The microbiome affects celiac severity in mice

In non-celiac people, gluten is broken down into its constituent proteins and does not elicit any immune response.  In celiac disease, however, the gluten proteins cause inflammation, which can result in a number of GI issues.  The microbiome has long been thought to play a role in this disease, because of its importance to immune mediation, and its role in gluten breakdown.  An international group of scientists recently tested the role of various different characteristic microbiome communities on the immune reaction in mice with celiac disease.  They published their results last week in the American Journal of Pathology.

The scientists used a mouse model for celiac disease that involved genetically modified mice that had an immune response to gluten.  They split the mice into three groups, one group had a typical healthy microbiome, the next had a healthy microbiome but without proteobacteria, and the final group was germ free (i.e. completely lacking a microbiome).  When the germ free mice were challenged with gluten they had the highest inflammatory response.  This included increases in immune cells, and breakdown of the intestinal villi.  Unsurprisingly, when the germ free mice were colonized with normal microbiota, their inflammatory response was attenuated.   The scientists then discovered an important relationship between celiac’s and Proteobacteria.  The mice that harbored this phylum had more severe responses to gluten, suggesting that these bacteria somehow worsen the inflammatory response to gluten.  Antibiotic treatment that increased the amounts Proteobacteria, and the relative abundances of Escherichia, Helicobacter, Pasteurella, and Lactobacillus, also increased the inflammatory response.

The exact mechanisms by which the microbiome are mediating the immune response are unclear.  Bacteria are known to induce various immune cells and also break down gluten, and these mechanisms may be involved.  In either case gluten sensitivity and celiac disease are clearly affected by the microbiome.

Microbiome affects blood glucose levels after eating, can help predict glycemic response to foods

Postprandial (post-meal) glycemic response (PPGR) is the effect that food has on blood glucose levels.   Eating a sugary candy, for example, will raise blood glucose levels, whereas drinking water will not.  PPGR remains an important predictor for metabolic syndrome and type II diabetes, so it has an important role the obesity epidemic.  Unfortunately, PPGR is difficult to predict, and efforts that are based on individual foods themselves have failed.  New research shows that there are many factors, including the microbiome, that are important to predicting blood glucose after a meal.  The research out of Israel and published in the journal Cell presents a new model that can more accurately predict PPGR that is based on personalized factors.

The researchers catalogued 800 peoples’ meals over 7 days while continuously measuring their blood glucose levels.  In addition they monitored their gut microbiota, weight, sleep, and various other lifestyle factors.  After evaluating the data, the scientists realized that identical foods had vastly different PPGRs.  For example, bread could have a 8 fold variation in glycemic response depending on the individual.  In order to explain these differences, the scientists identified several significant associations between the microbiome and the PPGR from specific foods.  For example, on the phyla level high abundances of Proteobacteria and Enterobacteriaceae were associated with poor glycemic controls.  On the species level Eubacterium rectale, which is known to ferment fiber, was correlated with low glycemic response, and Parabacteroides distasonis, which had previously been associated with obesity, was correlated with hight glycemic response.  The scientists then aggregated all of their data, including microbiome data, and created a predictive algorithm for the PPGR from foods for individuals.  This algorithm accurately predicted the glycemic response from foods on a personalized level, and was more informative than general food based predictions.

This study speaks to the power of personalized medicine that is based on the microbiome.  Knowledge of our own microbiome could be used to advise our dietary choices in order to choose foods that will lead to low PPGR, and decrease our risk for metabolic syndrome.  Overall, the scientists determined that of all foods, eating fiber was most beneficial because it lowers glycemic response over the long term.

The microbiome’s response to the flu and its treatment

In 2013 there was an avian flu (H7N9) outbreak in China that affected 140 people, killing 46 of them.  During the outbreak doctors from one of the major hospitals in China treated 40 of these patients by giving them antivirals and antibiotics, amongst other first line treatments.  In addition, they gave probiotics along with the antibiotics to restore the gut microbiome.  All the while, they measured the patients’ microbiomes to track how they changed throughout the course of treatment.  The results of this study were published last week in the journal Nature Scientific Reports.

Twenty six patients were enrolled in the study, and each of them was given antibiotics within 6 hours of admission to the hospital.  In addition, each one was given Clostridia probiotic capsules along with the antibiotics.  Thirty one healthy control stool samples that represented the demographics of those undergoing flu treatment were also measured as a part of the study.  Before the antibiotics were taken, the patients with the flu already had altered microbiomes that were low in diversity and had lower abundances of Bacteroidetes and higher levels of Proteobacteria.  After antibiotics were given there was a dramatic shift in the microbiomes, that was characterized by a relative increase in the abundance of Escherichia coli.  In addition, the scientists noted that the probiotics were in fact increasing the amounts of Clostridia in the guts of patients who took them, and that the probiotics may have led to better clinical outcomes.  In their hospital only 20% of patients died of the flu, whereas 40% died in the rest of China.

The major takeaway from this study is the changes that the flu has on the microbiome, decreasing diversity and altering the levels of certain phyla.  The fact that the probiotics did appear to take hold and improve clinical outcomes is interesting, but the study was extremely small and limited in its scope to reach any statistically significant conclusions.  Overall though, this study suggests that if you come down with a flu that it may be wise to feed and nourish your microbiome because it is ‘getting sick’ right alongside you.

Asthma could be brought on by maternal diet and lack of bacterial metabolites

Asthma has become increasingly prevalent in Western societies, and while many theories have been explored as to the reason for this rise in prevalence, many are beginning to explore connections between dietary intake and associations with the microbiome as a manifestation for this malady.  High fat, low fiber diets – which are common in the West – are associated with high rates of asthma.  Investigators in Australia sought to explore this relationship further by understanding the cellular underpinnings of these associations.  Specifically, they explored whether or not high fiber diets in mice could suppress the onset of Allergenic airway disease (ADD -i.e. asthma).  Furthermore, maternal fiber intake was also examined to see what affects would result for the progeny when challenged with asthma inducing conditions.  They published the results in Nature Communications.

Using 16S sequencing the researchers first confirmed that the high fiber diet shaped gut microbiome composition in mice.  Specifically, a significant difference was observed between control diet and no fiber diet.  Bacteroidetes were highly abundant in mice that were fed the high fiber diet, including high acetate producing Bacteroides acidifaciens strain, while Proteobacteria were found abundant in the no fiber diet.  High fiber diet mice also displayed higher levels of short-chain fatty acids, metabolic products of the gut microbiota that provide overall positive health benefits. 

Turning next to the pathology, experimenters were first able to validate that HDM did indeed induce AAD, as confirmed by inflammatory cells and signal markers found in the bronchoalveolar fluid of mice.  Indeed, mice that were on the high fiber diet did not develop AAD symptoms.  Interestingly, this was also shown in control animals who were administered HDM but were provided acetate (a short-chain fatty acid) in their drinking water. 

Mice were then bred and split into three dietary groups based on diet, a control group, high fiber group, and no fiber group.  Allergenic airway disease (AAD) was induced using a house-dust mite (HDM) model which replicates certain aspects of human asthma.  Diets were provided three weeks prior to sensitizing the animals to HDM, and AAD was evaluated after 16 days following 15-day HDM exposure.

Pregnant mice were also subjected to the three different diet regiments in the previous experiment.  The offspring were born and given a control diet, but after 6 weeks they were administered AAD.  The mice that were born from mothers on the high fiber diet did not develop AAD into adulthood, demonstrating that maternal diet can suppress AAD in adult offspring.  Interestingly, these findings were correlated with human data that demonstrated that high fiber diets in mothers’ in late-stage pregnancy was correlated to high acetate in serum samples.  Maternal acetate levels above median levels of samples taken was associated with significantly less visits to the general practitioner for wheezing complaints and/or asthmatic incidences in their children.    

Increasing numbers of studies are showing similar patterns that behaviors of the mother can affect microbiome transfer to progeny, consequently affecting the health and development of the offspring.  One of these important factors as we have seen is the diet of the mother.  As further evidence is uncovered as to the importance of high fat diets and specifically the diet of the mother, it will be important to have conversations on the best way to educate the public about this evidence as well as implement recommendations for dietary habits during pregnancy.