The Environment Within: Exploring the Role of the Gut Microbiome in Health and Disease

Lindsey Konkel; Jayne Danska; Sarkis Mazmanian; Lisa Chadwick

Disclosures

Environ Health Perspect. 2013;121(9):a276-a281. 

In This Article

The Shifting Microbial Landscape

Changes in microbial colonization of the gastrointestinal tract, a process that starts at birth, have been identified as a major risk factor in the development of food-related autoimmune diseases.[13] The infant gut goes through a series of changes over the first several months of life, especially during the transition from breast milk to solid food. By around 2 years of age, the gut microbial composition of the child more closely resembles that of an adult than that of an infant.[14] Although the microbial composition is thought to remain relatively stable after this point, new research has identified key periods of development for the gut microbial community beyond early childhood, including puberty[15] and lactation.[11]

Celiac disease is unique among autoimmune diseases because both the key genetic components and the environmental trigger—gluten—are known.[16] However, fewer than 10% of people with a genetic predisposition to celiac disease develop the condition when exposed to gluten, and most develop the disease years after their first gluten exposure.[14] "Genes and an environmental trigger are necessary but not sufficient for disease development. We knew there had to be a third key element," says Alessio Fasano, chief of pediatric gastroenterology and nutrition at Mass General Hospital for Children in Boston.

Fasano and colleagues hypothesize the answers lie with the health of the gut microbial ecosystem as a whole. In a small study, they analyzed changes in the microbial communities colonizing the guts of approximately 30 infants with a genetic susceptibility to celiac disease between birth and age 2 years.[16]

The gut microbial communities of the predisposed infants matured more slowly and were less stable at 24 months than those of the control infants, who had no known genetic susceptibility to celiac disease. What's more, genetically susceptible infants who were introduced to gluten at age 6 months were more likely to develop antibodies against gluten than those introduced to gluten at age 12 months.[16] These preliminary findings suggest there may be a critical window of susceptibility to the disease, although more study is needed to explore this possibility.

Celiac disease is one of more than 100 known human autoimmune diseases affecting 5–10% of people worldwide. The incidence of nearly all these diseases is higher among women, and their rising rates and sex specificity suggest an environmental and potentially a hormonal component.[17] "We have known for many years that males are protected from autoimmune disease relative to females. We have not yet found a way to use that information to help women with disease," Danska says.

Although diet may be the most important environmental factor in determining the functional composition of the gut microbiota, Danska and colleagues recently demonstrated an interaction between sex hormones and the microbiota. Using nonobese diabetic (NOD) mice with a genetic susceptibility to type 1 diabetes, they found that male protection against the disease relative to females was associated with early-life gut microbial colonization. They also found that the composition of the gut microbiota was similar in young males and females but started to diverge between the sexes after puberty.[15]

In a germ-free environment, NOD males lost their relative protection against diabetes and had lower levels of testosterone than microbe-colonized males, suggesting a protective interaction between testosterone and gut microbes. When the investigators transplanted microbes from the guts of adult male mice into the guts of young females, the females displayed elevated testosterone levels, changes to their microbiota, and strong protection against type 1 diabetes. Even with these hormonal fluctuations, the female mice that received the male microbiota remained fertile.[15]

Although the change in testosterone levels was significant and measurable, Danska calls it modest: "Transfer of the male microbiota to young females did not elevate levels of testosterone anywhere near levels of a normal male, though the metabolic and immune effects were profound." She says this evidence of interplay between hormones and microbes supports the general idea that "even modest changes in signaling from environmental hormones could have significant impacts on the microbiome."

The microbial composition of breast milk may also have hormonal determinants.[11] In a small preliminary study of 18 mothers, researchers found differences in the microbiota of breast milk between women who underwent an elective cesarean section and those who gave birth vaginally. Interestingly, the breast milk microbiota of those that underwent a nonelective cesarean section more closely matched the microbial communities of mothers who gave birth vaginally. These differences persisted at 1 and 6 months postpartum.

According to the authors, the findings suggest that milk bacteria are not contaminants but a distinct microbial community, and that hormonal signaling initiated during labor may influence microbial transmission to the milk.[11] Previous studies have shown that babies born vaginally have more diverse microbial communities than babies delivered by cesarean section.[18,19]

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