Pediococcus acidilactici KCTC 15831BP-fermented industrial hempseed (Cannabis sativa L.) supplementation corrects metabolite and gut microbiota dysbiosis, potentially mitigating Alzheimer's disease-like symptoms induced by obesity in high-fat diet-fed mice†

A long-term high-fat diet (HFD) intake causes obesity, disrupting the gut microbiota and body metabolite balance, and increasing the risk of Alzheimer's disease (AD). Fermented hempseed may restore microbiota balance, improve metabolism, and reduce neuroinflammation, potentially protecting against cognitive decline. This study investigates the protective effects and mechanisms of action of Pediococcus acidilactici KCTC 15831BP-fermented hempseed (FHS) against AD-like symptoms induced by obesity in high-fat diet-fed mice. Nine-week-old male C57BL/6 mice were fed an HFD and supplemented with either orlistat, raw hempseed, FHS, or live Pediococcus acidilactici KCTC 15831BP (PA) for 15 weeks. At the end of the experiment, the impacts of supplementation on obesity- and AD-related markers, brain and blood metabolites, and fecal microbiota were assessed. HFD-fed mice exhibited obesity markers, such as increased body weight, altered serum lipids, insulin resistance, high leptin but low adiponectin levels, fatty liver, and enlarged adipose tissue. They also showed AD-related disorders, including cognitive decline, oxidative stress, neuroinflammation, and beta-amyloid accumulation. HFD feeding also led to gut microbiota dysbiosis and unfavorable changes in serum and brain metabolites. FHS intervention reversed most adverse effects, restoring gut microbiome balance, improving the Firmicutes/Bacteroidetes ratio, and normalizing disrupted serum and brain metabolites, including increasing protective compounds like L-tryptophan and trans-cinnamic acid. The beneficial changes in the gut microbiota and metabolite profiles caused by FHS positively correlated with improvements in obesity and AD markers. These findings highlight the interconnection between the diet, gut, and brain, emphasizing the role of the diet–microbiota–gut–brain axis in mitigating neurodegenerative diseases.