Diet and microbiome may influence cognitive flexibility

There has been a lot of press recently about the microbiome’s impact on mood and behavior, the so-called ‘gut-brain axis’, and it appears now more than ever that the gut microbiome has a substantial impact on the brain.  A new paper out of Oregon State University, published in the journal Neuroscience, furthers this research by showing that different diets affect mice’s cognition and memory via changes in the microbiome.

Scientists fed groups of mice a normal chow and then switched their food to either high fat, or high diets, along with continuing some on the normal diet.   The researchers then put them through a battery of cognitive tests, all the while measuring their microbiomes using stool samples.  The mice on the high sucrose and high fat diets each had similar alterations of their microbiomes, such as an increase in Clostridiales and a decrease in Bacteroidales.  Mice on the high sucrose diet had decreased scores in their cognition tests, including memory and spatial reasoning tests, which corresponded to changes in the microbiome. For example, an increase in Lactobacilli was associated with a decrease in spatial reasoning.  Mice on the high fat diet, on the other hand, showed impaired working memory, which was associated with an increase in bacteroidales.

Some of these bacteria, such as Lactobacillus are used in probiotics to increase cognitive function, and there is some scientific basis for these effects, even though this study observes a somewhat different results.  The changes in this study though, were a diet intervention, which is more complex than a simple probiotic intervention.  That being said, we must remember that microbiome science is still developing, so each of these studies should be considered in the broader context of the field before any real conclusions can be made.

Maternal stress can alter the gut microbiome of progeny, possibly affecting brain development

The composition of the vaginal microbiome has been shown to have major health implications for a female’s health as well as the health of a newborn infant.  During birth, microbiota transfer from the mother to the neonate, which eventually go on to colonize the gut of the child.  It has already been shown that disruptions to the vaginal microbiome can impact microbiota colonization in the gut of a neonate, but downstream implications of this have not been thoroughly explored. 

Researcher’s from University of Pennsylvania set out to examine whether maternal stress in mice, and subsequent changes to the vaginal microbiome, could lead to disruptions in the gut microbiome of their progeny.  Expanding upon this, the researchers further investigated whether these disturbances to the gut impaired metabolism.  This transfer of microbiota occurs during a critical time in brain development, which requires a lot of energy and therefore effective metabolism to fuel this process.  The researchers wanted to identify whether or not maternal stress could disrupt the brain development process by way of alterations to microbiome transfer from the mother to its progeny and a subsequent disrupted metabolic process. 

Male C57 mice and female 129S1 mice were used in this study and were bred to form a hybrid F1 generation.  Stress was administered to the female mice using a well-established behavioral paradigm known as the early prenatal stress model.  Pregnant mice assigned to the EPS-stress group were exposed to a series of stressors (8 in total), but pain was not induce nor did these tests directly influence feeding schedule, weight gain, and litter size. 

Animals were then sacrificed and vaginal lavages were collected to examine bacterial composition between stressed (EPS) and non-stressed groups.  Quantitative PCR was used to characterize the microbiomes of the female mice and their offspring.  Lactobacillus, the predominant bacteria populations in the vagina, was significantly disrupted in the EPS group.  There was a reduction in Lactobacillus in the guts of F1 progeny as well.

Colon and plasma metabolic samples were examined in the F1 hybrid generation by extracting fatty acid metabolites using centrifugation.  Analysis showed that metabolic profiles were significantly different between groups.  Namely, of 29 signature metabolites assessed, 6 were increased and 23 were decreased in EPS progeny as compared to the control groups. 

Brain samples of the F1 hybrid generation were collected and amino acid concentrations were analyzed to assess substrate availability in the developing brain.  The F1 offspring from the EPS group displayed significantly less amino acids.  Interestingly, amino acids in a hypothalamic region of the brain were shown to be deregulated, and these concentrations were much lower in males as compared to females. 

It was interesting to see differences in amino acid availability in the hypothalamus between males and females in light of the fact that there are gender biases in neurodevelopmental disorders such as autism spectrum disorder.  Hopefully future studies can elucidate more on the microbiome to see how it relates to human behavior and brain disease.  

Proton pump inhibitors increase risk of C. diff in children

Alka seltzer treats acid reflux without proton pump inhibitors

Acid reflux is a common problem among adults, and is often treated with acid suppression medication such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). Acid suppression medication is also given to children over long periods of time. While there is a recognized connection between proton pump inhibition in adults and Clostridium difficile infection (CDI), a link between the drug intake by children and CDI has not been studied. As we’ve discussed on the blog before, infection by the bacteria C. difficile can cause serious harm to the intestinal tract and immune system. An article published by Clinical Infectious Diseases looks further into the relationship between acid suppression and CDI in children.

          Researchers at Columbia University Medical Center conducted a study using data from the Health Improvement Network, a medical records database. Data from 1995 to 2014 was used, and subjects were selected if they were aged 0-17 at the time of CDI diagnosis. The patients also needed the following requirements:  3 follow-up visits for patients younger than 1 year, and  1 follow-up visit for patients older than 1 year. Children with prior chronic conditions that may be linked to long-term acid suppression, such as neurological disorders and chronic gastrointestinal mucosal diseases, were excluded.

In the end, 650 cases were selected, with 68 of them being infants younger than 1 year. 3200 control cases were selected as well. After statistical analysis, it was found that there was no significant evidence of  age (1 year or 1-17 years) having an effect on the acid suppression-CDI relationship. It was found that the use of stronger proton pump inhibitors, rather than less-strong H2RAs, causes a significantly increased risk for CDI. Additionally, when the acid suppressant was used more recently (8-90 days) than distantly, the likely-hood of CDI was increased.

The researchers point out a potential error diagnosing CDI that could be causing the increase in children with the disease. In children, they say, symptoms of acid-related disorders may be very nonspecific, such as abdominal pain. Physicians then treat this with acid suppression medications, which, as discussed above, would then increase possibility of C. difficile colonization and growth.  However, the original abdominal pains may actually be symptoms of CDI. As a result, treating the CDI with acid suppressants is worsening the infection. With this new research, physicians might want to reconsider their options before treating what they think is an acid-related issue. 

Recapping Microbes in the City

Last week, the New York Academy of Sciences and NYU held an intensive one-day meeting on the microbiome, Microbes in the City, at the beautiful NYAS offices in 7 World Trade Center. The AMI was in attendance and in summary, the meeting was a resounding success.

The meeting kicked off with a talk by Jo Handelsman, Associate Director for Science in the White House Office of Science and Technology Policy, who did a wonderful job setting the tone for the day. Jo began by giving a bit of a history lesson and talked about some of the historical drivers of microbiome science. She talked about some major discoveries that have brought us to where we are today and concluded with a discussion of what The White House is thinking about in terms of microbiome science. An overarching theme was that while microbiome science includes many different habitats, there are cross-cutting questions that if answered in one area, can lead to advances across all microbiome fields.

There were a number of talks about microbiomes of our environment. We blogged about and talked with Chris Mason on the podcast about his work to profile the microbial communities in the New York City transit system and at this meeting we heard from Chris and Curtis Huttenhower from Harvard’s School of Public Health about the Metagenomics and Metadesign of Subways and Urban Biomes (MetaSUB), an initiatives to do the same in cities around the world. We also heard from Marty Blaser and Jane Carlton of NYU about their work that found samples in wastewater treatment plants in New York City included several genes for antibiotic resistance.

While it was largely due to the lineup of speakers, which looked like a who's who of microbiome scientists, there was an energy in the room you often don't see at scientific meetings. Part of that may have been due to the meeting's quick one-day format but the conversations after each talk were stimulating. The questions asked were frequently thought-provoking and I lost track of how many times the speakers said something along the lines of "good question, I will have to look into that." It was exciting to see such an engaging discussion among a community of some of the world's leading microbiome scientists.

Elderly people's microbiomes may contribute to their frailty

The ELDERMET program is a microbiome project in Ireland out of the University College Cork that is attempting to define the elderly microbiome and discover any associations between the microbiome and diseases linked with frailty and old age.  The team has published multiple papers from this project, some of which we have already blogged about, and last week they published another one in the ISME Journal.  In this latest paper the researchers described in fine detail just how the microbiota changes with diet within a geriatric population, and how this is actually independent of where the elderly people live.

The researchers studied the fecal microbiota of 384 elderly subjects over the course of one year.  They noticed immediately that the microbiomes clustered dependent upon whether the person was living in a nursing home or living amongst the general community.    The researchers characterized the microbiota in 4 groups based on a certain characteristics: M1, M2, M3, and M9.  M1 is a group of genera that is present in almost all subjects sampled, so it represents a core microbiome and is composed of genera such as Bacteroides, Alistipes, Parabacteroides, Faecalibacterium and Ruminococcus.   M2 is a cluster that is composed of bacteria that are associated with high-fiber diets and health, and is comprised of Coprococcus, Prevotella and Catenibacterium.  M3 is associated with folks who lived long-term residential care facilities, and consists of Anaerotruncus, Desulfovibrio and Coprobacillus genera.  Finally, M9 consists of other bacteria that were often found, like strains of Bacteroides, Parabacteroides and Alistipes.

The scientists then compared these microbiome groups with health indicators.  They discovered that highly diverse microbiomes were associated with health, especially among those living in the general community.  However, even though living in long term care facilities often increased diversity, having an M3 microbiome was overall associated with negative health.  In addition, the researchers noted that while individual foods were not strongly correlated with any health indicators, ‘healthy diets’ characterized by high fiber intake, were associated with better health than ‘unhealthy diets’.  Finally, when looking at how the microbiome changed over time, it was apparent that entering a nursing home increased the likelihood of shifting the subjects’ microbiomes to the M3 state, which is associated with bad health.  The researchers think this is likely due to the lack of fiber in nursing home food, and the high use of antibiotics.

The authors state that older people have many differences in their eating habits as compared to a normal adult population, like number of teeth, amount of chewing, and intestinal transit time, and all of these things may be contributing to the altered microbiome.    Regardless of these exogenous factors, this study reinforces the notion that lack of diet diversity and high use of drugs in nursing homes may be creating dysbioses that contribute to frailty disease.  If you have loved ones in an extended stay facility we recommend considering supplementing their diet with some fresh vegetables, so as to keep their microbiome from turning against them.

Study suggests penile microbiome can transmit bacterial vaginosis by sexual intercourse

Bacterial vaginosis (BV) is a microbiome-based disease characterized by a lack of Lactobacillus in the vagina.  We have covered this disease with multiple blog posts and encourage any interested readers to search for these blogs to learn more.  One outstanding question regarding BV is how sexual intercourse affects the disease.  One prevailing thought is that the penis can actually be colonized by BV-associated bacteria, and that through sexual intercourse it can be spread between partners.  A new paper published last week in mBio suggests this is true.

The researchers measured the penile microbiomes of 165 uncircumcised, black men from Uganda, as well as diagnosing BV status in their female partners.  The BV status was measured by Nugent score, which is a bacterial staining technique that basically measures the amount of anaerobic bacteria in the vagina (non-Lactobacilli).  The stain produces a score between 1-7 with 1 being healthiest and 7 being least healthy (mostly anaerobic bacteria).  After measuring the penile microbiomes, the scientists were able to be categorize them into 7 different community state types (CST1-7).  These community state types varied from 1 to 7 in terms of both overall abundance and composition, with CST1 having the lowest density of bacteria and the lowest diversity while CST7 had the highest density and the highest diversity of bacteria.

The scientists compared the female partner’s BV status with the men’s community state type, and noted that having a CST1-7 on the penile microbiome corresponded with a higher likelihood of the female partner being diagnosed with BV.  Two genera of bacteria, Corynebacterium and Staphylococcus, on the penile microbiome were associated with healthy vaginal flora, whereas Dialister, Mobiluncus, Prevotella, and Porphyromonas were associated with BV.  Interestingly penises that included Lactobacillus and Gardnerella, genera associated with healthy vaginas and BV vaginas, respectively, were not statistically associated with BV status.  Overall, men with CST4-7 were significantly more likely to have a sexual partner with BV, and had more BV associated bacteria colonizing their penises.  In addition, men with more than one sexual partner were more likely to have CST4-7, and again, their partners more likely to have BV.

It appears that men’s penises, especially uncircumcised ones, can be vectors for bacterial transmission.  This simple fact should make us reconsider BV as an STD, and actually fits in well with another that has shown promiscuity is a risk for BV.  It is likely that circumcision and condom would decrease BV transmission rate, as they do other STDs, but until a paper comes out that studies this connection no one can say for sure.