Insights Into the Role of the Microbiome in Obesity and Type 2 Diabetes

Annick V. Hartstra; Kristien E.C. Bouter; Fredrik Bäckhed; Max Nieuwdorp


Diabetes Care. 2015;38(1):159-165. 

In This Article

Diagnostic Value of Intestinal Microbiota in T2DM

Although bacteria are usually considered as pathogens, an essential symbiotic interaction between the human host and intestinal bacteria is the forging and maintenance of the immune system in the gut. The first recognition came from findings in germ-free (GF) mice of defects in the development and function of their immune system.[8] Another crucial interaction of gut microbiota is their endogenous metabolic function that enables the digestion of food components such as plant polysaccharides, which are otherwise nondegradable.[9] In this respect, it is interesting that studies in mice as well as humans have shown that gut microbiota differ in composition between obese and lean subjects.[10,11] In a leptin-deficient ob/ob mouse model Ley et al.[10] found a difference in the ratio of Bacteroidetes and Firmicutes, the two dominant intestinal bacterial phyla. Compared with their lean counterparts, obese mice showed a decrease in Bacteroidetes and a corresponding increase in Firmicutes.[10] When Ley et al.[10] compared gut microbiota of obese humans to lean controls, they found similar differences in this ratio.[12] Other studies in mice have corroborated these results.[13][16] However, other human studies have found contradicting data,[17][19] and it is considered that part of this controversy results from both the variations in diet composition around the globe as well as different methods used to determine microbiota composition.

The involvement of the microbiome in energy balance was further demonstrated in a study where it was found that GF mice were leaner compared with conventionally raised counterparts, despite a higher food intake. Additionally, when transferring intestinal bacteria from normal mice to GF counterparts, an increase in body fat of 60% was observed within 10–14 days, even though food consumption was decreased.[20] These results have led to the belief that the obese microbiome is more efficient at yielding energy from the diet.[11,17] This was supported by findings that the total body fat of GF mice colonized with "obese microbiota" increased significantly compared with those colonized with "lean microbiota".[11] The technique used in these studies in mice is known as fecal microbiota transplantation (FMT). In humans, FMT can be regarded as a working tool to dissect association from causality for a number of diseases.[21] The first clinical use was the successful treatment of patients with pseudomembraneous colitis, an unremitting infection with Clostridium difficile usually following the use of antibiotics.[22] Since then, FMT has been found effective in other chronic gastrointestinal infections and inflammatory bowel diseases, its therapeutic potential being attributed to a restoring ability of the gut microbial balance by replacing pathogens with more beneficial bacterial strains.[21,23] Considering the promising results of the effects of FMT on metabolism in mice, a current interest in the clinical use of FMT for humans is focusing on metabolic and cardiovascular disorders. We recently performed a double-blind randomized controlled trial in insulin-resistant males with metabolic syndrome, who received either autologous or allogenic feces infusion from lean donors.[24] Beneficial metabolic effects were observed in the group receiving the lean donor transplantation, including a significantly improved peripheral (muscle) insulin sensitivity. This was accompanied by a significantly increased intestinal microbial diversity, along with a distinct increase in levels of butyrate-producing bacteria, such as Roseburia in the feces and Eubacterium halii in the small intestine. Interestingly, not all lean donors exerted the same beneficial effects in the obese host. Based on the small sample size, however, one should take into account that the reported effect might be due to a variation around a mean (meaning no clear effect of lean donor FMT when larger numbers of individuals are studied). On the other hand, these findings might indicate the presence of "super fecal donors," a concept that is currently being studied at our departments. The results from this relatively small cohort of patients with metabolic syndrome on the relation between microbial diversity and amount of butyrate-producing bacteria are in line with similar findings in two large metagenome-wide association studies,[25,26] a type of study where clinical data are combined with metagenomic analysis. Both Karlsson et al.[25] and Qin et al.[26] independently found a decrease of butyrate-producing bacteria, namely Roseburia and Faecalibacterium prauznitzii, in the gut microbiota of patients with T2DM compared with healthy subjects. Moreover, we showed that increases in fecal concentrations of Lactobacillus gasseri and Streptococcus mutans (both inhabitants of the proximal intestine) as well as Escherichia coli were found to be predictive of the development of insulin resistance in postmenopausal obese Caucasian females in Sweden (see Table 1). It should be noted, however, that these correlations are not very strong and have not been reproduced in other cohorts; moreover, it is not known at this time whether these found changes in intestinal microbiota composition are secondary to altered gastrointestinal motility and small intestinal bacterial overgrowth often seen in T2DM. Nevertheless, such intestinal bacterial strains might function as early diagnostic markers in the clinic for better identification of those obese subjects that are prone to develop T2DM.[26] To strengthen the predictive potential of particular patterns of microbial diversity and composition as well as pathogenic alterations of the microbiota composition, further research both in prospective cohorts and therapeutic phase I/II intervention trials with specific bacterial strains are urgently needed. In this respect, it is promising that an increasing number of companies are starting to appear that focus on the development of intestinal microbiome diagnostics and therapeutics.[27,28]