Cell Article Gut Microbiota Orchestrates Energy Homeostasis during cold Claire Chevalier, 1,2,8 Ozren Stojanovic, .2.,8 Didier J. Colin, Nicolas Suarez- Zamorano, 1,21 Tarallo, 1.2 Christelle Veyrat-Durebex, 2 Dorothee Rigo, 2 Salvatore Fabbiano, ,2 Ana Stevanovic, ,2 Hagemann, 4 Xavier Montet, Yann Seimbille, 3 Nicola Zamboni, Siegfried Hapfelmeier, and Mirko Trajkovski",2, 7. Department of Cell Physiology and Metabolism, Centre Medical Universitaire(CMU), Faculty of Medicine, University of Geneva, 1211 Diabetes Centre, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland cEntre for BioMedical Imaging(CIBM), Geneva University Hospitals, 1211 Geneva, Switzerland aInstitute for Infectious Diseases, University of Bem, 3010 Bern, Switzerland SDivision of Radiology, Geneva University Hospitals, 1211 Geneva, Switzerland iNstitute for Molecular Systems Biology, Swiss Federal Institute of Technology(ETH) Zurich, 8093 Zurich, Switzerland "Division of Biosciences, Institute of Structural and Molecular Biology University College London(UCL, London WClE 6BT, UK 8Co-first author Correspondence: mirko trajkovski@unige. ch http://dx.doi.org/10.1016/.cell.2015.11.004 SUMMARY leads to elevated intracellular cyclic AMP (Cannon and Neder gaard, 2004) Young et al., 1984). The BAT is present at distinct Microbial functions in the host physiology are a result anatomical sites, including the interscapular, perirenal, and axil- of the microbiota- host co-evolution We show that lary depots. brown fat cells also emerge in subcutaneous WAT cold exposure leads to marked shift of the microbiota (SAT)(known as"beige"cells)in response to cold or exercise composition, referred to as cold microbiota. Trans- Cousin et al, 1992)(Guerra et al 2001), a process referred to plantation of the cold microbiota to germ-free mice as wAT browning. Loss of BAT function is linked to obesity is sufficient to increase insulin sensitivity of the and metabolic diseases (owell et al.,1993).Promotion of host and enable tolerance to cold partly by promot- increased BAT development, on the other hand, increases EE without causing dysfunction in other and is associated ing the white fat browning, leading to increased en- with a lean and healthy phenotype(Ghorbani et al.1997; Guerra ergy expenditure and fat loss. During prolonged et al, 1998; Kopecky et al, 1995), suggesting the manipulation of cold, however, the body weight loss is attenuated, the fat stores as an important therapeutic objective caused by adaptive mechanisms maximizing caloric The gastrointestinal tract is the body's largest endocrine organ uptake and increasing intestinal, villi, and microvilli that releases a number of regulatory peptide hormones that influ- lengths. This increased absorptive surface is trans- ence many physiological processes(Badman and Flier, 2005) ferable with the cold microbiota, leading to altered The intestinal epithelium undergoes rapid self-renewal fueled intestinal gene expression promoting tissue remod- by multipotent Lgr5-expressing stem cells located in the crypts eling and suppression of apoptosis-the effect of Lieberkuhn and is terminated by apoptosis/exfoliation of diminished by co-transplanting the most cold-down regulated strain Akkermansia muciniphila during the (Sato et al., 2009). At the apical surface, the epithelial cells cold microbiota transfer. Our results demonstrate the have microvilli that further substantially increase the absorptive area and mediate the secretory functions. The intestinal micro- microbiota as a key factor orchestrating the overall biota co-develops with the host, and its composition is influ- energy homeostasis during increased demand enced by several physiological changes (Koren et al., 2012 Liou et al., 2013: Ridaura et al., 2013). The colonization starts INTRODUCTION immediately after birth and is initially defined by the type of de- livery and early feeding. After 1 year of age, the intestinal mi- Food intake, energy expenditure(EE, and body adiposity are ho- crobiota is already shaped and stabilized but continues to be meostatically regulated, and malfunctions of this balance can influenced by environmental factors including diet (Sekirov cause obesity(Murphy and Bloom, 2006)(Farooqi and O'Rahilly, et al., 2010). A wide range of pathologies have been associated 005). Mammalian white adipose tissue(WAT) is an important with alterations of the gut microbial composition(e. g, asthma regulator of the whole body homeostasis that stores energy in arthritis, autism, or obesity)(Sommer and Backhed, 2013).The form of triglycerides (TGs). The brown adipose tissue(BAT) intestinal microbiota can also influence the whole-body meta- catabolizes lipids to produce heat, function mediated by the tis- bolism by affecting energy balance(Backhed et al, 2004) ue-specific uncoupling protein 1(Ucp1)abundantly present in (Chou et al., 2008)(Turnbaugh et al., 2006)(Koren et al., 2012) the BAt mitochondria. bat differentiation can be induced by (Ridaura et al., 2013). The mechanisms and the nature of the prolonged cold exposure and beta-adrenergic stimulation that phenotypic and morphological changes that regulate the energy 360 Cell 163. 1360-1374 December 3. 2015 2015 Elsevier Inc.Article Gut Microbiota Orchestrates Energy Homeostasis during Cold Claire Chevalier,1,2,8 Ozren Stojanovic, ! 1,2,8 Didier J. Colin,3 Nicolas Suarez-Zamorano,1,2 Valentina Tarallo,1,2 Christelle Veyrat-Durebex,1,2 Dorothe´ e Rigo,1,2 Salvatore Fabbiano,1,2 Ana Stevanovic, ! 1,2 Stefanie Hagemann,4 Xavier Montet,5 Yann Seimbille,3 Nicola Zamboni,6 Siegfried Hapfelmeier,4 and Mirko Trajkovski1,2,7,* 1Department of Cell Physiology and Metabolism, Centre Me´ dical Universitaire (CMU), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland 2Diabetes Centre, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland 3Centre for BioMedical Imaging (CIBM), Geneva University Hospitals, 1211 Geneva, Switzerland 4Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland 5Division of Radiology, Geneva University Hospitals, 1211 Geneva, Switzerland 6Institute for Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland 7Division of Biosciences, Institute of Structural and Molecular Biology, University College London (UCL), London WC1E 6BT, UK 8Co-first author *Correspondence: mirko.trajkovski@unige.ch http://dx.doi.org/10.1016/j.cell.2015.11.004 SUMMARY Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Trans￾plantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promot￾ing the white fat browning, leading to increased en￾ergy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is trans￾ferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remod￾eling and suppression of apoptosis—the effect diminished by co-transplanting the most cold-down￾regulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand. INTRODUCTION Food intake, energy expenditure (EE), and body adiposity are ho￾meostatically regulated, and malfunctions of this balance can cause obesity (Murphy and Bloom, 2006) (Farooqi and O’Rahilly, 2005). Mammalian white adipose tissue (WAT) is an important regulator of the whole body homeostasis that stores energy in form of triglycerides (TGs). The brown adipose tissue (BAT) catabolizes lipids to produce heat, function mediated by the tis￾sue-specific uncoupling protein 1 (Ucp1) abundantly present in the BAT mitochondria. BAT differentiation can be induced by prolonged cold exposure and beta-adrenergic stimulation that leads to elevated intracellular cyclic AMP (Cannon and Neder￾gaard, 2004) (Young et al., 1984). The BAT is present at distinct anatomical sites, including the interscapular, perirenal, and axil￾lary depots. Brown fat cells also emerge in subcutaneous WAT (SAT) (known as ‘‘beige’’ cells) in response to cold or exercise (Cousin et al., 1992) (Guerra et al., 2001), a process referred to as WAT browning. Loss of BAT function is linked to obesity and metabolic diseases (Lowell et al., 1993). Promotion of increased BAT development, on the other hand, increases EE without causing dysfunction in other tissues and is associated with a lean and healthy phenotype (Ghorbani et al., 1997; Guerra et al., 1998; Kopecky et al., 1995), suggesting the manipulation of the fat stores as an important therapeutic objective. The gastrointestinal tract is the body’s largest endocrine organ that releases a number of regulatory peptide hormones that influ￾ence many physiological processes (Badman and Flier, 2005). The intestinal epithelium undergoes rapid self-renewal fueled by multipotent Lgr5-expressing stem cells located in the crypts of Lieberkuhn and is terminated by apoptosis/exfoliation of terminally differentiated cells at the tips of small intestinal villi (Sato et al., 2009). At the apical surface, the epithelial cells have microvilli that further substantially increase the absorptive area and mediate the secretory functions. The intestinal micro￾biota co-develops with the host, and its composition is influ￾enced by several physiological changes (Koren et al., 2012; Liou et al., 2013; Ridaura et al., 2013). The colonization starts immediately after birth and is initially defined by the type of de￾livery and early feeding. After 1 year of age, the intestinal mi￾crobiota is already shaped and stabilized but continues to be influenced by environmental factors including diet (Sekirov et al., 2010). A wide range of pathologies have been associated with alterations of the gut microbial composition (e.g., asthma, arthritis, autism, or obesity) (Sommer and Ba¨ ckhed, 2013). The intestinal microbiota can also influence the whole-body meta￾bolism by affecting energy balance (Ba¨ ckhed et al., 2004) (Chou et al., 2008) (Turnbaugh et al., 2006) (Koren et al., 2012) (Ridaura et al., 2013). The mechanisms and the nature of the phenotypic and morphological changes that regulate the energy 1360 Cell 163, 1360–1374, December 3, 2015 ª2015 Elsevier Inc