Creative Minds: Can Microbes Influence Mental Health?

Posted on January 9th, 2014 by Dr. Francis Collins

While sitting in microbiology class as a college sophomore, Elaine Hsiao was stunned to learn that the human gut held between as much as 6 pounds of bacteria—twice the weight of an adult human brain. She went on to learn during her graduate studies in neurobiology that these microbes had co-evolved with humans and played important roles in our bodies, aiding digestion and immune function, for example. But more intriguing to her, by far, was new research that suggested that gut bacteria might even be influencing our thoughts, moods, and behavior.

Now a senior research fellow at the California Institute of Technology, Hsiao is launching her own effort to explore how these microbes can affect brain function—a very creative endeavor made possible through NIH’s Early Independence Award program—also known as the “skip the postdoc” award.

So, how might a bunch of bacteria living in your intestines, which are located a good distance away from your brain, play a role in your mental well-being? Well, it turns out that there are several different avenues through which microbes can exert what may amount to a type of mind control.

First of all, and perhaps most obviously, gut bacteria are engaged in a wide range of biochemical activities, producing metabolites that are absorbed into the human bloodstream. But there are other connections. One species of bacterium, for example, sends messages that are carried via the vagus nerve, which links the intestinal lining to the brain [1]. When this species is present, the mice demonstrate fewer depressive behaviors than when it’s absent. Another bacterium plays an enormous role in shaping the immune system, which goes awry in many neurological diseases. This species of bacterium interacts directly with the immune system’s regulatory T-cells to provide resistance against a mouse version of multiple sclerosis [2], a progressive disease in which the immune cells damage the central nervous system by stripping away the insulating covers of nerve cells.

In work conducted during graduate school and a brief postdoctoral fellowship, Hsiao laid an impressive foundation for her latest research efforts. Using mice as her model system, she studied how activating the mother’s immune system during pregnancy may raise her offspring’s risk of schizophrenia and autism. As part of this work, she looked at how inflammatory signals are relayed to the placenta [3] and how prenatal insults, such as maternal infections, can affect embryonic brain development [4]. She also examined how maternal immune activation shapes immune systems of offspring—a concept called prenatal programming [5].

Realizing that the immune system interacts closely with normal microbes, Hsiao is now focused on how gut bacteria influence immunity, brain function, and behaviors in mouse models of neurodevelopmental disorders. In a just-published study, she reveals that when mice that display core symptoms of autism spectrum disorder are given bacteria-laden treatments called probiotics, many of the mice’s behavioral abnormalities disappear [6].

To expand this research, Hsiao will use her 2013 NIH Early Independence Award to explore how microbes in the gut influence levels of the neurotransmitter serotonin. You may have heard of serotonin in the context of its effects on the brain, particularly its role in depression. However, this molecule also helps to regulate heart function, constriction of blood vessels, and differentiation of red blood cells. Hsiao plans to identify specific types of bacteria that modulate human serotonin levels, figure out the biochemical pathways they use, and understand the links to human disease.

Ultimately, Hsiao hopes that her work will translate into microbe-based therapies. Who knows? Perhaps someday one key to better mental health might be an extra dose of some of the trillions of microbes that hang out in our guts.

And Hsiao’s not the only creative mind whom I’d like to salute today. She’s among at least nine young researchers supported by NIH named to Forbes magazine’s annual “30 Under 30” list. The other up-and-coming scientists are: NIH intramural researchers Greg Alshuin (National Heart, Lung, and Blood Institute) and Anna F. Lau (NIH Clinical Center); NIH Early Independence Award winners Adam de la Zerda (Stanford University School of Medicine), Mitchell Guttman (California Institute of Technology), David Weinberg (University of California, San Francisco), and Daniela Witten (University of Washington); NIH Small Business Innovation Research awardee Rachel Haurwitz (Caribou Biosciences); and NIH-funded Graduate Student Fellow Zirui Song (Harvard Medical School).

Congratulations to all! I look forward to seeing how your work will help to shape the future of science and medicine.

References:

[1] Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16050-5.

[2] Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. Ochoa-Repáraz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, Kasper DL, Kasper LH. J Immunol. 2010 Oct 1;185(7):4101-8.

[3] Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Hsiao EY, Patterson PH.Brain Behav Immun. 2011 May;25(4):604-15.

[4] Effects of maternal immune activation on gene expression patterns in the fetal brain. Garbett KA, Hsiao EY, Kálmán S, Patterson PH, Mirnics K. Transl Psychiatry. 2012 Apr 3;2:e98.

[5] Modeling an autism risk factor in mice leads to permanent immune dysregulation. Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81.

[6] Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Cell. 2013 Dec 19;155(7):1451-63.

Links:

High-Risk, High-Reward Research. (NIH Common Fund)

NIH Director’s Early Independence Awards. (NIH Common Fund)

Mind-altering microbes: how the microbiome affects brain and behavior: Elaine Hsiao at TEDxCaltech

NIH Director’s Blog, “Forbes 30 Under 30 Highlights NIH Stars” (December 21, 2012)

NIH support: Office of the Director (Common Fund)