Introducing specific molecules in the gut could help protect beneficial bacteria

(this is a caffeine molecule, not what was used in the study but something we could all use on this Friday morning)

Antibiotics save countless lives by fighting off pathogens in the body, however they also kill beneficial bacteria in the body that are necessary for keeping us alive and healthy. A team of scientists in Portugal and Spain may have found a molecule that can help restore beneficial bacteria in the gut.

Quorum sensing is how bacteria interact and coordinate with one another. The scientists showed that by increasing levels of a specific quorom-sensing molecule, autoinducer-2 (AI-2), in the gut, mice that had been given antibiotics were repopulated of beneficial bacteria.

The scientists sequenced the bacteria in fecal samples of mice before and after a 28-day regimen of streptomycin treatment. Prior to antibiotic treatment, bacteria of the Bacteroidetes and Firmicutes phyla made up 48 and 43 percent, respectively, of the bacteria in the gut. After 28 days, diversity in the guy decreased significantly and the Bacteroidetes and Firmicutes ratios shifted to 90% of Bacteroidetes species and Firmicutes species made up only 0.7% of all species.

They then repeated this experiment but also generated E. coli that were mutated and not able to absorb AI-2 and introduced these bacteria into the mice that were treated with antibiotics. They used E. coli because streptomycin increases levels of E. coli in the gut when exposed to it. This resulted in AI-2 levels in the gut to be increased as well as increase of bacteria from the Firmicutes phylum, which had been greatly destroyed by the antibiotic in the previous experiment.  

They were able to increase AI-2 levels and therefore beneficial bacteria by introducing bacteria that could not absorb it.  AI-2 could also be directly given to individuals who were given antibiotics and the scientists are now working on developing drugs that would release AI-2 only in the gut. However, antibiotics are not the only cause of dysbiosis.  Diet and other factors can result in changes to gut bacteria and by introducing this molecule and other molecules that bacteria use to communicate with one another, it may be possible to treat gastrointestinal diseases as well as dysbiosis caused by external factors. 

An obese-type gut microbiome can lead to neurobehavioral pathology

Squirrel on high fat diet. (close enough to a mouse!)

Obesity is a complex condition with an extensive range of health complications.  Among many other issues, neurobehavioral deficits in learning, memory, and executive function are observed in this disorder.  However, the cause behind the manifestations of these deficits remains unclear, and new data suggest that obesity by itself may not be the origin of these neurobehavioral complications.  In other words, neurobehavioral deficits may not be caused by obesity, but rather by the microbiome that develops from the high-fat diet that leads to obesity.  A recent study supports this supposition, demonstrating that an “obese-specific” gut microbiome may be the driving force behind these neurobehavioral complications.

Researchers hypothesized that microbiome communities that develop from a sustained high-fat diet could by themselves induce neurobehavioral maladies, independent of diet, adipose fat accumulation, and/or metabolic dysfunction.  To test this theory, the researchers developed a paradigm in which microbiota taken from the gut of obese mice were recolonized in the gut of non-obese mice.  Specifically, mice were split into two groups, and members from each cohort were administered either a standard chow diet or a high-fat chow diet (to induce obesity).  After 10 weeks on their respective diets, the animals were sacrificed and their microbiota bacteria were harvested from cecal and colonic contents.  A third group of mice were administered an intense antibiotic regimen to wipe out their intestinal microbiota populations.  Microbiotas from either the normal chow diet mice or high-fat chow diet mice were subsequently implanted in the microbial-free guts of third group.  These mice were then subject to behavioral examinations and eventually sacrificed for biochemical analysis to characterize disease markers and pathology indications in the brain and gut. 

Behavioral assessments revealed significant increases in anxiety and anxiety-like behaviors concomitant to decreases in memory in mice administered the high-fat diet-associated microbiota.  To validate that differences in gut microbiomes were the root cause, analysis of cecal and fecal samples from mice indicated that the gut microbiomes in both high fat diet and normal diet groups had distinct phylogenetic profiles, demonstrating that microbiota populations from each group were indeed distinct. 

Researchers next analyzed biological protein markers associated endotoxins and inflammation in the gut, as well as markers for injury and inflammation in the brain.  Several inflammatory-associated markers were significantly upregulated in the high-fat diet group, indicating disruption to intestinal permeability and inflammation.  Furthermore, expression of inflammatory protein markers in the brain was significantly increased in the mice with the high-fat diet microbiota, and two proteins known to maintain integrity of brain vasculature were significantly reduced.  Additionally, a protein known to be present during normal synaptic function was significantly reduced. 

Collectively, these data link disturbances in gut and brain physiology resulting in behavioral dysfunction with obese-specific microbiota rather than the state of obesity.  Importantly, however, this study reveals a potential therapeutic target to remedy behavioral disorders that many have previously perceived as a consequence of simply being obese.  

Does eating fermented foods help you lose weight?

Kimchi is a Korean food that traditionally consists of fermented cabbage and spices.  It is a staple in the South Korean diet, and is one of the most frequently consumed fermented foods.  The presence of bacteria in the kimchi has led many to speculate that it can exert a positive influence on the microbiome, and kimchi is believed to have anti-obesity effects.  In order to test this hypothesis researchers from South Korea conducted a clinical trial in which they put obese women on a kimchi diet.  The women were split into two groups, one of which consumed fermented kimchi, while the other consumed non-fermented kimchi.  A summary of the study was recently published by Molecular Nutrition and Food Research.

Surprisingly, fermentated kimchi did not appear to affect the women’s body measurements or specific health indicators when compared to the non-fermented version.  For example, women on both diets had similar decreases in weight, waist circumference, body fat, blood pressure, and cholesterol. There were some important differences though, fermented kimchi increased fasting insulin levels and fasting blood glucose.

The scientists also measured the two groups’ gut microbiomes and blood gene-expression in the study.  The group that ate fermented kimchi had higher abundances of Bacteroides and Prevotella in their microbiomes, and an increased Bacteroides/Firmicute ratio, which has been linked to weight loss.  Bifidobacterium longum, a major lactic acid bacterium that ferments kimchi, has also been linked to weight loss, and to this end, a significant correlation between an increase of this bacterium in the microbiome and decrease in waist circumference was observed.    In addition, a gene known as Acyl-CoA synthetase long-chain family member 1 was found to be significantly upregulated in subjects consuming fermented kimchi compared to those consuming fresh kimchi. This gene plays an important role in metabolism, and it is important in breaking down fatty acids. A second gene, aminopeptidase N (ANPEP) was also expressed more in subjects consuming fermented kimchi.  ANPEP is important for regulating inflammation, and has been associated with a healthy blood pressure.

Overall, this study showed fermented kimchi possibly has beneficial effects on metabolism and immunity when compared to the non-fermented variety. While this study is limited by its small sample size, among other factors, it still shows that the bacteria involved in the fermentation process could benefit us in more ways than we currently know.  These bacteria not only make kimchi taste good, but they may make us healthy too!

Specific bacteria and overall diversity linked to severity of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is an inflammation of the gut that occurs due to bacterial infection in premature infants.  It has long been considered that a ‘healthy’ microbiome is important to preventing NEC in low birth weight infants, and, as we have written about before, there is a lot of science that supports this.  Still though, it is not known which bacteria are most responsible for causing NEC, and how overall diversity is associated with the disease.  Many studies have tried to nail this down, but there has been conflicting results.  Scientists at Louisiana State University thought that perhaps these conflicting results were from neglecting to consider the severity of the NEC as a variable in each study.  They hypothesized that the infants’ microbiomes would vary depending on the severity of the NEC, and that the most severe cases would show a characteristic microbiome that may be important to understanding the disease.  They published their results in the Journal Microbiome last week.  

The scientists studied the microbiomes of 74 healthy infants and 21 infants suffering from NEC.  They then categorized the NEC infants into three groups based on the severity of the disease.  The scientists learned that two bacterial genera, Veillonella and Streptococcus, were more abundant in all the NEC microbiomes compared to non-NEC controls.  They also discovered that overall microbiome diversity was decreased in NEC versus controls.  When the researchers looked microbiome differences that were a function of NEC severity they discovered that Clostridia were completely absent from the microbiomes of infants suffering from the most severe NEC and its increased with decreasing severity of NEC (15% in controls, 12% in mild NEC, 3% in moderate NEC, and 0% in severe NEC).  In addition, a similar trend was seen with diversity, it decreased with severity of NEC.

Many Clostridia species have been associated with a healthy microbiome, and they may be critically important to maintaining a homeostasis in the gut.  According to this study, their abundance appears to be of upmost importance in premature infants, and this should be considered moving forward.  Many countries administer probiotics to low birthweight infants who are at risk for NEC, but this is not yet down in the United States.  Fortunately, there are a number of clinical trials that are trying to nail down the science so that the FDA has enough evidence to make a recommendation.

Traditional societies’ and modern societies’ microbiomes differ

Traditional people of the Andes mountains.

There is a prevailing thought amongst some in the microbiome field that the 'Westernized' diet and lifestyle is responsible for many diseases that are not observed in traditional societies, which are afflicting a growing population.  Unfortunately, it is somewhat difficult to study how the 'Western' microbiome has changed because most of the world’s population could be considered to have this microbiome.  Fortunately, there are still some societies that forage for their own food and have had a consistent diet for much of their history.  The belief is that these 'traditional' societies have microbiomes that better resemble those of ancient peoples, and by unlocking the mysteries of these people’s microbiomes we can better understand these 'Western' diseases.

With this in mind, scientists from the University of Oklahoma studied the microbiomes of three groups of people with three different dietary habits: the Matsés hunter gatherers from Peru, the Tunapuco agriculturists from the Andes, and the residents of Norman, Oklahoma.  The Matsés ate primarily fish and meat along with many vegetables, the Tunapuco ate primarily potatoes and other roots along with small game, and the Oklahomans followed a typical Western diet.    The researchers found that both traditional societies had much higher microbiome diversities than the Oklahomans.  While each society had different comprised of different species of bacteria, interestingly, both traditional societies had higher levels of the genus Prevotella and Treponema than Oklahomans, who themselves were richer in Bacteroides.

Interestingly, Treponema are rarely seen in the microbiomes of Westerners, which may lead to the belief that these were important symbionts to our ancestors.  Nevertheless, there were many similarities between the all the microbiomes as well.  According to this study there is little doubt that our microbiomes have changed immensely in modern history.  How these changes may be related to so-called ‘diseases of wealth’, though, is still an open question. 

Social constructs and behaviors can predict microbiome composition

It has been well documented that the microbiome is linked to various health disorders or conditions such as obesity, cancer, heart disease, or autoimmune disease.  However, there are still many unknowns regarding specific host-species interactions and the exact role of the environment in shaping this relationship.  In particular, we do not entirely understand how social interactions can influence and even predict our microbiome compositions, nor do we truly understand the strength of this relationship.  Can our behaviors predict the composition of microbiota populations that reside inside of us?

A recent study addressed this by examining how social interactions can specifically influence and predict the gut microbiome compositions of baboons.  Baboons are highly social primates that live in extended family groups.  It has already been shown that common group membership and dietary intake can influence and predict gut microbiota composition.  However, there is a lack of understanding as to how more complex socially driven behaviors can modulate microbiota populations.  To address this, researchers examined grooming patterns in baboons – a characteristic primate behavior that solidifies social bonds – to assess whether these behaviors predicted microbiome populations.  Furthermore, researchers investigated if grooming patterns within groups could also predict microbiome composition, and if there are particular bacterial strains that have a greater aptitude toward social transmission.

Two distinct baboon groups of 48 animals in total that were geographically isolated by a few kilometers were studied in their respective natural habitats.  Behavioral observations and analyses were recorded and fecal samples were collected opportunistically to generate metagenomics data of the distal gut microbiota composition and genealogy.  In accordance with previous data, group membership was the strongest predictor of gut microbiome composition.  Additionally, group membership was shown to be the strongest predictor compared to other metrics including sex and age, explaining 18.6% of global variation in gut microbiota species.  Diet is a major confounding factor that the researcher’s considered, but they controlled for this variable by conducting the study in a homogenous savannah where food consumption was largely consistent between both groups. 

The researchers next turned to correlating grooming behaviors with variable microbiota gut composition, as it has been previously demonstrated that the “strength” of a grooming relationship can vary in baboons.  Data indicated that stronger grooming partners had higher degrees of similarities in respective gut microbiome composition; 51 out of 327 species were predicted by grooming strength.  Interestingly, the “socially enriched” bacterial species identified consisted of a cohort of gram negative bacteria that have been linked to health benefits in humans.

We have certainly grown to understand that the host-species relationship is variable and labile to external circumstance.  However, as this study indicates, the delicacy of this relationship may be extraordinarily profound – changing the dial on the strength our social interactions could shape the microbiome within us.  The correlation and predictive value of this relationship is an especially important consideration for human health.  If more confirmation of this relationship is demonstrated in the future, novel and creative behavioral preventive therapies can be devised to shape and/or manage our gut microbiome.