High-fat (HF) diet-induced neuroinflammation and cognitive decline in humans and animals have been associated with microbiota dysbiosis via the gut-brain axis. Our previous studies revealed that excretory-secretory products (ESPs) derived from the larval Echinococcus granulosus (E. granulosus) function as immunomodulators to reduce the inflammatory response, while the parasitic infection alleviates metabolic disorders in the host. However, whether ESPs can improve cognitive impairment under obese conditions remain unknown. This study aimed to investigate the effects of E. granulosus-derived ESPs on cognitive function and the microbiota-gut-brain axis in obese mice. We demonstrated that ESPs supplementation prevented HF diet-induced cognitive impairment, which was assessed behaviorally by nest building, object location, novel object recognition, temporal order memory, and Y-maze memory tests. In the hippocampus (HIP) and prefrontal cortex (PFC), ESPs suppressed neuroinflammation and HF diet-induced activation of the microglia and astrocytes. Moreover, ESPs supplementation improved the synaptic ultrastructural impairments and increased both pre- and postsynaptic protein levels in the HIP and PFC compared to the HF diet-treated group. In the colon, ESPs reversed the HF diet-induced gut barrier dysfunction, increased the thickness of colonic mucus, upregulated the expression of zonula occludens-1 (ZO-1), attenuated the translocation of bacterial endotoxins, and decreased the colon inflammation. Notably, ESPs supplementation alleviated the HF diet-induced microbiota dysbiosis. After clarifying the role of antibiotics in obese mice, we found that broad-spectrum antibiotic intervention abrogated the effects of ESPs on improving the gut microbiota dysbiosis and cognitive decline. Overall, the present study revealed for the first time that the parasite-derived ESPs alleviate gut microbiota dysbiosis and improve cognitive impairment induced by a high-fat diet. This finding suggests that parasite-derived molecules may be used to explore novel drug candidates against obesity-associated neurodegenerative diseases.

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The microbiota–gut–liver axis has emerged as an important player in developing nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease (NAFLD). Higher mushroom intake is negatively associated with the prevalence of NAFLD. This study examined whether lentinan, an active ingredient in mushrooms, could improve NAFLD and gut microbiota dysbiosis in NAFLD mice induced by a high-fat (HF) diet. Dietary lentinan supplementation for 15 weeks significantly improved gut microbiota dysbiosis in HF mice, evidenced by increased the abundance of phylum Actinobacteria and decreased phylum Proteobacteria and Epsilonbacteraeota. Moreover, lentinan improved intestinal barrier integrity and characterized by enhancing intestinal tight junction proteins, restoring intestinal redox balance, and reducing serum lipopolysaccharide (LPS). In the liver, lentinan attenuated HF diet-induced steatohepatitis, alteration of inflammation–insulin (NFκB-PTP1B-Akt-GSK3β) signaling molecules, and dysregulation of metabolism and immune response genes. Importantly, the antihepatic inflammation effects of lentinan were associated with improved gut microbiota dysbiosis in the treated animals, since the Spearman's correlation analysis showed that hepatic LPS-binding protein and receptor (Lbp and Tlr4) and pro- and antiinflammatory cytokine expression were significantly correlated with the abundance of gut microbiota of phylum Proteobacteria, Epsilonbacteraeota and Actinobacteria. Therefore, lentinan supplementation may be used to mitigate NAFLD by modulating the microbiota–gut–liver axis.

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Background Current treatment for functional dyspepsia (FD) has limited and unsustainable efficacy. Probiotics have the potential to alleviate FD; However, the underlying mechanism remains unclear. This study aimed to evaluate the effect and mechanism of probiotics in alleviating FD. Methods A randomized, positive-drug and placebo-controlled clinical trial was conducted; 200 FD patients were randomly divided into four groups (placebo, positive control [proton pump inhibitors, PPI] or Bifidobacterium lactis BL-99 [low, high doses]). The clinical response rates in 8-week treatment, 2-week follow-up and 6-week questionnaire survey periods were recorded. Faecal microbiota and metabolites were assessed by metagenomics, un-target and target metabolomics technology. Results The clinical response rate for BL-99_high [43 (95.6%) of 45] group was significantly higher than that for placebo [28 (62.2%) of 45, P = 0.001], BL-99_low [36 (76.6%) of 47, P = 0.019] or positive control group [34 (70.8%) of 48, P = 0.006] after an 8-week treatment. In particular, BL-99_high group was still higher than that for placebo or positive control group after 2-week follow-up and 6-week questionnaire survey periods. Further metagenomic and metabolomics studies found that PPI significantly decreased the gut microbiota diversity, induced the cluster of Escherichia enterotype and decreased butyrate contents. Interestingly, BL-99 converted the gut microbiota enterotype from Bacteroidetes (Alistipes finegoldii, Alistipes shahii) to Firmicutesc (Roseburia intestinalis, Roseburia inulinivorans) and Escherichia enterotype was not clustered after 8-week treatment, which activates carbohydrate esterase activity, and increases faecal and serum butyrate levels. Conclusion BL-99 sustainably alleviated FD symptoms by altering the taxonomic composition and functional potential of the FD microbiome. Trial registration Chictr.org.cn ChiCTR2000041430.