Age-Related Changes in the Gut Microbiota Modify Brain Lipid Composition

ORIGINAL RESEARCH published: 14 January 2020 doi: 10.3389/fcimb.2019.00444 Age-Related Changes in the Gut Microbiota Modify Brain Lipid Composition Mayssa Albouery 1 , Bénédicte Buteau 1† , Stéphane Grégoire 1† , Claire Cherbuy 2 , Jean-Paul Pais de Barros 3 , Lucy Martine 1 , Florian Chain 2 , Stéphanie Cabaret 4 , Olivier Berdeaux 4 , Alain M. Bron 1,5 , Niyazi Acar 1 , Philippe Langella 2 and Marie-Agnès Bringer 1* 1 Edited by: Frederic Antonio Carvalho, INSERM U1107 Douleur et Biophysique Neurosensorielle (Neuro-Dol), France Reviewed by: Sanjoy K. Bhattacharya, University of Miami, United States Maricela Rodriguez-Cruz, Instituto Mexicano del Seguro Social, Mexico *Correspondence: Marie-Agnès Bringer † These authors have contributed equally to this work Specialty section: This article was submitted to Microbiome in Health and Disease, a section of the journal Frontiers in Cellular and Infection Microbiology Received: 23 October 2019 Accepted: 10 December 2019 Published: 14 January 2020 Citation: Albouery M, Buteau B, Grégoire S, Cherbuy C, Pais de Barros J-P, Martine L, Chain F, Cabaret S, Berdeaux O, Bron AM, Acar N, Langella P and Bringer M-A (2020) Age-Related Changes in the Gut Microbiota Modify Brain Lipid Composition. Front. Cell. Infect. Microbiol. 9:444. doi: 10.3389/fcimb.2019.00444 Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, University of Bourgogne Franche-Comté, Eye and Nutrition Research Group, Dijon, France, 2 Micalis Institute, INRAE, AgroParisTech, University Paris-Saclay, Jouy-en-Josas, France, 3 Inserm U1231 “Lipids, Nutrition, Cancer”, Lipidomic Platform, University of Bourgogne Franche-Comté, Dijon, France, 4 Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, University of Bourgogne Franche-Comté, ChemoSens Platform, Dijon, France, 5 Department of Ophthalmology, University Hospital, Dijon, France Understanding the molecular mechanisms underlying the changes observed during aging is a prerequisite to design strategies to prevent age-related diseases. Aging is associated with metabolic changes, including alteration in the brain lipid metabolism. These alterations may contribute to the development of pathophysiological conditions. Modifications in the gut microbiota composition are also observed during aging. As communication axes exist between the gut microbiota and the brain and knowing that microbiota influences the host metabolism, we speculated on whether age-associated modifications in the gut microbiota could be involved in the lipid changes observed in aging brain. For that purpose, germ-free mice were colonized by the fecal microbiota of young or old donor mice. Lipid classes and fatty acid profiles were determined in the brain (cortex), plasma and liver by thin-layer chromatography on silica gel-coated quartz rods and gas chromatography. Gut colonization by microbiota of old mice resulted in a significant increase in total monounsaturated fatty acids (MUFA) and a significant decrease in the relative amounts of cholesterol and total polyunsaturated fatty acids (PUFA) in the cortex. Among the eight most represented fatty acids in the cortex, the relative abundances of five (C18:1n-9, C22:6n-3, C20:4n-6, C18:1n-7, and C20:1n-9) were significantly altered in mice inoculated with an aged microbiota. Liquid chromatography analyses revealed that the relative abundance of major species among phosphatidyl and plasmenylcholine (PC 16:0/18:1), phosphatidyl and plasmenylethanolamine (PE 18:0/22:6), lysophosphatidylethanolamine (LPE 22:6) and sphingomyelins (SM d18:1/18:0) were significantly altered in the cortex of mice colonized by the microbiota obtained from aged donors. Transplantation of microbiota from old mice also modified the lipid class and fatty acid content in the liver. Finally, we found that the expression of several genes involved in MUFA and PUFA synthesis (Scd1, Fads1, Fads2, Elovl2, and Elovl5) was dysregulated in mice inoculated with an Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 January 2020 | Volume 9 | Article 444 Albouery et al. Microbiota Modulates Brain Lipid Composition aged microbiota. In conclusion, our data suggest that changes in gut microbiota that are associated with aging can impact brain and liver lipid metabolisms. Lipid changes induced by an aged microbiota recapitulate some features of aging, thus pointing out the potential role of microbiota alterations in the age-related degradation of the health status. Keywords: aging, microbiota, lipid, cholesterol, fatty acid, phospholipid, liver, cortex INTRODUCTION tissue and liver, but also lipid-rich organs such as the retina (Backhed et al., 2004, 2007; Oresic et al., 2009; Rabot et al., 2010; Velagapudi et al., 2010). The composition of the gut microbiota also influences lipids in organs. Microbial dysbiosis are associated with metabolic diseases such as obesity and diabetes, and the use of prebiotics or probiotic bacteria was shown to ameliorate metabolic syndrome at least by acting on lipid metabolism (Yang and Kweon, 2016; He and Shi, 2017). Regulation of the lipid metabolism by gut microbes takes place at the gut level but also in distant organs. The microbiota regulates lipid metabolization and absorption at the level of the intestinal mucosa (Martinez-Guryn et al., 2018). In addition to that, gut microbes can modify hepatic de novo lipogenesis by modulating expression of genes involved in lipid metabolism and by generating short chain fatty acids (SCFA) that are substrates for hepatic lipogenesis (Singh et al., 2015; Kindt et al., 2018). Within human tissues, brain is one displaying the highest content in lipids, and diversity of lipid classes and molecular species (Han, 2007). Modifications of the brain lipid composition have been described in aged healthy and unhealthy brain (Rappley et al., 2009; Naudi et al., 2015). Considering the crucial roles played by gut microbes in the regulation of lipid metabolism and the existence of a gut-brain axis, we sought to evaluate whether changes occurring in the gut microbiota during aging would impact brain lipids. We inoculated germfree mice with the microbiota of young or old conventionally raised mice. We found that animals colonized with an aged microbiota displayed alterations of lipid profiles in the cortex and the liver. They were characterized by a decrease in the cholesterol and polyunsaturated fatty acids (PUFA) levels, while the monounsaturated fatty acid (MUFA) levels were increased. Moreover, we showed that changes in the gut microbiota that are associated with aging induce the generation of MUFA and has an impact on PUFA elongation and unsaturation, by modifying the expression levels of several genes (Scd1, Fads1, Fads2, Elovl2, and Elovl5) encoding enzymes involved in fatty acid biosynthesis. Aging leads to cell degeneration and deterioration of organ structure and function on an irreversible and gradual (...truncated)