Bone density and osteoporosis risk are not just determined by diet, exercise and genetics — tiny creatures that live in the intestinal tract exert their influence, too.
In fact, one day, scientists may be able to judge the risk of developing osteoporosis or breast cancer by analyzing bacterial strains that live in a particular person's gut.
Drs. Cara Frankenfeld and Johanna Lampe from the Public Health Sciences Division report that telltale markers of the presence of different strains of bacteria that can live in the human gut correlate with bone mineral density. This affects not only osteoporosis risk but may also be related to breast-cancer risk.
The study by Frankenfeld, who is now a Cancer Prevention Fellow at the National Institutes of Health, and Lampe — along with Public Health Science Division colleagues Wendy K. Thomas, Kristin LaCroix, Lynda McVarish, and Drs. Anne McTiernan, Victoria L. Holt, and Stephen M. Schwartz — was published online in July in the journal Maturitas.
Breaking down sex hormones, soy
Some scientists have suspected that intestinal bacteria influence bone density because these bacteria metabolize sex hormones like estrogen, and sex hormones are known to influence bone growth and function. Different people have different types of bacteria living in the gut, which means that their bodies may metabolize sex hormones differently and thus have different effects on bone density.
Intestinal bacteria also metabolize compounds called isoflavones, which are found mainly in soybeans. Isoflavones are phytoestrogens, which means that they're chemically similar to animal estrogens but instead come from plants. Because of this similarity, some researchers think that isoflavones may influence aspects of physiology — such as bone density — that are normally influenced by estrogens.
Previous work has shown that intestinal bacteria break soy isoflavones into two products, or metabolites, called O-desmethylangolensin (O-DMA) and equol. However, some people don't make these metabolites, which hints that their bodies don't harbor the bacterial strains necessary for isoflavone breakdown.
Because intestinal bacteria metabolize both isoflavones and sex hormones, and sex hormones have a known relationship to bone density, Frankenfeld, Lampe and their colleagues wanted to see if a woman's ability to break down isoflavones into equol or O-DMA correlates with her bone mineral density.
They studied this relationship in 92 postmenopausal women, ages 50 to 75. For three days, each woman ate either a soy bar or soy nuts and then took a urine sample.
The researchers analyzed the urine samples to determine whether each person had intestinal bacteria that produced O-DMA and equol metabolites. They found that 83 percent of the women in their study produced O-DMA and 26 percent produced equol. Some women produced only one metabolite, some produced both, and others produced neither.
Frankenfeld and Lampe then compared this information with each subject's bone mineral density, which had been measured using X-ray scans of the spine, ribs, arms, legs, pelvis and head.
They found that total bone mineral density was 6 percent greater in women who produced O-DMA than in those who did not. This means that women who have the intestinal bacteria that break down isoflavones into O-DMA have 6 percent denser bones, on average, than women whose bacteria don't perform this function. This discrepancy in bone density is large enough to make a discernible difference in postmenopausal women, according to the authors.
They didn't find the same relationship with equol — there was no association between equol-producing status and bone mineral density. When they took into account soy consumption, however, a correlation emerged. Among women who consumed soy regularly, those whose gut bacteria produced equol had about 10 percent lower bone density than those who didn't produce equol.
Breast density, cancer risk
It's difficult to know exactly what to make of this association, Frankenfeld said, because the number of women in their study who consumed soy regularly was very small: only 10 out of 92 women. None of these 10 women happened to be O-DMA producers, so they couldn't see if regular soy intake affected the influence of O-DMA status on bone density.
Because of the small size of the study, "we consider a lot of these data to be preliminary, hypothesis-generating," Lampe said.
In a study published in Cancer Epidemiology, Biomarkers & Prevention in 2004, Frankenfeld and Lampe found that these isoflavone-metabolizing gut bacteria were also related to breast density. Specifically, women who produce O-DMA have higher breast density than those who don't, and women who make equol have lower breast density than those who don't.
Estrogen levels in the body are thought to be related to bone density, breast density and risk of breast cancer. "Higher bone density is associated with higher breast-cancer risk, suggesting that lifetime exposure to estrogens, which helps to maintain your bones, also increases your breast-cancer risk," Lampe said.
Since O-DMA and equol are chemically similar to natural estrogens, it's reasonable to speculate that a person's ability to make these metabolites may affect the same processes as estrogens.
However, since the women in this study were mostly not regular consumers of soy, that's probably not what's going on here, Frankenfeld said. People who don't eat soybean products regularly probably don't have much of either O-DMA or equol circulating in their systems, even if their intestinal bacteria are capable of producing them.
Instead, Frankenfeld said, a woman's ability to make O-DMA or equol is likely a signal of what types of intestinal bacteria she has, and these different bacterial types may do other things differently, as well. It's possible, for example, that bacteria that metabolize soy isoflavones into equol also metabolize estrogens or other sex hormones in a different way from other bacteria. These differences could lead to differences in bone and breast density.
In support of this, Frankenfeld and Lampe found that women who had high levels of estrogen had higher bone density, but only if their gut bacteria produced equol. This could be evidence that the bacterial profile that makes someone an equol producer also influences how estrogens are processed in the body.
Follow-up studies
It is possible that isoflavone metabolism directly influences women's bone and breast density, but probably only in women who consume soy frequently and so have appreciable levels of these metabolites in their bodies, Frankenfeld said.
"It would be nice for somebody to do a larger study similar to ours where you could actually have more people who are regular soy consumers," such as women in Japan or Korea, Lampe said.
Also, researchers need to look at how intestinal bacteria process other chemicals and nutrients and how that can influence tissue density and risk of cancer, according to Lampe.
Intestinal bacteria probably influence the way our bodies handle carcinogens, as well as many other chemicals, Lampe said, and, since different people have different populations of these bacteria, risk of certain health problems may differ based on gut bacteria. "There are a lot of interindividual differences there that haven't even been looked at," she said.
"Intestinal bacteria can do a number of things," Frankenfeld said. "Different bacteria also have the capacity to upregulate different host genes. There are a number of possibilities as to what might be going on."
