Lactobacillus paracasei JY062 alleviates glucolipid metabolism disorders by adipoinsular axis and gut microbiota

doi:10.21203/rs.3.rs-1819571/v1

Download PDF

Article

Lactobacillus paracasei JY062 alleviates glucolipid metabolism disorders by adipoinsular axis and gut microbiota

https://doi.org/10.21203/rs.3.rs-1819571/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

High-glucose-fat diet-induced glucolipid metabolism disorder has become a global epidemic disease. Probiotic intervention is a new strategy to alleviate metabolic syndrome. The protective effect and mechanism of L. paracasei JY062 on high-glucose-fat diets mice were investigated. After 7 weeks L. paracasei JY062 intervention, the body weight of mice in the LPH group (28.07 ± 1.07 g) was significantly lower than that of HFD group (32.03 ± 0.89 g) (P < 0.05). Among three doses of JY062, 10⁸ and 10⁹ CFU/mL JY062 showed the strong ability to relieve blood glucose disorders, blood lipid disorders, tissue damage. LPH group had the best effect, significantly (P < 0.05) decreased the TC (40.11%), TG (42.46%), LDL-C (39.38%), leptin (54.34%), insulin (39.95%), FFA (40.68%) concentrations and increased (P < 0.05) the HDL-C (1.05 times), adiponectin (1.53 times) and GLP-1 (1.35 times) level compared to HFD group mice. JY062 could activate the APN-AMPK pathway, increase AdipoQ, AMPK GLUT-4 and PGC-1αmRNA expression, and decrease SREBP-1c, ACC and FAS mRNA expression. L. paracasei JY062 intervention decreased the relative abundance of harmful bacteria and increased the relative abundance of beneficial bacteria, restored the imbalance of gut microbiota homeostasis caused by high-glucose-fat diet. L. paracasei JY062 could also increase the content of SCFAs in the intestines, especially butyric acid.

L. paracasei JY062

Glucolipid metabolism disorder

Adipoinsular axis

Gut microbiota

In recent years, disorders of glucose and lipid metabolism have gradually become global epidemic diseases, mainly including hyperlipidemia, diabetes and other diseases seriously threatening human health¹. Some researchers have found that the disorder of glucose and lipid metabolism caused by a variety of factors, such as the abnormal metabolic processes of glucose and lipid synthesis, decomposition and absorption in the body, which lead to excess lipid, insulin resistance and liver damage ². However, the drug used in the market is controversial and expensive, there are many side effects, such as increased liver and kidney detoxification, as well as the possibility of gastroenteritis ³. It is worth noting that dietary intervention is considered to be an effective and safe method for regulating metabolic pathways and reducing risk ⁴, which makes the demand for safer and more effective natural health foods more urgent than ever.

The number of microorganisms colonize the human gut is not only huge, but also rich in variety, with more than 1,000 species and complex diversity. The main dominant bacteria are Firmicutes, Bacteroidetes and Actinobacteria, accounting for about 90% of the total number of gut microbiota ^{5, 6}. The gut microbiota is a part of the dynamic ecosystem in the host, which can connect tissues and organs such as the gut, liver, muscle, fat, and brain through the interaction between the host and the microbiota through the interaction of metabolism, signal transduction, and immune-inflammatory axis, participate in the body's metabolism, and then affect the nervous system, immune system and other key functional systems of the human body ⁷. When the gut microbiota is disturbed, it will cause GLMD diseases such as T2DM and obesity, which will seriously affect human health ⁸. Therefore, gut microbiota and its metabolites are important modifiers for disorders of glucose and lipid metabolism such as T2DM and obesity.

There is a adipoinsular axis in the human body, insulin can promote the secretion of leptin, adiponectin and other adipocytokines. Adipocytokines inhibits appetite through the central nervous system, promotes energy consumption, and reduces fat accumulation. The synthesis and secretion of insulin can also be directly suppressed, reversing high insulinmia, thus correcting the abnormalities of glycolipid metabolism ⁹. Some studies have shown that active substances such as Tetradecyl 2,3-Dihydroxybenzoate can balance the adipoinsular axis to increase insulin and leptin generation and secretion, increase the sensitivity of insulin and leptin, thereby correcting the abnormalities of glycolipid metabolism ¹⁰. However, the specific mechanism of the adipocytokines and insulin to regulate the metabolism of the glycolipid through the adipoinsular axis remains unclear.

Probiotics are defined as microorganisms that can exert health benefits for the host. Among the recognized probiotics, Lactobacillus are the most frequently used probiotics in humans, due to their health-promoting properties, such as regulating immune function ¹¹, reducing blood lipids, regulating gut microbiota balance ¹², anti-oxidation and hypoglycemia ¹³, and their effectiveness has been demonstrated in various in vitro and in vivo ¹⁴. There were also some studies shown that Lactobacillus strains were able to alleviate obesity in mice induced by high-fat diet via regulating the content of leptin and adiponectin to relieve fat accumulation, lipid metabolism¹⁵. In our previous study, Lactobacillus paracasei JY062 was separated from the Tibetan fermented dairy products. Our previous studies have demonstrated that L. paracasei JY062 have high α -glucosidase inhibitory activity, anti-diabetes ability, and can survive in simulated gastrointestinal fluids. In addition, in diabetic mice induced by combination of STZ and high-glucose-fat diets, the administration of L. paracasei JY062 can improve lipid metabolism, oxidative stress and glucose metabolism abnormalities ¹⁶. These results suggestted that L. paracasei JY062 played an important role in the prevention of type 2 diabetes.

Although L. paracasei JY062 was confirmed to correct glucose metabolism in diabetic mice, whether L. paracasei JY062 can improve glycolipid metabolism disorders based on the adipoinsular axis remains to be studied. The purpose of this study was to evaluate the effect of L. paracasei JY062 on glucolipid metabolism disorder induced by high-glucose-fat diets in mice, and to explore the possible mechanism of L. paracasei JY062 in improving glucolipid metabolism disorder based on the adipoinsular axis.

Changes of body weight and blood glucose in mice

Body weight changes of mice were shown in Fig 1(a). During the experiment, mice in N group gained weight slowly. Within 4 weeks of the experiment, the weight of the mice fed the high-glucose-fat diet increased continuously and was always higher than that of the mice fed the normal diet. At the fourth week, the mice fed high-glucose-fat diet had a 45.5% higher body weight gain than that in the N group (23.4±1.01 g). After the fifth week, the body weight growth rate of mice in LPL, LPM, and LPH group was slower and the body weight gain was significantly lower than that in HFD group, at the end of the experiment, the body weight of mice in the LPH group (28.07±1.07 g) was significantly lower than the body weight of HFD group (32.03±0.89 g) (P<0.05).

The changes of fasting blood glucose in mice were shown in Fig 1(b). During the experiment, the changes of blood glucose in group N were not obvious. Within 4 weeks of the experiment, there was no significant difference in blood glucose of mice fed high-glucose-fat diet compared with the N group, but the blood glucose began to increase significantly in the fifth week, up to 8.83 mmol/L. After the administration of L. paracasei JY062, the blood glucose of mice could decrease significantly, at the end of the experiment, the blood glucose in LPL, LPM and LPH group was 7.44 mmol/L, 7.00 mmol/L and 6.29 mmol/L, respectively, significantly lower than that in HFD group 9.17 mmol/L. Therefore, L. paracasei JY062 can alleviate the changes of body weight and blood glucose in mice with glycolipid metabolic disorder, thereby improving the symptoms of glycolipid metabolic disorder.

3.2 Changes of oral glucose tolerance in mice

The changes of oral glucose tolerance in mice were shown in Fig 1(c). Due to the administration of glucose, the blood glucose concentration of the mice increased rapidly within 30 min (N group: 12.2±0.36 mmol/L, HFD group: 18.6±1.05 mmol/L, LPL group: 16.9±1.29 mmol/L, LPM group: 16.6±1.21 mmol/L, LPH group: 14.7±0.64 mmol/L), but the blood glucose concentration of mice decreased significantly at 1 h (N group: 9.3±0.51 mmol/L, HFD group: 14.7±0.71 mmol/L, LPL group: 13.3±0.6 mmol/L, LPM group: 11.8±0.91 mmol/L, LPH group: 10.8±0.4 mmol/L), and at 2 h, the blood glucose concentration of mice in N group returned to normal level, the blood glucose concentration of mice in HFD group was still at high level(12.6±0.72 mmol/L), while the blood glucose of mice in LPL, LPM, LPH group decreased significantly compared with HFD group, but did not return to normal level, which were 11.1±0.61 mmol/L , 9.5±0.7 mmol/L, and 7.7±0.5 mmol/L respectively.

Glucose tolerance of mice was shown in Fig 1 (b). The AUC glucose value of HFD, LPL and LPM LPH groups were significantly higher than that of in N group mice. Compared with HFD group (1728), The AUC glucose value of LPL and LPM LPH group was significantly decreased (P<0.05), and the AUC glucose value of LPH group was the lowest (1260). The results showed that L. paracasei JY062 can improve glucose tolerance in a dose-dependent manner.

Changes of blood lipid index in mice

The changes of blood lipid in mice were shown in Table 1. After 10 weeks of high-glucose-fat diet, the mice in HFD group significantly (P<0.05) increased the TC (1.09 times), TG (84.5%), LDL-C (1.08 times) concentrations and decreased (P<0.05) the HDL-C (50.27%) level compared to N group mice. After 7 weeks of L. paracasei JY062 intervention, TG, TC and LDL-C in different dose groups of L. paracasei JY062 were significantly decreased compared with HFD group, while HDL-C was significantly increased (P<0.05). LPH group had the best effect, significantly (P<0.05) decreased the TC (40.11%), TG (42.46%), LDL-C (39.38%) concentrations and increased (P<0.05) the HDL-C (1.05 times) level compared to HFD group mice.

Table 1. Effects of L. paracasei JY062 on blood lipid index of mice

Group	TC（mmol/L）	TG（mmol/L）	LDL-C（mmol/L）	HDL-C（mmol/L）
N	2.73 ±0.18^c	0.97± 0.07^c	0.77 ±0.09^c	3.70 ±0.67^a
HFD	5.71 ±1.07^a	1.79 ±0.07^a	1.60± 0.18^a	1.84 ±0.55^c
LPL	4.20 ±0.39^b	1.30± 0.05^b	1.18± 0.09^b	2.69 ±0.18^b
LPM	3.08 ±0.63^bc	1.00 ±0.06^c	0.88± 0.16^c	2.98 ±0.08^ab
LPH	3.42 ±0.53^bc	1.03 ±0.20^c	0.97± 0.16^bc	3.78 ±0.46^a

Note: Different letters mean the significant difference between different groups of mice (P<0.05).

Changes on the adipoinsular axis

The changes of leptin, adiponectin, insulin, GLP-1 and FFA in mice were shown in Fig 2. After 3 weeks of a high-glucose-fat diet, the mice in HFD group significantly (P<0.05) increased the leptin (1.43 times), insulin (1.17 times), FFA (68.80%) concentrations and decreased (P<0.05) the adiponectin (64.25%) and GLP-1 (71.02%) level compared to N group mice. After 7 weeks of L. paracasei JY062 intervention, compared with the HFD group, The contents of leptin, insulin and FFA in different dose groups of L. paracasei JY062 were significantly decreased (P<0.05), while the contents of adiponectin and GLP-1 were significantly increased (P<0.05). LPH group had the best effect, significantly (P<0.05) decreased the leptin (54.34%), insulin (39.95%), FFA (40.68%) concentrations and increased (P<0.05) the adiponectin (1.53 times) and GLP-1 (1.35times) level compared to HFD group mice.

Histopathological analysis of liver and pancreas

As shown in Fig 3 (a), the liver structure of mice in N group was mildly abnormal, with mild edema of some liver cells, clear nucleus and vacuolated cytoplasm (yellow arrows).There was no inflammatory cell infiltration and steatosis in liver parenchyma of N group. While as shown in Fig 3 (b), the liver structure of mice was severely abnormal, with a large area of hepatic cell steatosis and a large number of lipid droplets of different sizes in HFD group (yellow arrows). Some cells were severely edematous, swollen and vacuolized, as shown by the red arrow in Fig 3 (b). After 7 weeks of L. paracasei JY062 intervention, compared with the HFD group, as shown in Fig 3 (c-e), the degree of edema and steatosis of liver cells was reduced, the liver cells were homogenized, and the liver cell space was reduced. In addition, among the three doses of L. paracasei JY062, LPH group had the best effect, which hepatocyte status was similar to that of N group.

It can be seen from Fig 3 (h) that the pancreatic tissue structure of mice in group N was clear, without vacuolation and inflammatory cell infiltration. The islet was a spherical cell-like structure, distributed between the acinus, with a clear boundary with the surrounding glands. And the islet cells were arranged regularly, with high cell density and abundant cytoplasm. In the HFD group, the islets were distributed between the acinus and the surrounding glands, and the islets were not clearly demarcated with the surrounding glands. The number of islets was also significantly reduced, with a large number of inflammatory cells infiltrating, as shown by the red arrow in Fig 6 (i). After 7 weeks of L. paracasei JY062 intervention, compared with the HFD group, the arrangement of islet cells gradually became regular, the number of islets gradually increased, and the boundary between islets and surrounding glands gradually became clear. In LPH group, some telangiectations occurred, as shown by the black arrow in Fig 3 (k).

Effect of L. paracasei JY062 on gene expression of glycolipid metabolism

The glycolipid metabolism-associated genes expression of experimental mice after diet intervention was shown in Fig 4. In the case of long-term intake of high-glucose-fat diet, L. paracasei JY062 relieved glycolipid metabolism disorders and reduced lipid accumulation and glycogen synthesis in mice. As shown in Fig 4, the expression levels of adiponectin related genes (AdipoQ, Adipor2), AMPK and insulin resistance related genes (GLUT-4, PGC-1α) in HFD group were significantly lower than N group (P<0.05). And fat synthesis related genes (SREBP-1c, ACC and FAS) in HFD group were significantly higher than N group (P<0.05). After 7 weeks of L. paracasei JY062 intervention, compared with the HFD group, the gene expression levels of AdipoQ, Adipor2, AMPK, GLUT-4, PGC-1α in different doses of L. paracasei JY062 group were significantly up-regulated (P<0.05). And the gene expression levels of SREBP-1c, FAS, and ACC were significantly down-regulated (P<0.05). Among them, LPH group had the best effect, significantly (P<0.05) increased the AdipoQ (1.82 times), Adipor2 (2.02 times), AMPK (3.84 times) GLUT-4 (1.38 times) and PGC-1α (1.85 times) and decreased (P<0.05) the SREBP-1c (47.2%), FAS (44.6%) and ACC (50.9%) relative expression levels compared to HFD group mice. Meanwhile, the key protein expressions in glycolipid metabolism were shown in Fig 4. Compared with the N group, the protein expressions levels of AdipoQ, AMPK, GLUT-4 in the liver tissue of the HFD group decreased (P<0.05), and the protein expressions of SREBP-1c increased (P<0.05). Compared with the HFD group, the expression levels of AdipoQ, AMPK, GLUT-4 protein in the liver tissue of mice in the LPL, LPM and LPH group increased (P<0.05), and the protein expression levels of SREBP-1c decreased (P<0.05). LPH group had the best effect. Compared with HFD group, the relative expression levels of AdipoQ, AMPK and GLUT-4 were increased by 152%, 169% and 157%, respectively. The relative expression of SREBP-1c protein decreased by 51.95% (P<0.05).The results suggested that L. paracasei JY062 can activate adiponectin by regulating glycolipid disorder in mice with glycolipid metabolism disorder through APN-AMPK pathway.

Gut microbiota analysis

As can be seen from the Fig 5, compared with the mice in the N group, the Chao1, Shannon and Simpson index of the mice in the HFD group were significantly decreased after 10 weeks of feeding with a high-glucose-fat diet (P<0.05). These indicated that the richness and diversity of gut microbiota species of mice were significantly reduced when glucose and lipid metabolism disorders occurred. Compared with the HFD group, the LPL group had no significant difference in Chao1, Shannon and Simpson index, while the LPM group and the LPH group had significant differences (P<0.05), LPH group had the best effects. The results suggested that L. paracasei JY062 can restore the richness and diversity of gut microbiota in mice with glucose and lipid metabolism disorders.

It can be seen from Fig 5 (d), the contribution of PC1 was 35.05%, the contribution of PC2 was 23.01%, and the three sample points in group N were relatively concentrated, indicating that the structure of gut microbiota of mice in group N was relatively similar, and the gut microbiota of mice in group N was relatively similar. The composition of flora species was relatively stable. After feeding with high-glucose-fat diet for 10 weeks, the flora of HFD group mice was significantly different from that of N group in the first and second principal coordinates, which showed that there were great changes in the gut microbiota of mice with glucose and lipid metabolism disorder. The LPL, LPM, LPH groups were separated from the HFD group flora and gradually approached the N group of mice. The results also indicated that L. paracasei JY062 could regulate the gut microbiota structure of mice with glucose and lipid metabolism disorders to a certain extent, and improved the similarity and stability of the gut microbiota community structure.

In this study, the relative abundances of Firmicutes and Bacteroidetes in the intestines of mice in the N group were 49.91% and 16.36%, the ratio of Bacteroidetes/Firmicutes was 0.328, and the relative abundances of Firmicutes and Bacteroidetes in the intestines of mice in the HFD group were 61.18% and 61.18%. 17.11%, the ratio of Bacteroidetes/Firmicutes was 0.18, and the ratio of Bacteroidetes/Firmicutes decreased significantly compared with N group mice (P<0.05). This showed that the ratio of Bacteroidetes/Firmicutes was significantly reduced in mice fed a high-glucose-fat diet after 10 weeks. In the LPL, LPM, and LPH groups, the ratios of Bacteroidetes/Firmicutes were 0.10, 0.14, and 0.15, respectively. In the LPH group, the relative abundances of Firmicutes and Bacteroidetes were 34.28% and 5.28%. The relative abundance decreased compared with the HFD group. In addition, Verrucomicrobia was proved to be closely related to the occurrence of diabetes and obesity, and the relative abundance of Verrucomicrobia was significantly increased in the LPH group, reaching 27.35% (P<0.05). L. paracasei JY062 can improve glucose and lipid metabolism disorder to a certain extent by reducing the abundance of Firmicutes, increasing the abundance of Bacteroidetes and the relative abundance of Verrucomicrobia. However, the effect of probiotics on gut microbiota was very complicated.

As can be seen from the Fig 6, compared with the mice in the N group, the gut microbiota of HFD group was dominated by Dubosiella (14.78%), Lachnospiraceae NK4A136 group (7.66%), and uncultured Muribaculaceae bacterium (13.60%). 3 harmful bacteria genera increased, Lactobacillus (3.07%), Coriobacteriaceae_UCG-002 (0.45%), Akkermansia (0.13%), Bifidobacterium (0.08%), Allobaculum (0.01%) were the main 5 beneficial bacteria The proportion had decreased. These results suggested that feeding a high-glucose-fat diet affects the composition of the intestinal microbiota in mice, thereby affecting the glucose and lipid metabolism in mice. In the LPL, LPM and LPH groups, compared with the HFD group of mice, five genera, mainly Lactobacillus, Coriobacteriaceae_UCG-002, Akkermansia, Bifidobacterium, Allobaculum, increased, Dubosiella (14.78%), Lachnospiraceae NK4A136 group (7.66 %), 4 genera dominated by Muribaculaceae (13.60%) declined, among which in LPH group, Lactobacillus (18.77%), Coriobacteriaceae_UCG-002 (19.92%), Akkermansia (27.35%), Bifidobacterium (8.5%) were The main dominant bacterial genera, Lactobacillus, Coriobacteriaceae_UCG-002, Akkermansia, Bifidobacterium, have protective effects in glucolipid metabolism diseases such as obesity caused by diet. The above results indicated that L. paracasei JY062 can enhance the intestinal homeostasis of mice, increase the abundance of Lactobacillus, Coriobacteriaceae_UCG-002, Akkermansia, and Bifidobacterium to alleviate the abnormal glucose and lipid metabolism caused by high-glucose-fat diet.

Effect of JY062 on the concentration of SCFAs

In order to further explore the mechanism of JY062 in resisting glycolipid metabolism, the levels of SCFAs in the feces of each group of mice were analyzed, and the results were shown in Fig 7. Among the SCFAs in the feces, compared with the N group, acetic acid, propionic acid, and butyric acid significantly decreased in the HFD mice, which were reduced by 42.75%, 53.37% and 39.56%, respectively. However, after 7 weeks of JY062 intervention, the concentration of acetic acid, propionic acid, and butyric acid were significantly increased, especially the concentration of butyric acid in the LPH group, which was 1.8 times higher than that of the HFD group (P<0.05).

Relationship between SCFAs and gut microbiota

As the metabolites of gut microbiota, the content of SCFAs is closely related to the composition of gut microbiota. Lactobacillus and Bifidobacterium in the gut microbiota can stimulate the production of SCFAs. In this study, a heat map of the relationship between the content of acetic acid, propionic acid, and butyric acid in SCFAs and the composition of gut microbiota in mice was analyzed. As can be seen from Fig 8, the acetic acid content was positively correlated with Bifidobacterium, Candidatus_Saccharimonas and Turicibacter, and negatively correlated with Faecalibaculum. In the analysis of species composition at the genus level and the content of SCFAs, it was found that the abundance of Bifidobacterium decreased and the relative abundance of Faecalibaculum increased in the HFD group. The relative abundance of Candidatus_Saccharimonas and Turicibacter increased, and the relative abundance of Faecalibaculum decreased. This indicated that L. paracasei JY062 could increase acetate content by increasing the abundance of Candidatus_Saccharimonas and Turicibacter and decreasing the abundance of Faecalibaculum. In addition, as can be seen from the figure, butyric acid content was positively correlated with Bifidobacterium, Muribacalum and Turicibacter, and negatively correlated with Faecalibaculum. In the analysis of species composition at the genus level and the content of SCFAs, it was found that the relative abundance of Bifidobacterium decreased and the relative abundance of Faecalibaculum increased after a long-term high-sugar and high-fat diet.

Nowadays, with the improvement of people's living standards, people's eating habits and dietary structure have changed a lot. People prefer to eat fast food with high fat and sugar, and lack of exercise and the increase of life pressure ¹⁷, glucose and lipid metabolism disorders and related diseases, including type 2 diabetes, dyslipidemia, hypertension, non-alcoholic fatty liver and its related cardiovascular complications have become epidemic ranks ¹⁸, posing a serious threat to human health. Insulin resistance is the core pathological changes of type 2 diabetes. At the earliest, it was considered that obesity, especially abdominal obesity, is an important risk factor for insulin resistance. However, it is found that fat atrophy can also lead to serious insulin resistance ¹⁹. Some research results suggested that adipose tissue plays a very important role in regulating insulin sensitivity. Accordingly, probiotics have become an alternative intervention for glycolipid metabolism ²⁰. In recent years, the weight loss and anti-diabetes effects of probiotics and probiotics preparations have been confirmed in animal models and clinical trials ²¹. Moreover, further evidence support that the gut microbiota, which can act on molecules that regulate appetite and satiety, plays a leverage role in energy efficiency and adipose tissue accumulation ²². Our results indicated that L. paracasei JY062 could alleviate high-glucose-fat-induced weight gain and fasting blood glucose elevation in mice.

Glycolipid metabolism disorder is a disease characterized by abnormal glucose and lipid metabolism. Therefore, we examined serum TC, TG、LDL-C、HDL-C, and OGTT. Long-term glycolipid metabolism disorder could bring about hepatic steatosis and liver injury characterized by abnormally elevated TC, TG, LDL-C, and lower HDL-C levels in liver, which caused damages to hepatocytes and glucose intolerance ²³. Therefore, successfully controlling serum cholesterol level was a powerful strategy to prevent the development of hyperlipidemia. Our results showed the L. paracasei JY062 intervention could ameliorate the hyperlipidemia and glucose intolerance induced by high-glucose-fat diet, and L. paracasei JY062 has been shown to reduce the risk of obesity-related factors while lowering TC, TG, LDL-C, and increase HDL-C. And our results were similar to Yang’s, L. rhamnosus JL1 intervene in mice on a high-fat diet for 10 weeks, which can effectively alleviate TG content in the mice serum ²⁴.

Improvement of glucolipid metabolism disorders depends on adipokines and insulin on the adipoinsular axis. On the one hand, adipokines, including adiponectin, leptin, were adipocyte-derived products and associated with glucolipid metabolism, such as glucose, lipid, and energy homeostasis ²⁵. Leptin is effective in long-term regulation of energy balance which can suppress food intake, and obese individuals are resistant to leptin, which was thought to be associated with decreased leptin receptors leading to increased adiposity, dyslipidemia and insulin resistance ^{26, 27}. In addition, adiponectin mediates insulin function and glucose homeostasis and circulating levels of adiponectin has a negative correlation with body fat mass and insulin resistance ²⁸. Stern.et al found that individuals with obesity, diabetes mellitus, and hypertension have significantly lower adiponectin levels, suggesting that plasma adiponectin levels may be closely related to the development of glycolipid metabolism ²⁹. On the other hand, the protein that plays an important role in glucolipid metabolism is GLP-1, a glucose-dependent hormone secreted by intestinal endocrine cells. GLP-1 inhibited glucagon secretion and promotes insulin secretion when blood glucose is high ³⁰. Meanwhile, insulin can promote leptin secretion and inhibit lipolysis to improve insulin sensitivity, increase fat oxidation and improve glucolipid metabolism ³¹. In our study, it was found that the contents of leptin, insulin and FFA in different dose groups of L. paracasei JY062 were significantly decreased (P < 0.05), the contents of adiponectin and GLP-1 were significantly increased (P < 0.05). Similar to our findings, administration of B. lactis BB12 ameliorated glycolipid metabolism disorders by activating adiponectin and stimulating the secretion of intestinal hormone GLP-1 ⁵. Taken together, these results explained that adipoinsular axis played an important role in improving glycolipid metabolism disorder.

The symptoms of glucolipid metabolism disorder are not only manifested in elevated blood glucose and lipid levels, but also accompanied by pathological changes of pancreas, liver and other organs ³². The hepatic pathological sections illustrated the liver cells in the HFD group had pathological conditions such as unclear boundary, disordered structure, enlarged cell space and sparse distribution of liver glycogen. Pancreatic slices of mice in the model group showed pathological states such as changes in cell morphology and decreased number, which were similar to the results of Zheng’s ³². However, L. paracasei JY062 intervention significantly improved the liver and pancreas health status. Our result was consistent with Yan’s³³.

Liver is an important metabolic organ. It played a critical role in glucolipid metabolism ³⁴. To elucidate the possible mechanisms of L. paracasei JY062 on improved of glucolipid metabolism disorders, we measured the expression of genes related to glycogenesis, lipogenesis and insulin signaling pathway. AdipoQ, derived from adipocytes, and can bind to adiponectin receptors 1 and 2, thereby enhancing insulin sensitivity ³⁵. In the liver, AdipoR2 activates adenosine-activated protein kinase AMPK ^{36, 37}. In the APN-AMPK pathway, AMPK was the main energy sensor in cells of the body and involved in fatty acid oxidation, glucose transport, triglyceride synthesis and metabolism and other cellular metabolic processes, as well as an important downstream factor of the APN signaling pathway ³⁸. Activated AMPK inhibits the activity of SREBP-1C, which was an important regulator of lipid synthesis and regulated adipocyte differentiation and intracellular ectopic accumulation of fat ³⁹. Downstream target genes of SREBP-1C were ACC and FAS.FAS was the key enzyme of endogenous fatty acid synthesis, ACC was the rate-limiting enzyme of fatty acid synthesis, which was closely related to the rate of fat synthesis. Inhibition of SREBP-1C could inhibit the transcription of ACC and FAS, thus reducing the synthesis of liver fat ⁴⁰. In this experiment, compared with HFD group, after L. paracasei JY062 intervention, the contents of AdipoQ and AMPK increased, while the expression levels of SREBP-1c, ACC and FAS decreased significantly, which was consistent with previous study. These results explained indicated that energy restriction could activate the APN-AMPK pathway, inhibit the expression of SREBP-1c, down-regulate its target genes FAS and ACC, and reduce lipid synthesis.

Moreover, AMPK activated the downstream factors GLUT-4 and PGC-1α. GLUT-4, as one of the markers of insulin resistance, was involved in glucose metabolism. After activation of AMPK, GLUT4 can be translocated to the plasma membrane to increase GLUT4 transcription and improve the uptake and utilization of glucose by the liver through an insulin-independent pathway ⁴¹. PGC-1α is a key signal molecule that regulated mitochondrial biosynthesis, promoted nuclear coding mitochondrial gene transcription, induced mitochondrial synthesis, and accelerated mechanical energy metabolism. Meanwhile, PGC-1α also leads to GLUT4 synthesis. In this experiment, compared with HFD group, after L. paracasei JY062 intervention, the contents of GLUT-4 and PGC-1α increased, which was consistent with previous study. In conclusion, L. paracasei JY062 could improve glucose and lipid metabolism through APN-AMPK pathway.

The gut microbiota could regulate the body's glycolipids by participating in the body's metabolism. Studies have shown that a long-term high-glucose-fat diet could cause disturbances in the intestinal environment, altering the composition, structure, and diversity of the microbiota ⁴². In this study, the Alpha diversity index of the mice in the HFD group decreased, indicating that a high-glucose-fat diet can reduce the richness and diversity of gut microbes, which in turn led to an imbalance in the gut microbiota. After L. paracasei JY062 intervention, it could reduce the abundance and diversity of gut microbes. Consistent with Zheng’s findings, the diversity of gut microbiota was restored and the richness of the microbiota increased ⁴³. The results of PCoA analysis in Beta diversity showed that the structure of gut microbiota in HFD mice was significantly different from those in the N group and L. paracasei JY062 intervention groups, indicated that gut microbiota imbalance could lead to the structure of gut microbes and composition changes, that the intervention of L. paracasei JY062 has a certain recovery effect.

Studies have shown that a high-fat diet could induce an increase in the abundance of Firmicutes and Proteobacteria in mice feces, while a decrease in the abundance of Bacteroidetes. Among them, Firmicutes could effectively absorb energy from food and promote the body to produce obesity symptoms. Proteobacteria includes many pathogenic bacteria, which induce inflammation, while the decrease in the proportion of Bacteroidetes can lead to metabolic disorders and cause metabolic diseases ^{44, 45}. The resulted showed that the abundance of Firmicutes at the phylum level was increased and the abundance of Bacteroidetes was decreased in the HFD group, while the LPL group increased Firmicutes after gavage with L. paracasei JY062, which might be the result of Lactobacillus at the phylum level. The increase in number can be verified in the results at the genus level in this study, while the abundance of Firmicutes decreased in the LPM and LPH group. Moreover, the abundance of Bacteroidetes, Proteobacteria in the three dose groups were lower than that in the HFD group. Overall, the ratio of upper Bacteroidetes to Firmicutes showed an increased trend, indicated that the intervention of L. paracasei JY062 could reduce harmful bacteria and increase the abundance of beneficial bacteria. At the genus level, the HFD group was dominated by Dubosiella, an uncultured Muribaculaceae, among which Dubosiella can produce lipopolysaccharide and cause inflammation, and its abundance is correlated with the occurrence of GLMD ⁴⁶. Muribaculaceae, one of the dominant bacteria, breaks down carbohydrates. In this study, the abundance of Muribaculaceae in the HFD group was lower than that in the N group but not significantly, which may be due to the difference in dietary fiber intake between the two groups of mice. The experimental results showed that the intake of cellulose in the HFD group was higher than that in the N group, and cellulose promoted the proliferation of Muribaculaceae ⁴⁷. In addition, the abundance of beneficial bacteria Lactobacillus, Akkermansia and Bifidobacterium significantly increased after L. paracasei JY062 was administered orally. Lactobacillus, Bifidobacterium is the most commonly used probiotic strain in clinical trials. Among them, Lactobacillus could change lipid and carbohydrate synthesis pathways, regulate glycolipid metabolism, and Bifidobacterium is SCFAs-producing bacteria, which can improve the metabolic activity of gut microbiota ⁴⁸. Studies has shown that the mixture of Lactobacillus and Bifidobacterium could inhibit the harm of high-fat diet to the human body through butyric acid, improve the barrier function of the gastrointestinal tract, and inhibit the expression of pro-inflammatory factors ⁴⁹. However, there is a direct relationship between Akkermansia and T2DM and other glucolipid metabolic diseases ⁵⁰. Compared with obese people, Akkermansia is more abundant in healthy people, and after supplementing Akkermansia, blood glucose and lipid indexes are significantly decreased, and alleviated ⁵¹.

SCFAs were carbon chain 1 ~ 6 organic fatty acids that are generated from undigested starch and fiber polysaccharides through glycolysis by anaerobic bacteria ⁵². Studies showed that the SCFAs played a critical role in the prevention and treatment of obesity and T2DM in both animal model and clinical trials ⁵³. Acetic acid is the most abundant SCFAs in serum, which can regulate the level of inflammation and resist the invasion of pathogens, inhibit the accumulation of fat in adipose tissue ⁵⁴, and propionic acid stimulates leptin to reduce TC level ⁵⁵. Butyric acid can promote the release of gastrointestinal peptide hormones such as peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), thus improving obesity and insulin sensitivity induced by high fat diet ⁵⁶. In addition, butyric acid activates the liver AMPK signaling pathway, which promotes fatty acid oxidation and inhibits gluconeogenesis and fat production ⁵⁷. In this experiment, L. paracasei JY062 significantly stimulated the production of acetic acid, propionic acid and butyric acid. The results showed that L. paracasei JY062 could promote the SCFAs, which was consistent with the above report ⁵⁸.

After the intervention of L. paracasei JY062, the gut microbiota composition of GLMD mice was improved and tended to be in a balanced state of flora, and the relative abundance of SCFAs-producing bacteria such as Lactobacillus, Akkermansia, Bifidobacterium increased, and stimulated the production of SCFAs and promoted the production of adipose tissue. The secretion of adiponectin increases leptin sensitivity, which in turn mediates the adipose-insulin axis. On the one hand, adiponectin could bind to AdipoR2 in the liver, activate the AMPK signaling pathway, inhibit the expression of SREBP-1c, promote the expression of GLUT-4, and improve the biochemical indicators of glycolipid. On the other hand, the improvement of leptin sensitivity can improve leptin resistance, and better play the role of leptin in controlling food intake, increasing energy consumption, and improving insulin sensitivity, thereby relieving GLMD. After L. paracasei JY062 intervention, it could be found that the relative abundance of Bifidobacterium, Muribacalum and Turicibacter all increased, and the relative abundance of Faecalibaculum decreased. It indicated that L. paracasei JY062 could increase the butyrate content by increasing the relative abundance of Bifidobacterium, Muribacalum and Turicibacter, and decreasing the relative abundance of Faecalibaculum. The above results suggest that L. paracasei JY062 can increase the content of SCFAs by increasing the relative abundance of bacteria such as Bifidobacterium, Candidatus_Saccharimonas, Muribacalum and Turicibacter in the intestinal contents of mice, thereby regulating glucolipid metabolism disorders

Strain and culture

L. paracasei JY062 was previously isolated from fermented dairy products in Tibet, China and stored at -80℃ until use. L. paracasei JY062 was inoculated into MRS liquid medium (Qingdao Haibo) at 5% dose, activated at 37°C for 18h, and subculture twice before the experiment. The oral bacterial solution samples were centrifuged at 4℃ 8000 r/min for 10 min, and cell microspheres were collected. After washing twice, they were suspended in 0.01 M PBS buffer (pH 7.4) at concentrations of 10⁹, 10⁸ and 10⁷CFU/ml for further experiments.

Animal groups and feeding

Fifty-five C57BL/6J male mice (18 ± 2 g, 4-week-old) were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd (Beijing, China). All animal procedures were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Northeast Agricultural University and experiments were approved by the Animal Ethics Committee of Northeast Agricultural.

All mice were housed at 22 ± 2 °C and 55 ± 10%relative humidity and were exposed to a photoperiod of 12 h light and 12 h dark. After 7-days of administration with normal diet, the mice were randomly divided into 5 groups (11 mice in each group): Normal group (N), model group (HFD), high-dose L .paracasei JY062 group (LPH), medium-dose L. paracasei JY062 group (LPM), and low-dose L. paracasei JY062 group (LPL). The specific intervention of mice in each group was shown in Fig 9.

Sample Collection

The experimental mice were fed for 11 weeks. On the last day of the experiment, orbital blood was taken from the mice after fasted for 12 h, then the serum was separated then stored at -20 °C for later use. Body weight was recorded every week. The mice were sacrificed, the abdominal cavity was opened, and the cecum and colon were cut off, and their contents were placed in 1.5 mL RNA free centrifuge tubes. The livers and pancreas were quickly removed from mice, washed with chilled normal saline, dried with filter paper, and weighed, then stored at -80 °C until use.

Oral glucose tolerance test (OGTT)

After 11 weeks of feeding, mice were subjected to 12 h of fasting and then orally administered a glucose bolus (2 g/kg body weight). Blood was drawn from the tail vein at 0, 30, 60, and 120 min after bolus administration, glucose levels were measured using a blood glucose metre (Roche Diagnostics, Germany), and the area under the curve (AUC) of blood glucose concentration (0–120 min) was calculated.

Serum biochemistry determination

The collected mice blood was placed at room temperature for 2 h, then centrifuged at 4°C, 3000 r/min for 10 min, and the serum was collected. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure TC、TG、HDL-C、LDL-C、free fatty acid、insulin and GLP-1，as well as the contents of adiponectin and leptin adipocytokine in serum were determined according to the manufacturer’s instructions.

Liver and pancreas histological analysis

The liver and pancreas tissues fixed in 4% paraformaldehyde solution were embedded in paraffin, sectionalized and stained with HE. Finally, the histopathological changes of liver and pancreas were observed and photographed by 400X light microscope.

Gene expression analysis

The cycling conditions and calculation methods of RT-PCR was carried out according to previous method ⁵⁹. Total RNA from mice livers was extracted. Reverse transcription of RNA into cDNA was carried out according to the kit operating instructions.

Analysis of Gut microbiota composition

DNA from mouse fecal samples was extracted using a fecal DNA extraction kit. The V3 and V4 regions of 16S rDNA were used as target sequences to amplify the PCR products by agarose gel electrophoresis to check whether the PCR products were qualified. The Illumina MiSeq sequencer was used and performed to detect the composition. proportion of the main bacterial groups in the fecal samples.

SCFAs analysis

The feces of the mice were collected and stored at -80 °C. Then the mice feces were freeze-dried and weighed. The content of SCFAs in feces was determined according to the previous method ⁶⁰.

Data availability

The authors declare that all data supporting the findings of this study are available in the paper and supplementary information.

Author Contributions

Writing-original draft, Yue Su; Data curation, Jing Ren, Jingwen Zhang; Method-ology, Jiapeng Zheng; Formal analysis, Yu Zhang; Project administration, Chaoxin Man; Conceptualization, Yujun Jiang. All authors discussed and commented the results and gave their final approval for submission.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgement

This work was supported by the National Natural Science Foundation of China (No. 32172231). Project Supported by the Open Research Fund for Key Laboratory of Dairy Science (Northeast Agricultural University), Ministry of Education, Heilongjiang Province, China (Contract No. 2015KLDSOF-06).

Srivastava, P.K., Pradhan, A.D., Cook, N.R., Ridker, P.M. & Everett, B.M. Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis.
Bai, Y., Zheng, J., Yuan, X., Jiao, S. & Cui, F. Chitosan Oligosaccharides Improve Glucolipid Metabolism Disorder in Liver by Suppression of Obesity-Related Inflammation and Restoration of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ). Marine Drugs 16, 455- (2018).
Sonnenburg, J.L. & B?Ckhed, F. Diet–microbiota interactions as moderators of human metabolism. Nature 535, 56–64 (2016).
Ehca, B. et al. Modulating lipid and glucose metabolism by glycosylated kaempferol rich roasted leaves of Lycium chinense via upregulating adiponectin and AMPK activation in obese mice-induced type 2 diabetes. Journal of Functional Foods 72.
Rivera-Piza, A. & Lee, S.J.J.A.B.C. Effects of dietary fibers and prebiotics in adiposity regulation via modulation of gut microbiota. 63, - (2020).
Fan, Y. & Pedersen, O.J.N.R.M. Gut microbiota in human metabolic health and disease. (2020).
Pickard, J.M., Zeng, M.Y., Caruso, R. & Reviews, G.N.J.I. Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease. 279, 70 (2017).
Aggeletopoulou, I., Konstantakis, C., Assimakopoulos, S.F. & Triantos, C.J.M.P. The role of the gut microbiota in the treatment of inflammatory bowel diseases. 137, 103774 (2019).
Ballantyne, G.H., Gumbs, A. & Modlin, I.M. Changes in insulin resistance following bariatric surgery and the adipoinsular axis: Role of the adipocytokines, leptin, adiponectin and resistin. Obesity Surgery 15, 692–699 (2005).
Xiang, L. et al. Tetradecyl 2,3-Dihydroxybenzoate Improves the Symptoms of Diabetic Mice by Modulation of Insulin and Adiponectin Signaling Pathways. Frontiers in Pharmacology 8 (2017).
Yang, X. & Li, L.J.J.o.F.E. Physicochemical, rheological and digestive characteristics of soy protein isolate gel induced by lactic acid bacteria. 292, 110243 (2020).
Abraham, B. & Quigley, E. Antibiotics and probiotics in inflammatory bowel disease: when to use them? Frontline Gastroenterology 11, 62- (2020).
Tiderencel, K.A., Hutcheon, D.A. & Ziegler, J. Probiotics for the treatment of type 2 diabetes: A review of randomized controlled trials. Diabetes/Metabolism Research and Reviews 36 (2020).
Koczarski, M. The Effect of Probiotic Supplementation on Glycemic Control in Women With Gestational Diabetes Mellitus A Systematic Review. Topics in Clinical Nutrition 35, 270–276 (2020).
Wang, M. et al. Intervention of five strains of Lactobacillus on obesity in mice induced by high-fat diet. Journal of Functional Foods 72 (2020).
Dang, F.F. et al. Administration of Lactobacillus paracasei ameliorates type 2 diabetes in mice. Food & Function 9, 3630–3639 (2018).
Kapar, F.S. & Ciftci, G. The effects of curcumin and Lactobacillus acidophilus on certain hormones and insulin resistance in rats with metabolic syndrome. Journal of diabetes and metabolic disorders 19, 907–914 (2020).
Chen, L.G. et al. Regulation of glucose and lipid metabolism in health and disease. Science China-Life Sciences 62, 1420–1458 (2019).
Guilherme, A., Virbasius, J.V., Puri, V. & Czech, M.P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nature Reviews Molecular Cell Biology.
Tang, C., Kong, L., Shan, M., Lu, Z. & Lu, Y. Protective and ameliorating effects of probiotics against diet-induced obesity: A review. Food Research International 147 (2021).
Chiou, W.C. et al. Synbiotic Intervention with an Adlay-Based Prebiotic and Probiotics Improved Diet-Induced Metabolic Disturbance in Mice by Modulation of the Gut Microbiota. Nutrients 13 (2021).
Wang, G. et al. Lactic acid bacteria reduce diabetes symptoms in mice by alleviating gut microbiota dysbiosis and inflammation in different manners. Food & Function 11, 5898–5914 (2020).
Kosakai, T. et al. Dietary fermented products using koji mold and sweet potato-shochu distillery by-product promotes hepatic and serum cholesterol levels and modulates gut microbiota in mice fed a high-cholesterol diet. Peerj 7 (2019).
Yang, M. et al. Preventive Effect and Molecular Mechanism of Lactobacillus rhamnosus JL1 on Food-Borne Obesity in Mice. Nutrients 13 (2021).
Shapira, S. et al. Mo1775 High Expression Level of PPARγ in CD24 Knockout Mice and Gender Specific Metabolic Changes: A Model of Insulin-Sensitive Obesity. Gastroenterology 146, S-656-S-657 (2014).
Amitani, M., Asakawa, A., Amitani, H. & Inui, A. The role of leptin in the control of insulin-glucose axis. Frontiers in Neuroscience 7 (2013).
Meek, T.H. & Morton, G.J. The role of leptin in diabetes: metabolic effects. Diabetologia 59, 928–932 (2016).
Jung, U.J. & Choi, M.-S. Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences 15, 6184–6223 (2014).
Stern, J.H., Rutkowski, J.M. & Scherer, P.E. Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk. Cell Metabolism 23, 770–784 (2016).
Gallwitz, B. Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass. Diabetes technology & therapeutics 7, 651–657 (2005).
Barr, V.A., Malide, D., Zarnowski, M.J., Taylor, S.I. & Cushman, S.W. Insulin stimulates both leptin secretion and production by rat white adipose tissue. Endocrinology 138, 4463–4472 (1997).
Zheng, F. et al. Lactobacillus rhamnosus FJSYC4-1 and Lactobacillus reuteri FGSZY33L6 alleviate metabolic syndrome via gut microbiota regulation. Food & Function 12, 3919–3930 (2021).
Yan, F. et al. Lactobacillus acidophilus alleviates type 2 diabetes by regulating hepatic glucose, lipid metabolism and gut microbiota in mice. Food & Function 10, 5804–5815 (2019).
Bechmann, L.P. et al. The interaction of hepatic lipid and glucose metabolism in liver diseases. Journal of Hepatology 56, 952–964 (2012).
Maury, E. & Brichard, S.M. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Molecular and Cellular Endocrinology 314, 1–16 (2010).
Handa, P. et al. Reduced Adiponectin Signaling Due to Weight Gain Results in Nonalcoholic Steatohepatitis Through Impaired Mitochondrial Biogenesis. Hepatology 60, 133–145 (2014).
Cavaglieri, R.C., Day, R.T., Feliers, D. & Abboud, H.E. Metformin prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction. Molecular and Cellular Endocrinology 412, 116–122 (2015).
Luo, J. et al. Antiobesity Effect of Flaxseed Polysaccharide via Inducing Satiety due to Leptin Resistance Removal and Promoting Lipid Metabolism through the AMP-Activated Protein Kinase (AMPK) Signaling Pathway. Journal of Agricultural and Food Chemistry 67, 7040–7049 (2019).
Li, Y. et al. AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulin-Resistant Mice. Cell Metabolism 13, 376–388 (2011).
Shen, L. et al. Hepatic Differentiated Embryo-Chondrocyte-expressed Gene 1 (Dec1) Inhibits Sterol Regulatory Element-binding Protein-1c (Srebp-1c) Expression and Alleviates Fatty Liver Phenotype. Journal of Biological Chemistry 289, 23332–23342 (2014).
Hajiaghaalipour, F., Khalilpourfarshbafi, M. & Arya, A. Modulation of Glucose Transporter Protein by Dietary Flavonoids in Type 2 Diabetes Mellitus. International Journal of Biological Sciences 11, 508–524 (2015).
Zhang, H.-J. et al. Sea cucumbers-derived sterol sulfate alleviates insulin resistance and inflammation in high-fat-high-fructose diet-induced obese mice. Pharmacological Research 160, 105191 (2020).
Zheng, F. et al. Lactobacillus rhamnosus FJSYC4-1 and Lactobacillus reuteri FGSZY33L6 alleviate metabolic syndrome via gut microbiota regulation.
Peng, Z. et al. Review of mechanisms of deoxynivalenol-induced anorexia: The role of gut microbiota. (2017).
Grigor'Eva, I.N.J.J.o.P.M. Personalized Medicine Review Gallstone Disease, Obesity and the Firmicutes/Bacteroidetes Ratio as a Possible Biomarker of Gut Dysbiosis. 11, 13 (2021).
Zhang, C. et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. 4, 232–241 (2010).
Wang, B. et al. Bifidobacterium adolescentis Isolated from Different Hosts Modifies the Intestinal Microbiota and Displays Differential Metabolic and Immunomodulatory Properties in Mice Fed a High-Fat Diet. LID – 10.3390/nu13031017 [doi] LID – 1017.
Besten, G.D. et al. Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation. 64 (2015).
Vemuri, R., Gundamaraju, R., Shinde, T., Perera, P. & Eri, R.J.N. Lactobacillus acidophilus DDS-1 Modulates Intestinal-Specific Microbiota, Short-Chain Fatty Acid and Immunological Profiles in Aging Mice. 11, 1297 (2019).
Zhao, S. et al. Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice. 58, JME-16-0054 (2016).
Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. 23, 107 (2016).
Knudsen, B. & K., E. Microbial Degradation of Whole-Grain Complex Carbohydrates and Impact on Short-Chain Fatty Acids and Health. Advances in Nutrition 6, 206–213 (2015).
Besten, G.D. et al. Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation. Diabetes 64 (2015).
Deehan, E.C. et al. Precision Microbiome Modulation with Discrete Dietary Fiber Structures Directs Short-Chain Fatty Acid Production. Cell Host & Microbe (2020).
Al-Lahham et al. Propionic acid affects immune status and metabolism in adipose tissue from overweight subjects.
Canfora, E., Jocken, J.W. & Blaak, E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nature Reviews Endocrinology (2015).
Gijs et al. Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation. Diabetes (2015).
Li, X. et al. Effects of Lactobacillus casei CCFM419 on insulin resistance and gut microbiota in type 2 diabetic mice. Beneficial Microbes (2017).
Sun, L. et al. Lactobacillus gasseri JM1 with potential probiotic characteristics alleviates inflammatory response by activating the PI3K/Akt signaling pathway in vitro. Journal of Dairy Science 103, 7851–7864 (2020).
Won, S.-M. et al. Lactobacillus sakei ADM14 Induces Anti-Obesity Effects and Changes in Gut Microbiome in High-Fat Diet-Induced Obese Mice. Nutrients 12 (2020).

(Not answered)

Download PDF

Version 1

posted

You are reading this latest preprint version

Lactobacillus paracasei JY062 alleviates glucolipid metabolism disorders by adipoinsular axis and gut microbiota

Status:

Version 1

Abstract

Figures

Introduction

Results

Discussion

Materials And Methods

Declarations

References

Additional Declarations

Status:

Version 1