation, gut permeability, inflammation and gut-brain interactions. In this study, we used a translational activity-based anorexia (ABA) rat model including groups with food restriction, running-wheel access and a combination to disentangle the influences on the gut microbiota and associated changes in brain volume parameters. Our data demonstrated that chronic food restriction but not running-wheel activity had a major influence on the gut microbiota diversity and composition and reduced brain volume. Negative correlations were found between global brain weight and α-diversity, and astrocyte markers and relative abundances of the genera Odoribacter and Bifidobacterium. In contrast, the presence of lactobacilli was positively associated with white and grey brain matter volume. ABA and food-restricted rats are an interesting pre-clinical model to assess the causal influence of starvation on the gut microbiome and gut-brain interactions and can help to dissect the underlying pathophysiologic mechanisms relevant to AN.