Mulberroside A repairs high fructose diet‐induced damage of intestinal epithelial and blood–brain barriers in mice: A potential for preventing hippocampal neuroinflammatory injury

Abstract

Our previous studies showed that high fructose diet (HFrD)‐driven gut dysbiosis caused fecal short‐chain fatty acids (SCFAs) reduction and intestinal epithelial barrier (IEB) damage in mice, which might play an important role in hippocampal neuroinflammatory injury. Mulberroside A is reported to have neuroprotective effects in animal experiments, while the underlying mechanisms are not yet fully elucidated. Here, we investigated whether and how mulberroside A prevented HFrD‐induced neuroinflammatory injury. HFrD‐fed mice were treated orally with mulberroside A (20 and 40 mg/kg) for 8 weeks. Mulberroside A was found to inhibit hippocampal neuroinflammation and neurogenesis reduction in HFrD‐fed mice. It reshaped gut dysbiosis, increased fecal and serum SCFAs contents, reactivated signaling of the colonic NLR family, pyrin domain containing 6 (NLRP6) inflammasome, and up‐regulated Muc2 expression to prevent IEB damage, as well as subsequently, reduced serum endotoxin levels in this animal model. Additionally, mulberroside A inhibited oxidative stress in colon of HFrD‐fed mice and hydrogen peroxide (H2O2)‐stimulated Caco‐2 cells. Blood–brain barrier (BBB) structure defects were also observed in HFrD‐driven hippocampal neuroinflammatory injury of mice. Interestingly, mulberroside A maintained astrocyte morphology and up‐regulated tight junction proteins to repair BBB structure defects in hippocampus dentate gyrus (DG). Our results demonstrated that mulberroside A was capable of preventing HFrD‐induced damage of IEB and BBB in mice, which might contribute to the suppression of hippocampal neuroinflammatory injury.

Sesamolin Attenuates Kidney Injury, Intestinal Barrier Dysfunction, and Gut Microbiota Imbalance in High-Fat and High-Fructose Diet-Fed Mice

“…Additionally, the sesamolin-treated group showed increases in the abundances of Muribaculaceae , Bacteroidaceae , and Prevotellaceae . Furthermore, the correlation analysis revealed that these harmful bacterial florae were positively correlated with these risk factors involved in intestinal barrier dysfunction, endotoxemia, metabolic disorder, and renal injury, whereas these beneficial bacterial florae display a negative correlation with them, which are consistent with these previous findings. − These results suggest that sesamolin treatment attenuates gut microbiota imbalance in HF–HF diet-fed mice, which might be highly correlated with the alleviation of intestinal barrier dysfunction, endotoxemia, metabolic disorder, and renal injury. The improvement of intestinal barrier dysfunction through modulating gut microbiota by sesamolin treatment might contribute to reducing the translocation of bacterial metabolites and endotoxins into blood circulation and thereby suppressing endotoxin-driven pathways and metabolic disorders to protect against the development of renal injury in HF–HF diet-fed mice.…”

“…Notably, the gut barrier dysfunction is often considered the main reason for an elevation in serum endotoxin concentrations and translocations of more bacterial metabolites into the systemic circulation . The intestinal barrier consists of multiple layers, and the epithelial cell layer that produces intestinal alkaline phosphatase (IAP) and antibacterial proteins plays a key role in the host defense, which protects against the translocations of more bacterial metabolites and active endotoxins into the systemic circulation. , However, evidence has shown that the ingestion of a high-fat diet or/and a high-fructose diet could cause intestinal epithelial cell damage and an increase in circling bacterial endotoxins, , Additionally, the intestinal epithelial cell damage often accompanies the metabolic disorders in high-fat diet-fed animals. , Notably, in addition to endotoxins, the microbial metabolites have also been found to be in association with the development of obesity and metabolic disorders. , In contrast, sesamolin treatment alleviated intestinal barrier dysfunction along with lowering levels of serum endotoxins and metabolic biomarkers. Therefore, the decrease in circling endotoxins as a result of sesamolin treatment might be linked to its effect on the improvement of intestinal barrier dysfunction.…”

“…50 The intestinal barrier consists of multiple layers, and the epithelial cell layer that produces intestinal alkaline phosphatase (IAP) and antibacterial proteins plays a key role in the host defense, which protects against the translocations of more bacterial metabolites and active endotoxins into the systemic circulation. 49,50 However, evidence has shown that the ingestion of a high-fat diet or/ and a high-fructose diet could cause intestinal epithelial cell damage and an increase in circling bacterial endotoxins, 51,52 Additionally, the intestinal epithelial cell damage often accompanies the metabolic disorders in high-fat diet-fed animals. 39,51 Notably, in addition to endotoxins, the microbial metabolites have also been found to be in association with the development of obesity and metabolic disorders.…”

Thioredoxin interacting protein drives astrocytic glucose hypometabolism in corticosterone‐induced depressive state

“…In all experiments, no blinding was performed. We designed the number of subjects used in this experiment based on the previous studies (Jun et al., 2018; Yu et al., 2021).…”

Identification and mechanism prediction of mulberroside A metabolites in vivo and in vitro of rats using an integrated strategy of UHPLC-Q-Exactive Plus Orbitrap MS and network pharmacology

“…Mulberroside A, presenting at relatively high abundance in the roots and twigs of Morus alba L. ( Zhou et al, 2013 ), is a natural polyhydroxylated stilbene compound ( Yu et al, 2021 ). Furthermore, it possesses various therapeutic effects through pharmacological studies, including hypoglycemic ( Li et al, 2014 ), antidiabetic ( Xu et al, 2021 ), anti-inflammatory ( Chung et al, 2003 ), analgesic ( Zhang and Shi, 2010 ), hepatic protective function ( Zhang et al, 2008 ), nephroprotective ( Wang et al, 2011 ), the inhibitory effect of melanogenesis ( Park et al, 2011 ) and neuroprotective ( Wang C. P. et al, 2014 ) effects, etc.…”