VSL#3 Resets Insulin Signaling and Protects against NASH and Atherosclerosis in a Model of Genetic Dyslipidemia and Intestinal Inflammation

Abstract

BackgroundSignals generated by the inflammed intestine are thought to contribute to metabolic derangement. The intestinal microbiota contributes to instructing the immune system beyond the intestinal wall and its modulation is a potential target for treating systemic disorders.AimsTo investigate the pathogenetic role of low grade intestinal inflammation in the development of steatohepatitis and atherosclerosis in a model of genetic dyslipidemia and to test the therapeutic potential of a probiotics intervention in protecting against development of these disorders.ResultsApoE−/− mice were randomized to receive vehicle or VSL#3, a mixture of eight probiotics, at the dose of 20×109 colony-forming units/kg/day for three months alone or in combination with 0.2% of dextran sulfate sodium (DSS) in drinking water. Administering DSS to ApoE−/− mice failed to induce signs and symptoms of colitis but increased intestinal permeability to dextran FITC and, while had no effect on serum lipids, increased the blood levels of markers of liver injury and insulin resistance. DSS administration associated with low level inflammation of intestinal and mesenteric adipose tissues, caused liver histopathology features of steatohepatitis and severe atherosclerotic lesions in the aorta. These changes were prevented by VSL#3 intervention. Specifically, VSL#3 reversed insulin resistance, prevented development of histologic features of mesenteric adipose tissue inflammation, steatohepatitis and reduced the extent of aortic plaques. Conditioned media obtained from cultured probiotics caused the direct transactivation of peroxisome proliferator-activated receptor-γ, Farnesoid-X-receptors and vitamin D receptor.ConclusionsLow grade intestinal inflammation drives a transition from steatosis to steatohepatitis and worsens the severity of atherosclerosis in a genetic model of dyslipidemia. VSL#3 intervention modulates the expression of nuclear receptors, corrects for insulin resistance in liver and adipose tissues and protects against development of steatohepatitis and atherosclerosis.

Multi-strain probiotics attenuate carbohydrate-lipid metabolic dysregulation in type 2 diabetic rats via gut-liver axis modulation

“…For example, the cysteine protease encoded by the Casp4 gene is a key biomarker for Salmonella infection ( 55 ). Its suppression indicates that probiotic intervention may help mitigate colonic mucosal damage and dysbiosis associated with T2DM, aligning with previous findings ( 56 , 57 ). Furthermore, the ProH intervention also modulated the intestinal expression of circadian rhythm-related genes, highlighting their systemic regulatory potential in reversing adverse effects induced by high-fat diet administration ( 58 – 60 ).…”

Multi-strain probiotics attenuate carbohydrate-lipid metabolic dysregulation in type 2 diabetic rats via gut-liver axis modulation

“…For example, the cysteine protease encoded by the Casp4 gene is a key biomarker for Salmonella infection ( 55 ). Its suppression indicates that probiotic intervention may help mitigate colonic mucosal damage and dysbiosis associated with T2DM, aligning with previous findings ( 56 , 57 ). Furthermore, the ProH intervention also modulated the intestinal expression of circadian rhythm-related genes, highlighting their systemic regulatory potential in reversing adverse effects induced by high-fat diet administration ( 58 – 60 ).…”

Lactobacillus fermentum MCC2759 and MCC2760 Alleviate Inflammation and Intestinal Function in High-Fat Diet-Fed and Streptozotocin-Induced Diabetic Rats

“…Lactobacillus casei strain Shirota showed a significant reduction in the levels of pro-inflammatory cytokines IL-6, IL-4, and C-reactive protein in STZ-induced diabetic rats [25]. Probiotic mixture VSL#3 was found to reduce the levels of TNF-α and concomitantly augment IL-10 in a diabetic mice model fed for 12 weeks [26]. Similar studies have shown the effects of probiotic lactobacilli on inflammatory markers [20,27].…”

Nonalcoholic fatty liver disease as trigger of cardiovascular and metabolic complication in metabolic syndrome

“…In mice models of genetic dyslipidemia (Apo-E deficient mice), destrane sulfhate sodium (DSS)-induced intestinal inflammation and consequent increased intestinal permeability (IP) are able to trigger the transition of steatosis to NASH, and how these disorders are efficiently prevented by a therapeutic intervention with a mixture of probiotics [60]. Similar results are also obtained in animal models of high-fat diet-induced liver disease that is attenuated by probiotic treatment [61].…”

Multi-strain probiotics attenuate carbohydrate-lipid metabolic dysregulation in type 2 diabetic rats via gut-liver axis modulation

“…For example, the cysteine protease encoded by the Casp4 gene is a key biomarker for Salmonella infection ( 55 ). Its suppression indicates that probiotic intervention may help mitigate colonic mucosal damage and dysbiosis associated with T2DM, aligning with previous findings ( 56 , 57 ). Furthermore, the ProH intervention also modulated the intestinal expression of circadian rhythm-related genes, highlighting their systemic regulatory potential in reversing adverse effects induced by high-fat diet administration ( 58 – 60 ).…”

Lactobacillus fermentum MCC2759 and MCC2760 Alleviate Inflammation and Intestinal Function in High-Fat Diet-Fed and Streptozotocin-Induced Diabetic Rats

“…Lactobacillus casei strain Shirota showed a significant reduction in the levels of pro-inflammatory cytokines IL-6, IL-4, and C-reactive protein in STZ-induced diabetic rats [25]. Probiotic mixture VSL#3 was found to reduce the levels of TNF-α and concomitantly augment IL-10 in a diabetic mice model fed for 12 weeks [26]. Similar studies have shown the effects of probiotic lactobacilli on inflammatory markers [20,27].…”

Nonalcoholic fatty liver disease as trigger of cardiovascular and metabolic complication in metabolic syndrome

“…In mice models of genetic dyslipidemia (Apo-E deficient mice), destrane sulfhate sodium (DSS)-induced intestinal inflammation and consequent increased intestinal permeability (IP) are able to trigger the transition of steatosis to NASH, and how these disorders are efficiently prevented by a therapeutic intervention with a mixture of probiotics [60]. Similar results are also obtained in animal models of high-fat diet-induced liver disease that is attenuated by probiotic treatment [61].…”

Multi-strain probiotics attenuate carbohydrate-lipid metabolic dysregulation in type 2 diabetic rats via gut-liver axis modulation

“…For example, the cysteine protease encoded by the Casp4 gene is a key biomarker for Salmonella infection ( 55 ). Its suppression indicates that probiotic intervention may help mitigate colonic mucosal damage and dysbiosis associated with T2DM, aligning with previous findings ( 56 , 57 ). Furthermore, the ProH intervention also modulated the intestinal expression of circadian rhythm-related genes, highlighting their systemic regulatory potential in reversing adverse effects induced by high-fat diet administration ( 58 – 60 ).…”

Lactobacillus fermentum MCC2759 and MCC2760 Alleviate Inflammation and Intestinal Function in High-Fat Diet-Fed and Streptozotocin-Induced Diabetic Rats

“…Lactobacillus casei strain Shirota showed a significant reduction in the levels of pro-inflammatory cytokines IL-6, IL-4, and C-reactive protein in STZ-induced diabetic rats [25]. Probiotic mixture VSL#3 was found to reduce the levels of TNF-α and concomitantly augment IL-10 in a diabetic mice model fed for 12 weeks [26]. Similar studies have shown the effects of probiotic lactobacilli on inflammatory markers [20,27].…”

Nonalcoholic fatty liver disease as trigger of cardiovascular and metabolic complication in metabolic syndrome

“…In mice models of genetic dyslipidemia (Apo-E deficient mice), destrane sulfhate sodium (DSS)-induced intestinal inflammation and consequent increased intestinal permeability (IP) are able to trigger the transition of steatosis to NASH, and how these disorders are efficiently prevented by a therapeutic intervention with a mixture of probiotics [60]. Similar results are also obtained in animal models of high-fat diet-induced liver disease that is attenuated by probiotic treatment [61].…”