Episode 6 of The Microbiome Podcast: The microbiome, autism, and serotonin production with Dr. Elaine Hsiao

The sixth episode of The Microbiome Podcast is now available. We had a great chat with Dr. Elaine Hsiao, a new professor at California Institute of Technology. Elaine was the first author on the seminal paper from 2013 that showed a connection in mice of the microbiome and autism spectrum disorder related behaviors. We talked with her about that work as well as more recent work that she published from her own laboratory describing the microbiome’s role in regulating serotonin production.

Listen to the podcast here on our website. Here on iTunes. And here on Stitcher. 

Below are more detailed show notes:

• (2:20) Last week’s guests Erica and Justin Sonnenburg were featured in a New York Magazine article. Read the article. 
• (3:48) The Gates Foundation’s Grand Challenges in Global Health launched a grand challenge titled Addressing Newborn and Infant Gut Health Through Bacteriophage-Mediated Microbiome Engineering. Learn more. 
• (6:22) uBiome launched a clinical laboratory. Read more. 
• (7:56) Second Genome partnered with the University of Cork in Ireland to develop therapies for inflammatory bowel diseases. Read more.
• (9:02) Dupont recently acquired Taxon Biosciences, a microbiome company. Read more. 
• (11:15) A caller asked how long his microbiome would take to recover to it’s previous state after taking antibiotics. We based the answer on a paper by David Relman published in 2010. Read the paper.
• (16:19) We start the interview with Elaine Hsiao. Check out her laboratory webpage.
• (18:00) We talked with Elaine about her seminal paper on the microbiome and it’s possible connection to autism spectrum disorders. Read the paper.
• (31:06) We talked with Elaine about her recent paper showing that gut bacteria are important for production of serotonin. Read the paper.

We will be back in two weeks with Drs. Eugene Chang and Vanessa Leone from the University of Chicago discussing how the microbiome may be involved in the complex relationship between disruptions to circadian rhythms and obesity. Please call in with any questions for Bill and David or for Drs. Chang and Leone to 518-945-8583. 

Probiotics may be able to prevent depression

Clinical studies have shown that probiotics can decrease anxiety, improve mental outlook, and induce positive mood changes and outlook.  In fact, some bacteria strains have been shown to reduce anxiety and depression in mice by directly modulating nerve firings associated with these cognitive maladies.  A recent study conducted by Leiden University in The Netherlands explored further in human subjects to assess whether or not probiotics, composed of various strains of Bifidobacteria and Lactobacilli could specifically modulate cognitive reactivity to sad mood, a well-characterized indicator for vulnerability to depression. 

In brief, cognitive reactivity is defined as a series of dysfunctional patterns of thinking prompted by subtle mood changes, such as rumination, aggression, and hopelessness.  It is thought that cognitive reactivity is central in the development, maintenance, and recurrence of depression episodes.  This behavioral reaction is considered to have significant predictive value in detecting vulnerability to developing clinical depression.  Due to this implication, cognitive reactivity is considered a target for therapeutic intervention to prevent depression onset, and was thus analyzed in this study. 

40 healthy, non-depressed adults were selected and split into two groups, each receiving a 4-week regiment of a probiotic or a placebo.  The participants filled out questionnaires before and after the regiment to assess cognitive reactivity and depression symptoms.  Of the several behavioral indicators of cognitive reactivity that were assessed, aggression and rumination were significantly modified according to the behavioral questionnaires.  Specifically, post-regiment scores in the probiotic group were significantly lowered from pre-regiment scores, and this was not observed in the placebo group.  All told, this suggests that a probiotic regiment eased cognitive reactivity to aggressive and ruminative thoughts.

This study is the first to show that probiotics can modulate an important cognitive process that determines vulnerability to clinically diagnosed depression.  These findings are additionally enlightening with respect to the gut microbiome’s role in overall cognitive health.  As is often the case however, there were some limitations.  Specifically, it would have been interesting to investigate biological underpinnings of these interactions in complementary animal models, especially in light of previous findings that indicate probiotics can facilitate microbiota to synthesize and release serotonin.  On Monday we highlighted work done by Professor Diane Hsiao’s group at Cal Tech that stressed the gut microbiome’s role in serotonin production.  As we mentioned, serotonin is implicated in many bodily functions, including a vast range of cognitive mechanisms.  Indeed, serotonin systems have been primary target for therapeutic treatment of depression.  Zoloft, one of the most highly prescribed antidepressants in the world, blocks serotonin metabolism to facilitate its endogenous mode of action in the brain. 

Not only do the current findings complement those from the Cal Tech lab, but they also highlight an exciting new potential toward therapeutic approach.  Conventional therapies that directly target serotonin systems can be ineffective and have many undesired side-effects and limitations.  Understanding the microbiome’s role in serotonin production can give us more insight and perhaps pave a way toward a more organic therapeutic approach aimed at preventing and/or treating depression.  

Gut bacteria help regulate serotonin levels

Ball-and-stick model of serotonin molecule

Editor’s Note:  In this blog we write about the most recent findings from Elaine Hsiao’s lab at Cal Tech.  You may remember Professor Hsiao’s previous work, which we wrote about last year.  She published the now seminal article that linked autism spectrum symptoms in mice with their gut microbiomes.  Diane will be joining us on the Microbiome Podcast, to be released on May 4.  If you have any questions about this study on serotonin, or on her work with autism and the microbiome, please call this number 518-945-8583 and leave a voicemail.  If possible we will ask her your question during the show.

Serotonin is a crucial multi-purpose hormone in our body that affects our mood, happiness, appetite, and gastrointestinal movement, among other functions.  It is produced in a few places around the body, but mostly in the epithelial cells that line the gut.  It should come as no surprise then, that Professor Diane Hsiao’s group, out of Cal Tech, recently uncovered a critical role that the gut microbiome has in stimulating the production of this molecule.  She published her results in the journal Cell.

The researchers first discovered that germ-free mice produced substantially less serotonin than normal mice in their colons, but not in the small intestines, suggesting the importance of the colon microbiome in serotonin production.  The scientists then investigated the levels of each enzyme responsible for serotonin production and pinpointed one called TPH1 that was produced at much lower levels in the germ free mice colons.  When the germ-free mice were given TPH1 their serotonin levels returned to normal, and when regular mice were given antibiotics their serotonin levels dropped.  Taken together, this suggests that the colon microbiome somehow increase TPH1 levels in the gut.   

The researchers then investigated the effects that specific bacteria had on increasing serotonin levels in germ free mice and discovered that spore forming bacteria, especially those belonging to Clostridia, were able to increase the levels of serotonin in the mice.  After, they tried to determine specific metabolites that may be produced by Clostridia that increase TPH1 production.  They found that deoxycholate, a-tocopherol, p-aminobenzoate, and tyramine all increased serotonin to normal levels when given to germ free mice.

Finally, the scientists colonized germ-free mice with spore producing bacteria and measured the effects on certain traits known to be associated with serotonin.  For example, germ free mice colonized with spore producing bacteria had longer food transit times and more frequent bowel movements.  In addition, blood platelets function better in mice colonized with spore forming bacteria than in germ-free mice.

Overall this work shows an important connection between serotonin production and the microbiome.  Serotonin has been implicated with many critical bodily functions, like bone development, appetite control, heart function, and mental well-being.  The fact that a dysbiosis in the microbiome may be responsible for lowering its levels may turn out to be crucial in developing next generation therapeutics.