There are complex links between the gut microbiota and obesity [1]. Obese individuals who are on low-carbohydrate or low-calorie diets (which depend mainly on fat intake) have a microbiota that changes over time to become similar to that of non-obese subjects [2]. In contrast, patients with tropical malnutrition or anorexia nervosa have a different microbiota that differs from those of obese individuals controls [3]. The nature of the changes of the intestinal microbiota associated with obesity is a subject of controversy. Gordon and his team reported a decrease of Bacteroidetes in the gut microbiota of obese study participants compared to non-obese participants. This work had been challenged in a large study that found three enterotypes but no connection between the gut microbiota and obesity [4]. Another large study found a decrease in the biological diversity of the gut microbiota of the obese patients compared to the non-obese subjects [5]. These contrasting data suggest that gut microbiota studies may suffer from biases that lead to differences in the analyses, including those originating from the same laboratory [4, 5]. These discrepancies are partly due to subject selection, the evolution of molecular techniques, DNA extraction and amplification methods, and sequencing technologies. This is highlighted by the hiatus between the morphological observation and molecular analysis or analyses by microbial culture of patient stool samples [6]. We also believe that a significant part of the problem results from the fact that fecal analysis is not the optimal method to examine the link between obesity and gut flora [6]. In the duodenum and jejunum, the bacterial concentration is relatively low, between 10 and 10/ml, much less than that of stools that can reach 10/ml. The bacterial composition is also very different between the two sites. The anaerobic/aerobic bacteria ratio in the feces is much higher than it is in the small intestine. Surprisingly, few studies have used pyrosequencing to study the bacterial content of the jejunum and ileum, and no such studies have been performed in obese patients despite the fact that the small intestine is thought to play a critical role in the uptake of food calories [7]. Moreover, the diet that is most often associated with weight gain does not appear to be the complex carbohydrates that the Bacteroidetes break down in the colon [8]. Instead, the food intake of overweight subjects often includes simple sugars, such as glucose and sucrose, that are readily and completely taken up in the small intestine. Another readily digestible carbohydrate that is abundant in the diet of overweight subjects is starch; this carbohydrate is also broken down efficiently via salivary and pancreatic amylases and by intestinal maltases and isomaltases. The microbial flora of the colon therefore has little impact in the absorption of glucose, sucrose and starch [7]. Lipids, particularly triglycerides, are also essential contributors to weight gain, but these are also fully absorbed in the small intestine. Therefore, the colonic flora is unlikely to play a significant role in the absorption of fatty acids (Fig. 1a). The manipulation of the gastrointestinal microbiota by probiotics or antibiotics may be accompanied by weight gain in humans (children or adults), farm animals, and laboratory animals [1, 8]. Antibiotics have also been used D. Raoult (&) Unite des Rickettsies, URMITE, UMR 7278, CNRS 6236, IRD 198, Faculte de Medecine, Aix-Marseille Universite, Marseille, France e-mail: didier.raoult@gmail.com