LETTER TO THE EDITOR Gut microbiota and metabolic diseases: myth or reality?

Microorganisms inhabiting human gastro-intestinal tract exceed the overall number of eukaryotic cells of about one order of magnitude [1–4]. Among the estimated 500–1,000 species [3], the majority has an unknown function, is neither beneficial nor harmful to host and represents the so-called ‘‘normal flora’’ or ‘‘microbiota’’ [5]. Noteworthy, the development of ‘‘next-generation’’ sequencing techniques, as part of the so-called ‘‘Omics’’, provided an holistic investigation allowing the study of the totality of gut microbiota, avoiding the need for lab-cultivation. These new molecular approaches opened the route toward a deeper investigation of the relationship between gut microbiota and host metabolism, focusing on multiple sides. Nowadays, Metagenomics [6, 7], Metatranscriptomics, Metabolomics [8] and Proteomics [9, 10] allow the study of gut microbiota genome, transcriptome and its impact on host metabolic profiles, respectively. In the last decade, an increasing attention has been paid on gut microbiota, given its involvement in functions other than digestion, as the etiology of inflammatory bowel diseases [11–13], autoimmunity [14–16], allergy [17] and even cancer [2]. However, the inner relationship between gut microbiota and host metabolism has been extensively investigated especially focusing on metabolic diseases [5, 18], even if the molecular actors underlying this inner link are yet to be fully understood. Gordon’s team performed pioneering studies using axenic (germfree) mice as a powerful model to study the impact of gut microbiota. Albeit these mice represent a non-physiologic model since the lack of gut microbiota impairs gut physiology [19], it has been shown that the establishment of a gut flora by colonization of axenic recipient mice with gut microbiota from donor mice is able to reverse this phenotype [20]. In addition, axenicity makes these mice resistant to dietinduced obesity, through a mechanism involving the enzyme lipoprotein lipase (LPL) and its inhibitor, the intestinal Fasting-induced adipocyte factor (Fiaf), which is over-activated in germfree conditions. This results in a diminished capacity to harvest energy from nutrients [21]. Gut microbiota ecology has been shown as deeply unbalanced in relation to metabolic diseases and on the top of it, obesity. The division of Firmicutes, a major phylum of gut microbiota in adulthood [22], has been positively correlated to body weight gain and obesity [23, 24]. Conversely, the division of Bacteroidetes, the second most represented phylum of gut bacterial ecology, characterizes a lean phenotype, both in humans and mice [23, 24]. Gordon’s team was even the first to show the transmissibility of obesity by transferring its microbial component (gut microbiota issued from obese mice) into axenic recipient and showing an increased adipose tissue development when compared to recipient mice colonized with gut microbiota issued from lean mice [25]. However, metabolic diseases are always associated with a low-grade chronic inflammation in metabolically active tissues [26, 27]. Therefore, in the quest of a missing link between gut microbiota and inflammation, Burcelin’s team was the first to link inflammation to intestinal microbiota and metabolic diseases by showing that an increase in lipopolysaccharides (LPS) plasma levels (referred to as ‘‘metabolic endotoxemia’’) was the initiator of metabolic M. Serino (&) R. Burcelin Institut National de la Santé et de la Recherche Médicale (INSERM), U858, Toulouse, France e-mail: [email protected]