Lupus, Sjögren’s syndrome, and the microbiome

Drawing of the typical 'butterfly rash' found in Lupus.

Sjögren’s syndrome is an autoimmune disorder characterized by the destruction of exocrine glands, like those that produce tears and saliva. Lupus is an autoimmune disease characterized by inflammation of various body tissues. People suffering from both these disorders produce antibodies and mount an immune response against a peptide, Ro60, that occurs naturally in the body. While this autoimmune response may not be the cause of these diseases, it likely contributes to their severity. An article published by Clinical Immunology shows that specific proteins derived from bacteria in the microbiome can activate the production of these self-destructive antibodies, suggesting that the microbiome could play a role in initiating autoimmunity.

Researchers at the University of Virginia used T cell hybridoma activation and epitope mapping to discover which peptides activate the specific Ro60 immune response.  When they compared these molecules with molecules known to be produced by the human microbiome, they found several instances of proteins produced by the microbiome that could potentially activate antibodies against Ro60.

The most potent peptide from the screening was derived from a specific bacterium, Capnocytophaga ochracea, that is commonly found in people’s mouths and is sometimes pathogenic. According to their data, these bacteria should produce a protein that most strongly activates the antibodies against Ro60. After experimentation, they found that the microbe alone was not able to activate the antibodies. However, a synthetically produced version of the protein from C. ochracea, was successful in activating the antibodies.   

This work is important because it suggests that host bacteria may have a strong connection in generating autoimmune responses.  At least in the cases of Lupus and Sjögren’s syndrome, certain bacteria may induce humans to create antibodies against natural body products, and this immune response contributes to the diseases.

Probiotics help prevent mammary cancer in mice

Happy Halloween!

Editors note:  We know we wrapped up the breast cancer awareness last week, but then we found this fascinating paper and just had to write about it.  Plus, it is the last day of Breast Cancer Awareness Month, so this post is officially wrapping it up.  And oh yeah, Happy Halloween!  We hope all our trick-or-treating readers receive plenty of fermented foods tonight.

An article published in the International Journal of Cancer explores the effects of probiotic consumption on mice with a predisposition to mammary cancer.  The article also attempts to establish a link between the probiotic and its influence on the immune system.

First, researchers fed mice a high fat diet, similar to a fast food diet.  Compared to controls, these mice had a higher incidence of mammary cancer.  They then repeated these trials but gave some of these fast food mice Lactobacillus reuteri.  Those mice that received the probiotic had a significantly lower rate of mammary cancer symptoms than those that didn’t.  The researchers then conducted a study to see if L. reuteri could help protect from cancer when the factor of obesity was removed.  In this experiment they genetically predisposed some mice to get mammary cancer, and fed these mice the probiotic.  They found that consumption of L. reuteri delayed or completely prevented the development of tumors, when compared to untreated mice.  The researchers go on to suggest that L. reuteri may be increasing the production of a specific type of immune cell, the CD25 T-cell, and this immune cell may be exerting the underlying anticancer effects they are observing.  They tested this hypothesis by transplanting CD25 T-cells into cancerous mice, and blocking CD25 T-cells in mice that were predisposed to cancer, though given the probiotic.  In the mice injected with CD-25 T-cells, their cancer rate decreased.  In the mice where CD25 T-cells were blocked, their cancer rates were the same as mice without the probiotic.

Probiotic bacteria decreased already developed tumors, and, in some cases, prevented tumor growth in animals predisposed to cancer by directly influencing the immune system.  These results reinforce the idea that probiotics are important for a healthy immune system, which is important for overall health.  So keep eating that yogurt, kimchi, and kombucha!

The effects of fasting and starvation on the microbiome

Researchers at St. Mary’s University, in Texas, published a study in FEMS Microbiology Ecology about the impact that fasting and starvation have on the gut microbiome. Organisms from five different vertebrate classes were studied and the changes in the composition of their colon and cecum microbiome were observed in response to different fasting periods.

Results differed among the animals studied in terms of diversity of their colon microbiome. Tilapia showed a continuous increase in diversity, southern toads showed a 33% increase in early-fasting and a 51% increase in late-fasting, leopard geckos showed no difference, Japanese quail showed less diversity in long-term fasting, and weanling mice showed a 15-22% increase in diversity. Results for the observed cecum microbiome phylogenetic diversity, compared to the respective nourished vertebrates, are as follows: Tilapia showed a decrease in diversity, quail showed a decrease at the early-fasting stage but a return to normalcy at later stages, mice showed no changes.

The only similarity in colon bacteria identified from this study was that the tetrapods (toads, geckos, quail, mice) all showed a decrease in abundance of Coprobacillus and Ruminococcus. In the cecum, tilapia, quail, and mice showed an increase in Oscillospira and a decrease in Prevotella and Lactobacillus. While it must be considered that these diverse hosts tend to house different microbial communities when healthy, which can account for the few similarities observed between the different vertebrates, the study results are important because they show that microbial responses to prolonged fasting varies between vertebrates.  

While these studies were conducted in non-humans, we know that starvation results in important changes in the microbiome.  People around the world suffer from starvation and malnutrition, and it is not only because they lack food and nutrients.  Instead they suffer from immature microbiomes, which can severely impact health.  Furthermore, diet interventions only temporarily repair the microbiome, so the effects of malnutrition persist after the intervention ceases.  Finally, the differences in microbiomes between developed nations and traditional societies may even play in a role in vaccine effectiveness, as we have previously discussed in our blog.

Asthma, COPD, and the Microbiome

Asthma and chronic obstructive pulmonary disease (COPD) are both illnesses that are caused by chronic inflammation of the respiratory tract, and recent research suggests that the microbiota of the lower respiratory tract may influence the development of these two diseases.  The upper respiratory tract, though, remained unstudied, until a new article was recently published in PLoS ONE.  This article characterized the microbiome of the oropharynx (in the upper respiratory tract) to discover the association between these problems and the microbiome.

Samples were swabbed from the oropharynx of patients who were recently diagnosed with asthma and COPD, as well as from a healthy control group.  Researchers performed 16S rRNA gene sequencing of the bacteria collected from the patients, in order to determine which bacteria were present. They found that there are few differences in microbiome diversity between asthma and COPD patients, however there was a prevalent presence of the bacteria Lactobacillus (phylum Firmicutes) and Pseudomonas (phylum Proteobacteria) in both, which were identified in only very small amounts in healthy patients. On the contrary, the upper respiratory tract of healthy individuals was found to be dominated by Streptococcus, Veillonella, Prevotella, and Neisseria, from the phylum Bacteroidetes, compared to individuals with asthma and COPD.

This study showed distinct differences in the microbiomes of diseased and healthy individuals.  The researchers also note that the low abundance of Neisseria they observed in this study has also been seen in studies of smokers, meaning that this bacteria may be important to respiratory health.  Further work is still needed, though, to determine if the bacteria identified in this study are contributing to the diseased individuals.  Even if they are not, they could still potentially be used in diagnosis. 

Can we prevent C. diff infections with other bacteria?

The microbiome of the mammalian gut helps protect the body from intestinal colonization of harmful pathogens. Antibiotic use can destroy the beneficial bacteria in our gut and allow for harmful bacteria to colonize it. Specifically, Clostridium difficile (C. diff) infection is a condition that is frequently seen in patients taking antibiotics and is often fatal.  A study published in Nature last week led by scientists at Memorial Sloan Kettering Cancer Center identified another bacteria, Clostridium scindens, that helped fight against C. diff infection. This study opens a new avenue to better predict what patients are at a higher risk of C. diff infection as well as the development of products that could prevent or even treat this condition.

A few weeks ago we wrote about an study published in the Journal of the American Medical Association that described the treatment of patients suffering from C. diff infection with a pill containing fecal material of healthy individuals.  The pill restored the microbiome to a healthy state and prevented future infection. However, little is known about what specific bacteria are responsible for resistance to infection. Why do some patients taking antibiotics get C. diff and others do not?

The scientists conducting this study identified 24 human patients undergoing allogeneic hematopoietic stem-cell transplantation, 12 who had C. diff infections and 12 who were C. diff carriers but were not infected after their transplant.  In the human study, as well as in mouse studies, they found that Clostridium scindens, an intestinal bacterium, is connected with resistance to C. diff infection. C. scindens produces an enzyme necessary for secondary bile acid synthesis, which was shown to be absent in the gut of patients infected with C. diff but present in recovered patients. This study suggests that it may be possible for doctors to better predict what patients are at a higher risk of C. diff infection by measuring the presence of C. scindens in the patient’s gut.  C. scindens could also be used in the development of preventative agents or therapeutics given to patients at higher risk or infected with C. diff.

Antibiotics decrease microbiome diversity in premature infants

In a study published in August by Nature Pediatric Research, researchers at the University of Rochester Medical Center investigated the development of preterm infants’ microbiomes after taking antibiotics.

Twenty-nine premature infants under antibiotic therapy were observed in the study.  Of the 29, 27 were fed diets of mostly breast milk, and the other two were formula fed.  Each infant was given antibiotics between 2 and 10 days, after which they had their microbiomes examined.  Then, these infants were given new courses of antibiotics for the next 20 days, after which their microbiomes were examined again.

The study showed that the amount of antibiotics taken by the infants is directly associated with microbiome diversity.  For example, after 10 days, the group that had been given 7-10 days of antibiotics had significantly less diversity in their gut microbiome than the group that only received 2 days of antibiotics. Over the next 20 days the microbiomes of each infant increased, however, suggesting that the gut continues to acquire new bacteria, and that diversity rebounds with time.  In all cases, the microbiomes contained mostly bacteria from the firmicutes and bacteroidetes phyla, which is similar to normal infants.   These results are important as they attempt to define the microbiome of preterm infants exposed to antibiotics, which is an important cohort of infants as they are most at risk for microbiome associated diseases like necrotizing enterocolitis (NEC).