Folate and metabolic-associated liver fibrosis (FAMIS)

Metabolic bariatric surgery (MBS) is a powerful tool against obesity, often reversing fatty liver and inflammation. However, around 1 in 5 patients still develops liver fibrosis - a progressive scarring that may go unnoticed until late-stage disease. The FAMIS project seeks to understand why. A major focus is folate, an essential B vitamin. But it`s not just about how much folate is present qualitative aspects likely play an important role. The body uses a range of folate types (the active folate pool), such as 5-methyltetrahydrofolate (5-MTHF), which are critical for immune regulation, cell repair, and detoxifying harmful compounds. Following MBS, nutrient absorption is impaired, and changes in gut bacteria may further hinder the conversion of folic acid into these active forms. This can be further impacted by underlying genetic particularities in the folate pathway. FAMIS explores how deficiencies in these specific folate metabolites might affect immune cells in the liver, especially macrophages, which can either resolve or worsen inflammation. Using advanced metabolomic techniques (LC-MS), the research team precisely measures active folate species and related one-carbon (1C) cycle intermediates in blood, liver, and cell samples, such as 5-MTHF, tetrahydrofolate (THF), methenyl-THF, and other intermediate compounds. In a newly established rat model, folate deficiency in combination with a high-fat diet led to significant liver fibrosis. Crucially, only animals with depleted folate showed increased inflammation, impaired gut barrier function, and dysfunctional liver macrophages. A poor folate status impairs macrophage function, leading to persistent inflammation and fibrosis despite weight loss. Even if total folate levels are normal, an underlying deficiency in bioactive folate could drive the disease. Importantly, the study also includes human participants undergoing MBS. By comparing those with and without liver fibrosis, researchers will assess: how folate metabolism differs between individuals, whether specific folate forms are liver protective, and how genetic variants in folate processing or changes in the gut microbiota may alter folate bioavailability. Establishing a personalized folate profile may help identify who might benefit from targeted supplementation (e.g., 5-MTHF rather than standard folic acid). This could mark a shift toward precision nutrition in liver care, improving outcomes for bariatric patients and offering new insights into nutrition-based liver disease prevention.