Research has demonstrated that a high-fat, low-fiber diet (common in the U.S.) causes an imbalance in the gut microbiome—the community of trillions of bacteria, good and bad, that line the walls of the human digestive system. In recent years, evidence has grown that a maternal high-fat diet during pregnancy may raise the risk of health problems in the child, ranging from obesity and other metabolic disorders to neurodevelopmental disorders, possibly including autism spectrum disorder.

A research team led by 2019 BBRF Young Investigator Shelly A. Buffington, Ph.D., of the University of Texas Medical Branch, Galveston, recently reported on a series of experiments that extended discoveries they have previously made in rodents. In those studies, they had investigated the impact of a maternal high-fat diet in male offspring. Males born to these mothers themselves were found to have imbalanced microbiomes and to display a variety of social dysfunctions, as well deficits in the plasticity of the synapses across which brain cells communicate.

In their new study, Dr. Buffington and colleagues including Claudia Di Gesù, Ph.D. and Lisa Matz, Ph.D., who were first authors of the team’s paper appearing in Cell Reports, explored multigenerational impacts of a high-fat maternal diet. They confirmed, first, that female offspring of mouse mothers with imbalanced gut microbiomes also had imbalanced microbiomes. The next questions were: would these female offspring, like the male offspring observed in past research, also have social deficits? Further, would their offspring (in effect, “grandchildren” of mouse mothers with high-fat diets) have the same issues—imbalanced microbiomes and behavior issues?

One possible outcome of such research, the team said, was providing insight into whether and how diet-induced pre-pregnancy obesity in humans predisposes offspring to neurodevelopmental disorders. They were also interested in testing, in mice, whether targeted probiotic treatment during pregnancy—introducing helpful microbes—might have a protective role in offspring neurodevelopment.

One result of the research was that, in mice at least, female offspring of mothers raised on high-fat diets did have imbalanced microbiomes—as in male offspring, their gut microbe colonies were less complex and lacking in diversity, which is linked with various negative health effects. The female offspring had significant but less severe social deficits than were observed previously in male offspring of the same mothers.

But the next generation—offspring of the female “children” of mothers with high-fat diets—were observed to have normal microbiomes. In this 3rd generation, microbial richness in the gut had mostly been restored. Still, these 3rd-generation female mice did display social deficits.

“Our findings emphasize the need to consider [in humans] family history of diet-associated metabolic dysfunction and obesity in the maternal lineage as potential risk factors for neurodevelopmental disorders,” the team said. This advice would pertain “independent of the mother’s own diet, lifestyle, and medical history.” The latter is based on the demonstration that high-fat diet-induced dysregulation of the microbiome in a single generation had behavioral impacts that crossed multiple descendant generations.

Importantly, the team found that if, after weaning, they treated the 3rd-generation mice by transferring to their gut a bacterial species called L. reuteri, no social dysfunction was seen as they matured. In the treated mice, the team observed “a highly significant increase in both reciprocal social interaction and preference for social novelty.” Why? One possible mechanism for the efficacy of the “treatment” was that it promoted the production of microbes that make an abundance of short-chain fatty acids (SCFAs). These molecules are thought to reduce heightened responses to social stress.

The team made another observation of potentially great importance. Treating 3rd-generation mice with L. reuteri modified the composition of the gut microbiome very differently in females and males. The treatment had a much more robust impact in females, increasing the presence of several helpful microbial species. The team noted “the relative malleability of the female gut microbiome [compared with the male] in response to probiotic intervention.”

The pronounced positive reactivity of females to this treatment—and the team suggested other microbial species can probably be found with similar positive impact—suggests to the team the potential value of the prenatal period as a time in which to test microbiome interventions to reduce risk of neurodevelopmental disorders in offspring. Obesity and high-fat diet in the mother, this research suggests, carries behavioral risk for multiple subsequent generations; thus it makes sense to test the idea of “treating” females either during pregnancy or when they are lactating, to see if behavioral risk in newborns can be reduced.  The place to begin, of course, would be in studies with mice or other animals; if successful, such treatments could then be tested in people—among the team’s research objectives.