REVIEW ARTICLE https://doi.org/10.1038/s42255-018-0017-4 1 Metabolism and Nutrition Research Group, WELBIO—Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium. 2 These authors contributed equally: P. D. Cani, M. Van Hul, C. Lefort, C. Depommier, M. Rastelli, A. Everard. *e-mail: patrice.cani@uclouvain.be Facts and figures on the gut microbiota The term microbiota refers to all the microorganisms present in the various ecosystems in the human body. Diverse communities of microorganisms are located throughout the human body, including the gut, lungs, vaginal and urinary tracts and skin. The microbiota is composed of several types of microbes: bacteria, archaea, viruses, phages, yeast and fungi 1 . Humans have constantly coevolved in the presence of these microorganisms, thereby establishing symbiotic relationships. Several lines of evidence suggest that in addition to bacteria, other types of microbes, such as fungi, protozoa and viruses, also have important interactions with the human in which they reside, referred to as the host in this review 2,3 . Nevertheless, interactions between bacteria and human cells have been studied the most and will be the focus of this review. The human body carries approximately 3.9 × 10 13 bacterial cells, with the largest amount residing in the large intestine: 10 11 bac- teria cells g –1 of wet stool 4 . At the most recent estimation, almost 10 million non-redundant microbial genes have been identified in the human gut 5 . This number is 150-fold higher than the number of genes in the human genome 6 . Therefore, the metabolic capac- ity of the gut microbiota greatly exceeds the metabolic capacity of human cells. Diversity and richness in the gut microbiome Importantly, in addition to analysing gut microbiota composi- tion, investigating bacterial genes (referred to as the microbiome) that are present in the host generates complementary information regarding the metabolic potential of the gut microbiota. In that context, it appears that the number of gut microbial genes (that is, the gene count) positively correlates with a healthy metabolic status. For example, individuals with low bacterial gene richness have increased adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype 7–9 . Similarly, it was recently proposed that the key microbiome signal associated with diseases such as Crohn’s disease is more of an overall modification of microbial cell counts rather than an alteration of the proportions of various microbes 10 . Therefore, study of the metabolic potential of the gut microbiota may elucidate potential interactions with the host. Of particular interest is the production of various gut microbiota compounds, such as metabolites. In this Review, we will focus on various gut microbial metabolites that are capable of interacting with the host via direct or indirect mechanisms and thereby influence host metabolism. The theory of energy harvest Pioneering studies linking SCFAs and energy harvest. The com- plex and dynamic ecosystem of the gut microbiota contributes to the metabolism of various compounds, thereby leading to the pro- duction of numerous metabolites. In the early 2000s, pioneering studies from Gordon and colleagues 11 linked the production of spe- cific metabolites, such as short-chain fatty acids (SCFAs), to host energy homeostasis (Table 1). Bäckhed et al. 12 demonstrated the role of the gut microbiota in host energy metabolism and growth by showing that germ-free mice gained less body weight and fat mass than conventionalised mice (that is, those harbouring a gut micro- biota). This difference was observed despite increased food intake in germ-free mice. The same group of researchers found that the microbiota of genetic obese mice (ob/ob) harvests more energy than their lean ob/+ counterparts. In addition, this phenotype was trans- ferred in germ-free mice transplanted with the microbiota from the obese donors 11 . Initially, the hypothesis was that this shift provided more SCFAs (acetate, propionate, butyrate and lactate) that could be used as metabolic substrates by the host (Fig. 1). In addition, it was suggested that the gut microbiota contributed to energy metabo- lism through a direct interaction with the digestive tract. Indeed, the germ-free mice exhibit a lower level of caecal SCFAs than Microbial regulation of organismal energy homeostasis Patrice D. Cani 1,2 *, Matthias Van Hul 1,2 , Charlotte Lefort 1,2 , Clara Depommier 1,2 , Marialetizia Rastelli 1,2 and Amandine Everard 1,2 The gut microbiome has emerged as a key regulator of host metabolism. Here we review the various mechanisms through which the gut microbiome influences the energy metabolism of its host, highlighting the complex interactions between gut microbes, their metabolites and host cells. Among the most important bacterial metabolites are short-chain fatty acids, which serve as a direct energy source for host cells, stimulate the production of gut hormones and act in the brain to regulate food intake. Other microbial metabolites affect systemic energy expenditure by influencing thermogenesis and adipose tissue browning. Both direct and indirect mechanisms of action are known for specific metabolites, such as bile acids, branched chain amino acids, indole propionic acid and endocannabinoids. We also discuss the roles of specific bacteria in the production of specific metabo- lites and explore how external factors, such as antibiotics and exercise, affect the microbiome and thereby energy homeostasis. Collectively, we present a large body of evidence supporting the concept that gut microbiota-based therapies can be used to modulate host metabolism, and we expect to see such approaches moving from bench to bedside in the near future. NATURE METABOLISM | VOL 1 | JANUARY 2019 | 34–46 | www.nature.com/natmetab 34