Of Microbes and Men

In this issue of Diabetes Care, Simon et al. (1) report the results of a study testing the hypothesis that the administration of Lactobacillus reuteri in subjects without diabetes improves insulin sensitivity. A quick review of the background may help us put this work in context. Our digestive tract hosts some 2 kg of microbes, made up of ;100 trillion microorganisms. Present in sparse colonies in the upper intestine, this indigenous microbial community (microbiota) jams into the cecum, colon, and rectum; the appendix is the ultimate shelter when antibiotics wage a mass killing. The taxonomy lists hundreds of species of bacteria (and minority groups of yeasts and viruses), whose collective genome is called microbiome (ninefold larger than our genome). Having coevolved with Homo sapiens, these microbes are so adapted to the human gut environment that they do not grow in culture as easily as do other germs and are therefore identified by their genetic material that is usually retrieved from feces. Microbiota have long been known to train our immune system, process indigestible foodstuffs, manufacture vitamins, andbreakdown toxins andmedications. In the past decade, variants of gut microbiome have been associated with diverse human diseases ranging from enterocolitis to psychiatric disorders. Of special interest to us is the association with obesity (2) and diabetes, both type 2 (3) and type 1 (4). While learning that the ratios of Bacteroidetes to Firmicutes and of Bacteroides-Prevotella to Clostridium coccoides-Eubacterium rectale correlate with plasma glucose concentration (3) is neither immediately telling nor particularly exciting, the general questions, what are the mechanisms underlying these associations and whether the gut microbiota may be a vehicle of treatment, are relevant. In obesity, for example, the microbiome is enriched with genes encoding enzymes that break down indigestible dietary polysaccharides, thereby extracting more energy from nutrients; this heightened efficiency of caloric retention may contribute to obesity (2). Additional mechanisms involve changes in intestinal permeability to endotoxins (e.g., lipopolysaccharide [5]) and bile acid signaling (6). Whether the obese microbiome is a cause or consequence of obesity remains to be decided. In a heroic (for the participants) proof-of-concept study, Vrieze et al. (7) infused fecalmicrobiota from lean, insulinsensitive donors into the duodenum of obese subjects with metabolic syndrome and showed that this supplementation improved their insulin sensitivity. This approach, which has been used clinically to manage recurrent Clostridium difficile infection (8), is a less palatable application of a time-honored general theory, that of probiotics. Over a century ago, Metchnikoff (9) postulated that the ingestion of some microorganisms had beneficial effects for a variety of human ailments essentially by replacing pathogenic intestinal flora. Sufficient to convince my motherd who in my childhood would suavely but firmly dispense a preparation of Lactobacillus following enteritis or a course of antibioticsdthe evidence supporting the theory is still unconvincing on systematic scrutiny (10). However, it is interesting that Lactobacillusda genus of gram-positive, acid-producing bacteria with over 60 different speciesdhas been consistently popular as a nutraceutical product. Perhaps this preference is some carryover from the circumstance that Lactobacilli are the first colonizers of germ-free neonates as they pass through the birth canal and ingest the first maternal milk. Simon et al. (1) conducted a placebocontrolled randomized trial of L. reuterid two oral doses of 10 Lactobacilli per daydadministered for 4 weeks to participants without diabetes who were either lean (BMI 19–25 kg/m) or obese (BMI 30–45 kg/m). A number of physiological end points were measured: energy expenditure and substrate oxidation rates (by indirect calorimetry), gastric emptying (by [C]octanoic acid breath test), oral glucose tolerance (by