Ampicillin has been shown to improve glucose tolerance in mice. We hypothesized that this effect is present only if treatment is initiated prior to weaning and that it disappears when treatment is terminated. High-fat fed C57BL/6NTac mice were divided into groups that received Ampicillin at different ages or not at all. We found that both diet and Ampicillin significantly changed the gut microbiota composition in the animals. Furthermore, there was a significant improvement in glucose tolerance in Ampicillin-treated, five-week-old mice compared to nontreated mice in the control group. At study termination, expressions of mRNA coding for tumor necrosis factor, serum amyloid A, and lactase were upregulated, while the expression of tumor necrosis factor (ligand) superfamily member 15 was downregulated in the ileum of Ampicillin-treated mice. Higher dendritic cell percentages were found systemically in high-fat diet mice, and a lower tolerogenic dendritic cell percentage was found both in relation to high-fat diet and late Ampicillin treatment. The results support our hypothesis that a “window” exists early in life in which an alteration of the gut microbiota affects glucose tolerance as well as development of gut immunity and that this window may disappear after weaning. 1. Introduction Type 2 diabetes (T2D) is an increasingly omnipresent disease not only in the western world but also in many of the fastest developing third world countries [1]. It is caused by peripheral insulin resistance and an insulin production unable to compensate [2]. During the past decade, gut microbiota composition has been in focus to unravel the enigma of such lifestyle diseases and their development [3]. In animal models, gut microbiota composition has been shown to influence the development of a variety of autoimmune and inflammatory diseases such as type 1 and type 2 diabetes, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, and a range of allergies [4]. Leptin-deficient obese mice that develop glucose intolerance have a significant reduction in Bacteroidetes and an increase in Firmicutes compared with their wild-type lean litter mates [5]. Furthermore, the obese phenotype from mice may be transplanted with the gut microbiota to germ-free wild-type mice [6]. Diet-induced obese (DIO) mice also exhibit a modified composition of the gut microbiota, endotoxemia, and an increased intestinal permeability [7]. Mechanistic explanations are still somewhat theoretical, and theories range from decreased early priming of intestinal regulatory T cells leading to
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