Gut Reaction: Bacteria to Autism in Four (Not-So-) Easy Steps

Mouse studies suggest that adding a common type of gut bacteria, Lactobacillus reuteri, to the diets of fatty food–eating, overweight pregnant women and their children may help prevent and even reverse some of the maternal diet–induced behavioral deficits in offspring with neurodevelopmental disorders, including autism spectrum disorder (ASDs). Maternal obesity during pregnancy is associated with a significantly increased risk of neurodevelopmental problems in the offspring. Although perplexing, this association has been consistently reported. A recent large-scale study revealed that obese ­mothers were 1.5 times more likely than normal-weight women to have a child with ASD, and the risk was twofold greater when the obese mothers also had gestational diabetes. Researchers from Baylor College of Medicine in Houston, led by Mauro Costa-Mattioli, appear to have discovered why this is so. Working with mice, a well-tested physiological stand-in for humans, these scientists found that feeding maternal mice high-fat diets shifted the microbial ecology in their guts. The bacterial species in the pups’ gastrointestinal system were identified by RNA sequencing of fecal samples. Behavior was assessed by measuring how long each pup spent with ­unfamiliar mice or with inanimate objects such as wire cups. The gut microbiomes of offspring of mothers fed high-fat diets were less diverse, and notably, there were nine times fewer L. reuteri in the feces of these pups compared with that of pups whose mothers ate regular diets. The offspring of obese mothers also had problems socializing, spending as much time in the company of a wire cup as with a fellow mouse when given the choice. In contrast, all of the pups born to normal-weight mothers socialized normally. Mice eat each other's feces; therefore, gut dysbiosis and social deficits in the pups born to obese moms on high-fat diets were totally reversed by housing them with offspring of normal-weight mothers endowed with abundant L. reuteri. “Social ­behavior in the [obese-mother] offspring was presumably rescued because they picked up [microbial] species ­previously ­missing from their microbiome, including L. reuteri, from the droppings of their new cage mates,” according to Costa-Mattioli. It has been previously shown that L. reuteri promotes the production of oxytocin, a neuropeptide that neurons use to communicate with one another and that plays an important role in mammalian social behavior. To determine if L. reuteri alone could improve the behavior of the affected offspring, Costa-Mattioli and his colleagues added L. reuteri directly to the drinking water of mouse pups with both high-fat diet and regular-diet mothers. The researchers compared the pups to a similar set of young mice drinking either pure water or water laced with heat-killed L. reuteri. The young mice with obese mothers drinking live lactobacillus developed normally, whereas those drinking the heat-killed L. reuteri did not. “This is a remarkable finding because it suggests that a single species of gut bacteria can have a big effect on offspring behavior,” says Costa-Mattioli. The researchers then examined the brains of the mice and noted 29 percent fewer oxytocin immunoreactive neurons in the obese-mom's offspring. Costa-Mattioli and Shelly Buffington, the project's lead scientist, say their findings “causally link maternal diet, gut microbial imbalance, ventral tegmental area plasticity [responsiveness of the nerve group in charge of emotion], and behavior.” Considering that many patients with ASDs have abnormal gut ecology accompanied by gastrointestinal problems and that maternal obesity in both human and nonhuman primates results in alterations of their offspring's microbiome, “the findings in this mouse model hold translational potential for humans,” Buffington adds. Therefore, Costa-Mattioli predicts that “probiotic treatment with L. reuteri could eventually be used to reduce the severity of some autistic-like behaviors in children at risk for ASDs because of maternal diet-related abnormalities to their gut microbiomes.” “Documenting how environmental factors can affect neurodevelopment by interacting with a very complex neurobiological system makes this a landmark study,” says autism expert Karam Radwan at the University of Chicago. “Although not the first investigation linking microbiome changes and autism, it is the first one to link a bacterium, L. reuteri, with a neuropeptide, oxytocin, well known for its association with social behaviors,” adds Radwan (who did not participate in the work). “Although this is unlikely to be a breakthrough in terms of finding a cure, it is one of the most exciting studies I have seen in a decade,” says Radwan. “How gut bacteria can change a neuropeptide is as yet unknown, but it is one of the most intriguing questions we have to answer in the next decade. It is, after all, a great time to witness science unravel the mysteries of our brain.”

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