Elevated serum ceramides are linked with obesity-associated gut dysbiosis and impaired glucose metabolism
Low gut microbiome richness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes.
Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obese patients with increased diabetes risk.
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.
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.
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.
KeywordsMicrobiome Ceramides Sphingolipids Endotoxin Glucose metabolism
Thank you to Sophie Gougis, Soraya Fellahi (Dept. of Biochemistry and Hormonology, Tenon hospital), Dominique Bonnefont-Rousselot and Randa Bittar (Department of Metabolic Biochemistry, Pitié-Salpêtrière hospital) for their contributions to data collection and analysis. We would also like to thank the nurses and technicians, and of course, the patients themselves for their invaluable contribution.
MICRO-Obes consortium: Aurélie Cotillard; Sean P Kennedy; Nicolas Pons; Emmanuelle Le Chatelier; Mathieu Almeida; Benoit Quinquis; Nathalie Galleron; Jean-Michel Batto; Pierre Renault; Stanislav Dusko Ehrlich; Hervé Blottière; Marion Leclerc; Tomas de Wouters; Patricia Lepage, Joel Doré.
BDK conceived the research question, performed the analyses, and wrote the manuscript. ML performed the lipidomics analysis and reviewed the data. EP and EB implemented the metagenomics pipeline and bioinformatics. MCD and JAW assisted in data collection, reviewed the data, and carefully reviewed the manuscript. AK supervised the lipidomics analysis and reviewed the data. SWR designed and coordinated the clinical study, and reviewed the data. ID supervised the research project and contributed to the research questions and manuscript. KC designed the study and supervised clinical and metagenomics analyses, contributed to the research question, and wrote the manuscript.
This work was supported by Agence Nationale de la Recherche (ANR MICRO-Obes), KOT-Ceprodi and the association Foundation Coeur et Arteres (clinical investigation) as well as European Union’s Seventh Framework Program Metacardis under grant agreement HEALTH-F4-2012-305312 and Horizon 2020 Framework Program (EPoS, grant #634413). The European Foundation for the Study of Diabetes Albert Renold travel fellowship have contributed to the work of BDK and Danone Research to the work of MCD and KC.
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflicts of interest.
This study was initiated when the investigators held positions at Hôtel-Dieu Hospital, therefore the study was authorized by the Ethical Committee of Hôtel-Dieu Hospital in Paris, France in 2008 under the number 0811792. All procedures were performed in accordance with ethical and institutional standards, and all participants provided written informed consent. The study is registered on clinicaltrials.gov: NCT01314690.
Informed consent was obtained from all individual participants included in the study.
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