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 bacteria 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 capacity of the gut microbiota greatly exceeds the metabolic capacity of human cells. The theory of energy harvest Pioneering studies linking SCFAs and energy harvest. The complex and dynamic ecosystem of the gut microbiota contributes to the metabolism of various compounds, thereby leading to the production of numerous metabolites. In the early 2000s, pioneering studies from Gordon and colleagues 11 linked the production of specific 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 microbiota). 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 transferred 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 metabolism through a direct interaction with the digestive tract. Indeed, the germ-free mice exhibit a lower level of caecal SCFAs than

Variations in N-acylethanolamines (NAE) levels are associated with obesity and metabolic comorbidities. Their role in the gut remains unclear. Therefore, we generated a mouse model of inducible intestinal epithelial cell (IEC)-specific deletion of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), a key enzyme involved in NAE biosynthesis (Napepld∆IEC). We discovered that Napepld∆IEC mice are hyperphagic upon first high-fat diet (HFD) exposure, and develop exacerbated obesity and steatosis. These mice display hypothalamic Pomc neurons dysfunctions and alterations in intestinal and plasma NAE and 2-acylglycerols. After long-term HFD, Napepld∆IEC mice present reduced energy expenditure. The increased steatosis is associated with higher gut and liver lipid absorption. Napepld∆IEC mice display altered gut microbiota. Akkermansia muciniphila administration partly counteracts the IEC NAPE-PLD deletion effects. In conclusion, intestinal NAPE-PLD is a key sensor in nutritional adaptation to fat intake, gut-to-brain axis and energy homeostasis and thereby constitutes a novel target to tackle obesity and related disorders.

The past decade has been characterized by tremendous progress in the field of the gut microbiota and its impact on host metabolism. Although numerous studies show a strong relationship between the composition of gut microbiota and specific metabolic disorders associated with obesity, the key mechanisms are still being studied. The present review focuses on specific complex pathways as well as key interactions. For instance, the nervous routes are explored by examining the enteric nervous system, the vagus nerve, and the brain, as well as the endocrine routes (i.e., glucagon‐like peptide‐1, peptide YY, endocannabinoids) by which gut microbes communicate with the host. Moreover, the key metabolites involved in such specific interactions (e.g., short chain fatty acids, bile acids, neurotransmitters) as well as their targets (i.e., receptors, cell types, and organs) are briefly discussed. Finally, the review highlights the role of metabolic endotoxemia in the onset of metabolic disorders and the implications for alterations in gut microbiota‐host interactions and ultimately the onset of diseases.