Allison Tracy is a Chemicals Policy Fellow. EDF Health Scientist Dr. Jennifer McPartland and Senior Scientist Dr. Richard Denison contributed to this post.
When you’re standing at the kitchen counter this holiday season wrestling with the nebulous world of weight gain, think about synthetic chemicals. A good number of them are in you. And studies show that some of them are pretty busy in there, interacting with various biological systems – including your metabolism.
But they’re not the only show in town. Microbes are busy in your gut doing important things like digesting food and degrading harmful compounds. But could they also influence the size of your love handles? New science suggests that these microbes—in concert with certain chemicals—may have just this effect.
It is becoming increasingly clear that it’s not just your genes and your self control that determine your risk for obesity and related complications like diabetes. Environmental factors are a big part of the equation, and those factors just might extend to synthetic chemicals to which you’re exposed, such as the flame retardants in your furniture and the plasticizers in food can linings.
A review by Suzanne Snedeker and Anthony Hay in Environmental Health Perspectives summarizes recent research on how the interplay between two environmental factors – the microbial community in your gut (your “microbiome”) and exposure to synthetic chemicals – may relate to a set of diseases and disorders that are on the rise. The authors pose their hypothesis right in the title of the article: “Do Interactions between Gut Ecology and Environmental Chemicals Contribute to Obesity and Diabetes?”
Our last post on the microbiome described some of this interplay: the effects of our resident microbial community on chemical metabolism, that is, how intestinal processing of ingested chemicals by gut microbes can make them more – or less – bioavailable or toxic. Snedeker and Hay’s review focuses on how these same factors may be tied to specific disease outcomes: obesity and diabetes.
Now, it is generally accepted that both genetic and behavioral or lifestyle factors contribute to the risk of developing obesity and diabetes, but we’re talking about a third potential factor here: the environment. Environmental contributors like the activity of bacteria in your gut microbiome and your exposure to synthetic chemicals haven’t been a part of the picture until very recently. Given the toll that these diseases take on both our health and our nation’s bank account, researchers should be assessing all potential factors.
In their review article, Snedeker and Hay cite various studies that address each of three crucial sets of links that are central to the hypothesis they proffer:
(1) the links between the microbiome and obesity and diabetes;
(2) the links between chemical exposures and obesity and diabetes; and
(3) the links between the microbiome, chemical exposure, and obesity and diabetes.
In this two-part post, we take a brief look at some of the major studies cited in the review that support these three intriguing relationships. This first part will discuss the first two links while the second part will discuss the third. Because there are fewer data on the third set of links – the combined influence of the microbiome and chemical exposures – Snedeker and Hay use this section to provide suggestions for filling data gaps.
The research supporting these relationships frequently points to emerging and still-contentious dimensions of toxicology, such as the roles of individual variability, low-dose effects, and timing of exposure. Each of the three sections will include information being gleaned on these emerging concepts.
The first link: the microbiome, obesity, and diabetes
The first section of the review article describes studies that indicate a bidirectional connection between obesity, diabetes, and the microbiome, lending support to the following findings:
#1: Obesity and diabetes alter the composition of the microbiome in people
In 2010, researchers in Italy identified specific metabolites in the urine of obese, insulin-resistant people and compared them to metabolites from non-obese participants (the control group). Most of the metabolites they looked at were products of microbial activity. Notably, they found that the two groups have distinct microbial metabolite profiles, each providing a signature of sorts. The study also looked at changes in the metabolite profiles of obese individuals who underwent bariatric surgery, finding that their microbial metabolite signature changed from that of an obese person to that of a lean person! Snedeker and Hay reference several studies in support of the idea that weight-loss surgery changes the composition of the gut microbiome.
Another study from 2006 characterized the gut microbial community in lean and obese people by comparing the ratios of different phyla of microbes present in each group’s gut. This ratio was consistently different, another indication of a microbiome-based signature for obesity and diabetes.
#2: Microbiome transplants can lead to obesity in mice
One intriguing way to study the effects of the gut microbiome is to transfer microbiota from “conventional” mice to “germ free” mice (a breed of mice that do not have a microbiome of their own). Scientists have found that this transfer leads to weight gain and insulin resistance in the receiving mice, which corroborates other findings that the absence of a microbiome seems to have a protective effect against weight gain and insulin resistance. Moreover, a 2006 study shows that the receiving germ-free mouse follows the phenotype of the donor mouse: it becomes obese if the donor was obese and lean if the donor was lean.
A study from 2010 provides an explanation for why germ-free mice remain lean despite consuming the same, high-fat diet as mice with a microbiome: they absorb fewer calories and excrete more fat. The germ-free mice also had healthier cholesterol levels and demonstrated increased insulin sensitivity. That is, they were better able to use insulin to harvest energy from glucose, a form of sugar that the body produces from the food it ingests. Reduced insulin sensitivity, or “insulin resistance”, which compromises the body’s ability to use glucose, can lead to Type II diabetes.
Findings are not all consistent, however: Another 2010 study found no differences when both conventional and germ free mice are fed low-fat diets; in fact, it found that, with a high-fat diet, “germ free” status exacerbates weight gain. This study argues against the concept of a protective effect of a germ-free gut.
In a different approach to this same question, a 2008 study asked whether transforming conventional mice into germ-free mice affects their metabolism. The study used antibiotics to eliminate the gut microbiome from obese mice and found that physiological conditions linked to diabetes were ameliorated after only two weeks.
Although there are conflicting results, there is clearly something very interesting going on here and further research is needed to sort out the details.
#3: Changes to the microbiome influence satiety in humans
Studies on people have found that prebiotics, supplements that are intended to beneficially alter the microbiome, can lead to a feeling of being full (the technical term is “satiety”). For example, a recent study suggests that prebiotics can curb one’s appetite by increasing the concentrations of chemical messengers that are involved in signaling satiety.
#4: Environmentally-mediated changes in the microbiome can predispose fetuses and newborns to obesity
In a 2008 study, a team of Finnish and Spanish researchers compared the microbial gut composition of pregnant women who had different body mass indexes (BMIs), weights, and degrees of weight gain during pregnancy. They found that variation in each of these three features correlated with different microbial phyla in the gut. In a follow up study in 2010, the same team studied infants at one month and six months of age, concluding that the compositions of their microbiomes varied based on the BMIs, weights, and weight gain of their mothers during pregnancy. In conjunction with a separate study that found a correlation between the composition of the microbiome in infants and weight gain in later years, these results suggest that obesity in pregnant women affects the microbiomes of their children so as to predispose them toward obesity.
While these studies paint a compelling picture of the microbiome’s potential effect on obesity and diabetes, Snedeker and Hay urge caution in over-interpreting these results and emphasize the need for further research.
The second link: chemicals, obesity, and diabetes
The role that chemical exposures may play in influencing the risk of developing obesity and diabetes is the second link explored in the review article. Chemicals that mimic natural messengers for controlling our bodies’ energy stores (i.e., certain hormones) are the most problematic. My colleague, Jennifer McPartland, blogged on “obesogens” earlier this year, but Snedeker and Hay also look at the effects of “diabetogens.”
While there are several epidemiological studies correlating certain chemicals exposures with obesity and diabetes, studies providing mechanistic insights are probably the most convincing. Highlighted below are a few of the strongest of these studies.
A strong correlation between arsenic exposure and Type II diabetes has been found in the human population. Additional research has identified specific mechanisms underlying this relationship. For example, arsenic has been shown to interfere with the ability of the pancreas to regulate insulin in studies using rat cells. Impaired insulin regulation is a telltale sign of diabetes.
Tributyltin (TBT) is an important chemical of focus in research on obesogens. By binding to certain cellular receptors, TBT is able to affect the fate of differentiating stem cells. Specifically, TBT exposure can cause stem cells to differentiate into fat cells instead of bone cells. This effect has been shown in stem cells derived from both mice and humans.
TBT was initially identified as a developmental obesogen because exposure of rodents during pregnancy yielded pups that were predisposed to obesity and diabetes. A team of Chinese scientists found that exposure to TBT during puberty also predisposed mice towards weight gain. This effect was seen at an extremely low dose of 5 micrograms per kilogram. Snedeker and Hay note that researchers are trying to determine what environmental doses of TBT are relevant for humans.
A 2008 study on the class of flame retardants called polybrominated diphenylethers (PBDEs) and a 2010 study on persistent organic pollutants (POPs) reveal that even low-dose exposure to a chemical can carry consequences. The study of POPs found that exposure to low concentrations of polychlorinated biphenyls (PCBs), trans-nonachlor, oxychlordane, mirex, and a polybrominated biphenyl (PBB) put people at greater risk for diabetes.
Taken together, these studies show the importance of considering the timing of exposure and the potential for low-dose effects in toxicological studies. Further research is needed on these emerging concepts.
#3: Bisphenol A (BPA)
BPA and other endocrine-disrupting chemicals appear able to influence the differentiation of stem cells into fat cells by binding to glucocorticoid receptors inside the cells. These effects are seen even at very low doses of BPA, as is expected if these chemicals are acting like hormones. In addition, a 2008 in vitro study of human cells indicates that BPA may influence insulin regulation, again at low doses.
Snedeker and Hay acknowledge that the results vary across different species, genders, and routes of exposure. Although the studies’ findings may be greeted with skepticism in some camps because of the variability in results, the differences could be an indication of the complexity of the interaction rather than shortcomings in the studies.
Drawing conclusions from studies that identify correlations between exposure to synthetic chemicals and outcomes such as obesity and diabetes needs to be approached with caution, of course. In addition to the fact that mechanistic data are often lacking, Snedeker and Hay note that not all PCBs, all PBDEs or all phthalates have positive associations with these diseases.
Stay tuned for the second part of this post, which will focus on the links between the microbiome, chemical exposures, and obesity and diabetes.