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.

Specific bacteria implicated with microscopic colitis

Occurrence of Akkermansia muciniphila in healthy people and those with MC.
From:  Fischer et. al. 2015. Altered microbiota in microscopic colitis. Gut doi:10.1136/gutjnl-2014-308956

Microscopic colitis (MC) is a disease which is characterized by chronic diarrhea and an increase in the immune cells characteristic of inflammation in the colon, but an otherwise healthy looking colon based on a colonoscopy.  Interestingly, it most often afflicts middle aged and elderly women, and is highly associated with smoking.  Researchers in Sweden recently hypothesized that that MC was somehow related to the microbiome and designed an experiment to find out.  The results of that study were published this week in the journal Gut.

The scientists sampled the microbiomes of 10 women suffering from MC and 7 healthy controls.  They discovered that while the microbiomes in all the women were quite similar, there was one conspicuous difference.  The women with MC had much lower levels of Akkermansia sp. (100x to 1000x lower).  This genus is known to be important in healthy guts, where it breaks down the mucous lining of the gut.  It is associated with thicker mucous, which is likely a healthy trait, as well as glucose metabolism.

While the number of patients was low, the connection between MC and Akkermansia sp. certainly deserves further investigation.  Of course, these bacteria are only associated with the disease, and this study is in no way proof that the lack of this bug causes the disease.  Diseases like colitis are very complex, and there are likely many factors involved, but studies like this are certainly a step in the right direction in showing an association with the microbiome.

Microbiomes of centenarians differ from other elderly individuals in Chinese region

Bama County, a rural area in China, is home to a significant number of individuals who live to be over 100 years old, so-called centenarians. Why is it that people who live in this region have a much greater chance of living to be over 100 than almost anywhere else in the world? It is largely unknown however many people have hypothesized that while it may partly be genetic, lifestyle plays an important role in these people living longer lives.

Scientists in China set out to study the microbiome of individuals in this county and find associations between age and diet. 8 centenarians between 100-108 from rural Bama County, 8 elderly individuals between 85-99 from Bama County, and 8 elderly individuals between 80-92 from Nanning, a Chinese city in the same region as Bama, each provided stool samples as well as detailed long-term dietary information.

The researchers found that centenarians had greater diversity of bacteria in their guts compared to the younger elderly individuals. They also found several bacterial species that were more or less abundant in centenarians than the other elderly from both rural and urban environments. While some of these results were not in line with previous studies, the results did indicate that age played an important role in shaping the microbiome.

They also found that there were specific bacteria that were more or less abundant in the study participants living in rural areas who ate a diet with more fiber than those elderly living in an urban environment who ate a diet with less fiber.  These findings suggest that both age and a high-fiber diet can help establish a gut microbiota that promotes beneficial health. These studies were only conducted on 24 individuals with 8 people in each study group and therefore significantly more work will need to be done to better understand if and how the microbiome is playing a role in elongating the lives of these centenarians. 

The lung microbiome changes during cystic fibrosis flare-ups

Cystic fibrosis is a genetically inherited disease characterized in part by thick mucus secretion that can obstruct the lungs and aid in the harboring of bacteria in airways. A leading cause of death within persons with cystic fibrosis (CF) is infection of the lungs and inflammation that leads to respiratory failure. In a study performed by members of the Department of Pediatrics and Communicable Diseases at the University of Michigan Medical School, and published by Microbiome, sputum (mucus) samples were taken from four CF patients over a period of a days leading up to pulmonary exacerbation, a period of worsening lung infection. The hope was to identify possible bacterial changes that lead to exacerbation.

 The samples collected from individuals with cystic fibrosis – referred to as subjects A, B, C, and D – were sequenced to identify bacterial and viral content during the period leading up to and including exacerbation. At baseline, the most abundant bacteria in subject A was Staphlyococcus, in subject C Streptococcus, and in subjects B and D Burkholeria. Subject A showed to most change in bacterial communities during the week prior to exacerbation symptoms, subject B showed bacterial community change just after onset of exacerbation, and subjects C and D remained relatively stable with the onset of exacerbation. After the changes that occurred in subject A’s bacterial community it never bounced back to its pre-exacerbation population, and stabilized to one with reduced Staphylococcus and increased Pseudomonas and Prevotella. Different from subject A, subject B’s bacterial community shifted one week after the onset of exacerbation from one dominated by Burkholderia  to Pseudomonas.

 While there were many differences among the four subjects sampled in the study, there was one similarity in that the dominant taxa of subjects A, B, and C all decreased in relative abundance around the period of exacerbation. The study’s findings also suggest that rather than changes in total bacterial density, it is more likely that shifts in relative abundance of a member of a bacterial community is associated with changes in CF symptoms. Additionally, none of the respiratory viruses tested for were found present during time of exacerbation, which was surprising to the researchers.

 The results of this study do not give us any solid rules for the characteristics of bacterial communities in the lungs during time of exacerbation in cystic fibrosis patients; however it is a step in the right direction toward identifying such characteristics. Perhaps with a larger sample size we can better understand the changes in community composition that lead to changes in CF symptoms.  

New info on fecal microbiota transplants for C. difficile and ulcerative colitis

"Fecal bacterial communities of recurrent [C. diff]  patients shift towards [healthy] fecal bacterial communities after FMT. Pre-FMT patient samples (red circle); post-FMT patient samples (green circles); trajectory of patient fecal communities after FMT (blue line)."
Image and caption from the C. diff paper: Weingarden et al. Microbiome 2015 3:10   doi:10.1186/s40168-015-0070-0

Two important papers regarding fecal microbiota transplants (FMTs) were published last week.  The first was an examination of a patient’s microbiome over time after he or she undergoes an FMT to treat C. difficile.  The second showed the results of clinical trials that used FMTs in an attempt to treat ulcerative colitis.   The FMT papers, which are described below, improve our understanding of this procedure, which holds promise to treat various microbiome-based diseases.

The C. diff paper, published in the journal Microbiome, attempted to answer the question: Do the microbiome changes that occur after FMT remain long after the procedure?  We know that FMTs are highly effective in treating C. diff because they install a healthy microbiome that can crowd out the infection.  However, it is unknown if these new bugs that take hold are transient, or if they become permanent members of the gut.  The researchers sampled the microbiomes of FMT donors and recipient patients before and up to 84 days after an FMT procedure to treat C. diff.  They discovered that the recipients’ dysbiotic microbiomes stabilized quickly, and after just one day they closely resembled the donors’ microbiomes.  Continued measurements showed that the microbiomes deviated over the next few weeks, but that they remained healthy.

The colitis clinical trial, published in the journal Gastroenterology, attempted to discover if FMTs could treat ulcerative colitis.  Ulcerative colitis is widely considered to somehow be related to a dysbiosis in the microbiome, so can FMTs from healthy donors treat this disease?  The study was a double blind randomized clinical in which 48 people suffering from ulcerative colitis either received stool from healthy donors (treatment) or just an FMT of their own stool (control).  7/23 patients who received stool from a healthy donor were in remission after 12 weeks, while 5/25 patients who received their own stool were in remission at that time.  Unfortunately, this is not a clinically significant result based on the number of patients involved.  The researchers measured the bacterial abundance in all of the patients microbiomes before and after treatment.  Before treatment the microbiomes all had some baseline similarity.  After treatment, though, the patients who responded to treatment from a healthy donor all had an increase in certain Clostridia, and the patients who responded to treatment from their own stool all had in increase in certain Bacilli, Proteobacteria and Bacteriodetes.  The researchers feel that this information warrants further study.

FMTs are an exciting new therapy that may be important in treating some really nasty diseases.  We do want to remind people, though, that it is still an unproven technique that should only be performed under the guidance of a doctor.  As we have written about before, the promise of the microbiome is what makes FMTs both attractive, but potentially dangerous at the same time.

Episode 4 of The Microbiome Podcast: What's hot in the microbiome field with Kristina Campbell

On this week's podcast, we talked with Kristina Campbell from Gut Microbiota for Health. Kristina had recently traveled to three conferences around the world so we talked with her about what's going on in the field and the most recent breakthroughs in the field.  We also announced that we set up a voicemail for callers to call-in and ask us questions or leave comments for the next episode of the podcast. The number is 518-945-8583 and we hope to hear from you with any questions, simple or complex, that you want us to answer on the podcast. 

Listen here: 

And listen here on iTunes and Stitcher. 

See below for more detailed show notes: 

The episode begins with a few recent news stories:

• (2:57) The Obama administration announced a $1.2B plan to fight antibiotic resistant bacteria. Read more. 

• (5:00) A group at the University of Nottingham used a 1000 year old recipe to kill MRSA and it was very successful. Read more.

• (7:13) The Massachusetts Host-Microbiome Center is being created by a $4.8M grant from the Massachusetts Life Sciences Center. Read more. 

In the conversation with Kristina (@bykriscampbell on twitter and read her personal blog here) we discussed:

• (9:29) Gut Microbiota for Health, the website that Kristina writes for. Check out the site.

• (10:46) The Keystone Symposia that she attended. Link. 

• (12:48) Skip Virgin’s keynote address discussing the virome and IBD. Read our blog post about his paper on the subject.

• (15:40) The Gut Summit that she attended in Barcelona. Link. 

• (17:24) Maria Gloria Dominguez Bello’s work on c-sections. Watch a replay of her talk from the Gut Summit.

• (19:38) The Experimental Biology conference in Boston. Link.

• (20:13) Emeran Mayer’s work using fMRIs. Read about Dr. Mayer.

• (23:10) Fecal microbiota transplants

• (24:10) OpenBiome

• (30:35) The milk microbiome

• (33:58) Obesity and the microbiome and (34:50) research on using FMTs for treating obesity. Link.

(41:35) After the interview with Kristina, we again discussed the NCAA tournament and how our picks before the Round of 32 are faring.

The next podcast will be with Justin and Erica Sonnenburg, scientists at Stanford University School of Medicine. Leave a voicemail for us at if you have a question for Erica and Justin about the impact of diet on the microbiome or anything else microbiome related.