Regulation Of Goat Milk On Glycolipid Metabolism In Type 2 Diabetic Mice

Goat milk contains active substances with unique medical and health values.Type 2diabetes is usually caused by inadequate secretion of insulin by pancreatic beta cells or insulin resistance of target cells,which seriously threatens human health.Adjusting diet and increasing exercise can effectively prevent and alleviate diabetes.Previous studies have reported that goat milk feeding can alleviate insulin resistance in rats under high-fat diets,but the mechanism by which goat milk relieves type 2 diabetes symptoms is still unclear.To explore the regulatory mechanism of goat milk diet on glucose and lipid metabolism in type 2 diabetes mice,we first established a metabolomics characteristic substance map of goat milk.Then,we constructed a type 2 diabetes mouse model induced by streptozotocin and high-sugar diet and conducted a 10-week goat milk diet feeding experiment.We analyzed the effect of goat milk diet on the gut microbiota structure of mice using 16 S r RNA sequencing technology,and then used metabolomics analysis to explore the key metabolites that respond to goat milk diet feeding in mouse blood metabolism.We used transcriptomics technology to explore the regulatory mechanism of goat milk diet feeding on mouse liver function,and finally,through multi-omics analysis methods,we deciphered the regulatory mechanism of goat milk diet feeding on glucose and lipid metabolism in type 2 diabetes mice through the pathway of Active ingredient of goat milk-gut microbiota regulation-blood metabolite regulation-liver function response.The main research results obtained are as follows:(1)Metabolomic characterization and functional analysis of goat milkA metabolomic feature map of goat milk was constructed,detecting a total of 1,126 metabolites,mainly including alcohols and amines(4.09%),amino acids and their metabolites(36.23%),benzene and its derivatives(5.77%),bile acids(2.22%),carbohydrates and their metabolites(6.31%),coenzymes and vitamins(1.95%),fatty acids(6.22%),glycerophospholipids(5.68%),heterocyclic compounds(6.31%),nucleotides and their metabolites(10.48%),organic acids and their derivatives(12.52%),among others.Metabolites involved in animal homeostasis regulation,such as L-lysine,glycochenodeoxycholic acid,7-ketolithocholic acid,and beta-muricholic acid,as well as related signaling pathways(such as bile secretion),were identified in goat milk.(2)Effects of goat milk diet on blood glucose and Organs in type 2 diabetic miceAfter being fed with goat milk diet for 10 weeks,the fasting blood glucose of mice in the type 2 diabetes goat milk intervention group(T2DM-GM)was significantly lower than that before at the start of the experiment and tended to be that of the normal group(NC)mice.The area under the glucose tolerance curve by intraperitoneal injection was decreased significantly compared with that in the type 2 diabetes model group(T2DM).The results of tissue sections showed that goat milk dietary intervention could reduce the tissue damage in liver,pancreas and small intestine of type 2 diabetic mice,indicating that goat milk dietary intervention had certain effects on the control of blood glucose and the alleviation of tissue lesions in type 2 diabetic mice.Feeding a goat milk diet can improve glucose and lipid metabolism homeostasis in type 2 diabetic mice,alleviating insulin resistance,reducing hepatic inflammatory infiltration and abnormal lipid accumulation,relieving intestinal inflammation,and promoting the recovery of pancreatic beta cells.(3)The regulatory effect of goat milk on the gut microbiota diversity of type 2diabetic miceThe results of gut microbiota analysis showed that feeding type 2 diabetic mice with a goat milk-based diet increased the relative abundance of Akkermansiaceae,[Eubacterium]＿coprostanoligenes＿group,Anaerovoracaceae and Enterococcaceae in the mouse gut,while reducing the relative abundance of Muribaculaceae,Lactobacillaceae,Prevotellaceae,Rikenellaceae,Marinifilaceae,and Helicobacteraceae.Akkermansiaceae,[Eubacterium]＿coprostanoligenes＿group and Anaerovoracaceae were found to regulate physiological metabolism of type 2 diabetes,positively regulate intestinal barrier repair,and improve glucose and lipid metabolism balance.(4)Study on the regulatory effect of goat milk on blood metabolomics in type 2diabetic miceSerum metabolomics analysis showed that the main pathways involved in the regulation of glucose and lipid metabolism in type 2 diabetic mice fed with goat milk included carbon metabolism,bile acid secretion,and cholesterol metabolism.Among them,the signaling pathways upregulated by goat milk in T2 DM mice included the serotoninergic synapse pathway,while those downregulated by goat milk included cholesterol metabolism,bile acid secretion,and primary bile acid biosynthesis.(5)Study on the regulatory effect of goat milk on liver transcriptomics in type 2diabetic miceA total of 2747 differentially expressed genes were detected between type 2 diabetic mice and those fed with goat milk,including 769 downregulated genes and 1978 upregulated genes.After being fed with goat milk,the upregulated genes in type 2 diabetic mice were mainly enriched in PI3K-Akt signaling pathway,focal adhesion pathway,ECMreceptor interaction pathway,protein digestion and absorption,and relaxation signaling pathway.The downregulated genes in type 2 diabetic mice fed with goat milk were mainly enriched in metabolic pathways,diabetic cardiomyopathy,chemical carcinogenesis,retinol metabolism,cytochrome P450-mediated drug metabolism,complement and coagulation cascades,arachidonic acid metabolism,bile secretion,as well as glycine,serine,and threonine metabolism pathways.(6)Mechanism of goat milk diet feeding on type 2 diabetes mellitus based on multi-omics analysisThrough a combined analysis of the gut microbiome,blood metabolome,and liver transcriptome,it was found that feeding type 2 diabetic mice with a goat milk diet can regulate the antagonistic relationship between beneficial gut bacteria such as Akkermansia＿muciniphila(species),and harmful bacteria such as Clostridium＿sp＿Clone-49、Clostridium＿sp＿ND2、Helicobacter＿typhlonius(species)by active ingredients as Carnitine C15:DC,allopurinol,UDP-xylose,taurocholic acid,and glycoursodeoxycholic acid,then affects the levels of key metabolites such as tauroursodeoxycholic acid,glycocholic acid,carnitine C7:0,and lysyl-valine in the circulatory system,and in turn alters the expression of genes such as Cyp8b1、Slc7a5、RAD51、CD79A、Sds、Sec31B in the liver tissue,thereby playing an important role in regulating the glucose and lipid metabolism homeostasis in the mice body.In summary,this study constructed a metabolic profile of goat milk and revealed its positive regulatory effect on the physiological metabolism of type 2 diabetic mice through dietary intervention.It was found that the beneficial gut bacteria Akkermansia(genus)and harmful bacteria [Eubacterium]＿ruminantium＿group(genus)in the gut of type 2 diabetic mice have an antagonistic relationship,and by regulating the bile acid metabolism pathway and related metabolites,they participate in the regulation of glucose and lipid metabolism homeostasis in the blood and liver of mice.It was also demonstrated that goat milk diet intervention can improve the glucose and lipid metabolism homeostasis of type 2 diabetes through this pathway.This study provides a foundation for elucidating the active ingredients and metabolic regulatory mechanisms of goat milk,and for studying the positive effects of goat milk dietary intervention on the symptoms of type 2 diabetes in humans.