This morning at the EASD in Stockholm, I attended a session with the title, “Manipulating the Gut to Treat Metabolism”.
In the first presentation, Alberto Morabito (Italy) and colleagues discussed a meta-analysis showing the beneficial effect of bariatric surgery on cardiovascular mortality. However, as pointed out by many discussants, this data is confounded by lack of ransomised studies, poor controls, and other methodological shortcomings. Nevertheless, the impact of bariatric surgery on mortality is so obvious that it is difficult to doubt the positive effect.
Ji Yan and colleagues (Sweden) examined the effect of gastric bypass surgery on the methylation of various mediators of metabolic control measured in skeletal muscle biopsies. The researchers found changes in DNA methylation patterns of various genes, which can significantly alter their expression and function. Of course, as patients undergoing surgery also show profound changes in their dietary intake patterns, it is not clear from these studies whether or not the observed changes are indeed simply related to weight loss or other factors induced by surgery.
Sergio Vencio and colleagues (Brazil) examined the effect of ileal interposition on insulin secretion and insulin sensitivity in diabetic patients with a BMI less than 35. Improvements in glucose tolerance, insulin sensitivity, and both first and second-phase insulin secretion was markedly improved within the first few months after surgery (i.e. with minimal if any weight loss). The study shows that even diabetic patients below the current cut-offs for bariatric surgery (i.e. with a BMI less than 35) show marked improvements in metabolic control after gut surgery. Whether or not these improvements are related to changes in incretin secretion remains unclear but seems highly likely.
Claudia Ress and colleagues (Austria) examined the expression of Apo-lipoprotein 5 expression in liver biopsies before and after bariatric surgery. Despite an almost 6 pt drop in BMI units and a marked decrease in hepatic steatosis, there was no significant change in plasma lipids. However, Apo-5 expression in the liver was substantially decreased. Using in vitro knockdown of Apo-5, they also showed that reducing Apo-5 reduces intracellular triglyceride accumulation in liver cells – suggesting that this molecule may play a role in fatty liver disease.
But the most novel and intriguing studies were the following:
Thomas Adrian and colleagues (United Arab Emirates) presented data on the concept that a “bile salt brake” on the enteroendocrine L-cells in the distal gut (rectum) may provide a novel target for improving diabetes. These L-cells secrete GLP-1, PYY and oxyntomodulin, three gut peptides that all increase satiety. Interestingly, the release of these enterohormones is stimulated by bile salts, mediated through the TGR5 receptor. In a study involving 10 obese individuals with type 2 diabetes, the researchers demonstrated that rectal infusion of taurocholate (a bile salt) results in a dose-related increase in plasma levels of PYY and GLP-1 as well as a significant reduction in subsequent food intake (75 min after the end of the infusion). These observations not only prove the existence of the “bile salt brake” but also so that this system could possibly be harnessed to affect food intake and glucose metabolism (e.g. rectal TGR5 agonist suppositories, inhibition of ileal bile salt reabsorption, etc.).
And finally, in this session, Anne Vrieze and colleagues (Netherlands, France, Finland) presented a fascinating study on the transplantation of gut microbes from lean donors to obese subjects with the metabolic syndrome. Fecal transplantation has been previously assessed as a way to treat patients with recurrent clostridium difficile infections. In the present study, faeces from lean subjects (first screened for parasites and other infections) was “transplanted” to obese volunteers after bowel lavage. Controls consisted of “autotransplantation” of stool samples. While stool “allotransplanation” did not change weight, energy expenditure or body weight, it had a marked effect on systemic and hepatic insulin sensitivity and a marked decrease in plasma triglyceride level (the latter effect only lasted 12 weeks). Both faecal allo- and auto-transplantation was associated with a transient inflammatory response as measured by CRP levels. Obviously, at this time it is not clear which bacteria may be responsible for these effects or how this observation can be used to develop novel therapies for improving metabolic control – but the possibilities are truly intriguing.
Apart from the studies that I have blogged about before, readers may have seen the paper on twins published in NATURE earlier this year by Jeffrey Gordon and colleagues from Washington University School of Medicine, St Louis, MI showing that the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers showing that obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways.
In a paper, just out in Science Translational Medicine, Gordon and his colleagues provide new evidence that diets can modulate bacterial flora and that these changes can be associated with weight gain – at least in mice.
But these were special mice, grown to be germ-free and then colonized with human gut bugs.
Metagenomic analysis of the temporal, spatial, and intergenerational patterns of bacterial colonization showed that these “humanized” mice were stably and heritably colonized and reproduced much of the bacterial diversity of the human donor’s microbiota.
When these animal were switched from a low-fat, plant polysaccharide–rich diet to a high-fat, high-sugar “Western” diet, the structure of the microbiota changed within a single day, thereby also changing the representation of metabolic pathways in the microbiome.
A series of reciprocal “trans-colonization” experiments showed that although colonization history influences the initial structure of the microbial community, these effects can be rapidly altered by diet.
In summary, this latest study shows that humanized mice fed a “Western” diet have increased adiposity and that this trait is transmissible via microbiota transplantation.
The authors suggest that it may not be long before analyses of stool samples may soon provide a clinical test to determine people’s risk of developing excess weight.