Brandon D Kayser1,2, Edi Prifti2,3, Marie Lhomme2, Eugeni Belda2, Maria-Carlota Dao1,2, Judith Aron-Wisnewsky1,4, Anatol Kontush5, Jean-Daniel Zucker3, Salwa W Rizkalla1,2, Isabelle Dugail1, Karine Clément6,7. 1. Sorbonne Université, INSERM, Nutrition and Obesities; Systemic Approaches Research Unit (NutriOmics), Paris, France. 2. Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France. 3. Sorbonne Université, IRD, Unité de Modélisation Mathématique et Informatique des Systèmes, Paris, France. 4. Assistance-Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital, Nutrition Department, CRNH Ile de France, 43-83 Boulevard de L'Hôpital, IE3 M, 75013, Paris, France. 5. Sorbonne Université, INSERM, UMRS 1166, Dyslipidemia, Inflammation, and Atherosclerosis Team, Paris, France. 6. Sorbonne Université, INSERM, Nutrition and Obesities; Systemic Approaches Research Unit (NutriOmics), Paris, France. karine.clement@inserm.fr. 7. Assistance-Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital, Nutrition Department, CRNH Ile de France, 43-83 Boulevard de L'Hôpital, IE3 M, 75013, Paris, France. karine.clement@inserm.fr.
Abstract
INTRODUCTION: Low gut microbiome richness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes. OBJECTIVES: Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obese patients with increased diabetes risk. METHODS: This was a cross-sectional and longitudinal retrospective analysis of a dietary/weight loss intervention. Fasted serum was collected from 49 participants (41 women) and analyzed by HPLC-MS/MS to quantify 45 sphingolipids. Shotgun metagenomic sequencing of stool was performed to profile the gut microbiome. RESULTS: Confirming the link to deteriorated glucose homeostasis, serum ceramides were positively correlated with fasting glucose, but inversely correlated with fasting and OGTT-derived measures of insulin sensitivity and β-cell function. Significant associations with gut dysbiosis were demonstrated, with SM and ceramides being inversely correlated with gene richness. Ceramides with fatty acid chain lengths of 20-24 carbons were the most associated with low richness. Diet-induced weight loss, which improved gene richness, decreased most sphingolipids. Thirty-one MGS, mostly corresponding to unidentified bacteria species, were inversely correlated with ceramides, including a number of Bifidobacterium and Methanobrevibacter smithii. Higher ceramide levels were also associated with increased metagenomic modules for lipopolysaccharide synthesis and flagellan synthesis, two pathogen-associated molecular patterns, and decreased enrichment of genes involved in methanogenesis and bile acid metabolism. CONCLUSION: This study identifies an association between gut microbiota richness, ceramides, and diabetes risk in overweight/obese humans, and suggests that the gut microbiota may contribute to dysregulation of lipid metabolism in metabolic disorders.
INTRODUCTION: Low gut microbiomerichness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes. OBJECTIVES: Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obesepatients with increased diabetes risk. METHODS: This was a cross-sectional and longitudinal retrospective analysis of a dietary/weight loss intervention. Fasted serum was collected from 49 participants (41 women) and analyzed by HPLC-MS/MS to quantify 45 sphingolipids. Shotgun metagenomic sequencing of stool was performed to profile the gut microbiome. RESULTS: Confirming the link to deteriorated glucose homeostasis, serum ceramides were positively correlated with fasting glucose, but inversely correlated with fasting and OGTT-derived measures of insulin sensitivity and β-cell function. Significant associations with gut dysbiosis were demonstrated, with SM and ceramides being inversely correlated with gene richness. Ceramides with fatty acid chain lengths of 20-24 carbons were the most associated with low richness. Diet-induced weight loss, which improved gene richness, decreased most sphingolipids. Thirty-one MGS, mostly corresponding to unidentified bacteria species, were inversely correlated with ceramides, including a number of Bifidobacterium and Methanobrevibacter smithii. Higher ceramide levels were also associated with increased metagenomic modules for lipopolysaccharide synthesis and flagellan synthesis, two pathogen-associated molecular patterns, and decreased enrichment of genes involved in methanogenesis and bile acid metabolism. CONCLUSION: This study identifies an association between gut microbiota richness, ceramides, and diabetes risk in overweight/obesehumans, and suggests that the gut microbiota may contribute to dysregulation of lipid metabolism in metabolic disorders.
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