Aberrations in gut microbiota are associated with metabolic disorders, including obesity. However, whether shifts in the microbiota profile during obesity are a characteristic of the phenotype or a consequence of obesogenic feeding remains elusive. Therefore, we aimed to determine differences in the gut microbiota of obese-prone (OP) and obeseresistant (OR) rats and examined the contribution of this microbiota to the behavioral and metabolic characteristics during obesity. We found that OP rats display a gut microbiota distinct from OR rats fed the same high-fat diet, with a higher Firmicutes-toBacteroidetes ratio and significant genera differences. Transfer of OP but not OR microbiota to germ-free (GF) mice replicated the characteristics of the OP phenotype, including reduced intestinal and hypothalamic satiation signaling, hyperphagia, increased weight gain and adiposity, and enhanced lipogenesis and adipogenesis. Furthermore, increased gut permeability through conventionalization resulted in inflammation by proinflammatory nuclear factor (NF)-kB/inhibitor of NF-kB kinase subunit signaling in adipose tissue, liver, and hypothalamus. OP donor and GF recipient animals harbored specific species from Oscillibacter and Clostridium clusters XIVa and IV that were completely absent from OR animals. In conclusion, susceptibility to obesity is characterized by an unfavorable microbiome predisposing the host to peripheral and central inflammation and promoting weight gain and adiposity during obesogenic feeding.

Current fructose consumption levels often overwhelm the intestinal capacity to absorb fructose. We investigated the impact of fructose malabsorption on intestinal endocrine function and addressed the role of the microbiota in this process. To answer this question, a mouse model of moderate fructose malabsorption [ketohexokinase mutant (KHK)−/−] and wild‐type (WT) littermate mice were used and received a 20%‐fructose (KHK‐F and WT‐F) or 20%‐glucose diet. Cholecystokinin (Cck) mRNA and protein expression in the ileum and cecum, as well as preproglucagon (Gcg) and neurotensin (Nts) mRNA expression in the cecum, increased in KHK‐F mice. In KHK‐F mice, triple‐label immunohistochemistry showed major up‐regulation of CCK in enteroendocrine cells (EECs) that were glucagon‐like peptide‐1 (GLP‐1)+/Peptide YY (PYY−) in the ileum and colon and GLP‐1−/PYY− in the cecum. The cecal microbiota composition was drastically modified in the KHK‐F in association with an increase in glucose, propionate, succinate, and lactate concentrations. Antibiotic treatment abolished fructose malabsorption‐dependent induction of cecal Cck mRNA expression and, in mouse GLUTag and human NCI‐H716 cells, Cck mRNA expression levels increased in response to propionate, both suggesting a microbiota‐dependent process. Fructose reaching the lower intestine can modify the composition and metabolism of the microbiota, thereby stimulating the production of CCK from the EECs possibly in response to propionate.—Zhang, X., Grosfeld, A., Williams, E., Vasiliauskas, D., Barretto, S., Smith, L., Mariadassou, M., Philippe, C., Devime, F., Melchior, C., Gourcerol, G., Dourmap, N., Lapaque, N., Larraufie, P., Blottière, H. M., Herberden, C., Gerard, P., Rehfeld, J. F., Ferraris, R. P., Fritton, J. C., Ellero‐Simatos, S., Douard, V. Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism. FASEB J. 33, 7126–7142 (2019). http://www.fasebj.org