Friday, 23 September 2016 12:25

“I Can’t Eat That” or How our Microbiome Influences Our Dietary Restrictions

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Published in Microbial Sciences

Allergy Testing ImageFigure 1. Food allergen patch testing. In this technique the allergen is placed on the upper back under a bandage and removed in 48 hours. The skin is observed for reaction 48-72 hours later. Source

Microbes of all kinds influence our body’s immune system and most readers are likely familiar with the example of a pathogen invading the body and being met with an army of innate and adaptive immune cells. The pathogen is identified and killed. Boom. The body did its duty, no more threat. However, our benign microbes have a surprisingly big influence our immune system. Out of the frenzy of new microbiome research, a link has emerged between overactive immune responses (such as those in autoimmune diseases we read about last week) and gastrointestinal bacteria. It appears that an imbalance of microbes in the GI tract can adversely affect how the immune system functions. In fact, we are learning more and more how normal human development is dependent on the microbes that have coevolved with us. Research to date has revealed several examples of food-centric autoimmune disorders that, surprisingly, are linked to the composition of microbes in and on our bodies. While we have only just investigated the tip of the iceberg, I’ll go over a few examples of these disorders including type-1 diabetes, allergies, and celiac disease.

 

insulin moleculeFigure 2. Human Insulin hexamer. Source

The Rise of Antimicrobials and Food Allergies

If you haven’t heard, food allergy rates are on the rise, and are now so common that schools and airlines have enacted regulations on certain foods. Children are no longer allowed to bring peanut butter sandwiches to school, bake sales have banned homemade food, and several airlines are participating in allergy-free travel to protect afflicted passengers. The first peanut allergy in modern times was officially reported in 1920 by J. D. Blackfan, and since then, reports of food and airborne allergies have become more and more common. The World Health Organization estimates that 1-3% of adults and 4-6% of children have an allergy to at least 1 of 70 reported foods. Symptoms of food allergies range from a mild itchiness in and around the mouth, vomiting, and gastrointestinal distress to anaphylaxis and possible death. There is no treatment for food allergies; those who suffer must abstain from eating foods that cause allergic reactions and often must carry around a life-saving epinephrine injector (such as the EpiPen® of recent controversy) that can prevent anaphylaxis by delivering a jolt of epinephrine to the body.

Allergies are caused by an overactive immune response to a foreign particle or protein that the body mistakes as a threat. There are a few theories on why this happens, but the the Hygiene Hypothesis is the most prevalent, and posits that the root of increasing allergy rates is due to modern access to antimicrobials and an obsession with disinfectants. Being “too clean” has ultimately led to too little microbial colonization early in life. Microbes are necessary for the development of a normal immune system (and thus, a normal immune response to non-pathogens). Some data suggest that commensal microbes acquired during vaginal birth and shortly thereafter are needed for the development of immune “tolerance” to themselves and other antigens. In studies done on infants that later developed allergies, fewer Bifidobacteria were detected during the first weeks of life. Colonization is so important, in fact, that developing allergies within the first year of life was correlated with less colonization by commensals in the first week of life. Not only that, but interaction with microbes is required for T-cell maturation in newborn infants. Unfortunately, we have yet to discover the exact species required for immune system maturation, and only have general trends to go on. In adults, it was reported that there was an inverse relationship between orofecal infections and prevalence of allergies; the sicker you were, the fewer allergies you developed. Altogether, colonization by microbes both early-on and later in life appears to be extremely important in preventing allergies, but is a hard pill to swallow for a generation raised to believe that cleaner is better, and sterile is best.

 

celiac-disease-imgFigure 3. Normal (left) and celiac (right) duodenal mucosa samples from the New England Journal of Medicine. Source

Viral Causes of Type 1 Diabetes Mellitus

Another example of an autoimmune disease linked to microbes is type 1 diabetes. Insulin is an essential hormone normally secreted by the pancreas in response to high levels of glucose in the blood, and signals the cellular uptake of glucose by recruiting glucose transporter molecules to cell membranes. But in the case of type 1 diabetes, also known as juvenile diabetes, the immune system malfunctions and causes CD4+ and CD8+ T-cells to misidentify insulin as an antigen and destroy insulin-producing β-cells in the pancreas. Insulin keeps blood glucose levels steady by ensuring that the liver is releasing sufficient amounts of glucose: if there is insufficient insulin in the liver, the liver releases glucose into the bloodstream faster than tissues can metabolize it, causing hyperglycemia. In the case of diabetes, high levels of glucose remain in the blood and put a serious strain on blood vessels and can damage them. Unmanaged hyperglycemia increases the risk of heart disease and stroke, as well as renal, vision, and nerve disorders. As a result, people with diabetes must inject themselves with insulin (commercially made today by E. coli and sometimes yeast) after meals to ensure that blood glucose levels remain constant.

Sources of GlutenFigure 4. Sources of gluten include wheat flour, spelt, barley, rye (Clockwise from top). Source

Although genetics can play a role in the development of type 1 diabetes, epidemiological studies have linked type 1 diabetes development with exposure to certain viruses. Common viral infections correlated with with diabetes include the enteroviruses Coxsackievirus B, rotavirus, mumps virus, and cytomegalovirus. Children of mothers infected with Rubella virus during pregnancy (congenital rubella syndrome) are also at risk for developing the disease. Not only can type 1 diabetes be triggered by a viral infection, but it is also associated with disruption of the normal gut microbiome. Patients have a reduced amount of beneficial microbes such as Firmicutes along with increased levels of Bacteroidetes, as well as overall decreased diversity of gut bacterial species.

Despite the massive amount of research on type 1 diabetes, there is still no cure. However, the disease can be managed through constant monitoring of sugar intake and insulin injections after meals. However, given the rising price of insulin, more research on the viral and microbial aspects to the disease may soon shed light on new treatments for this disorder.

 

An Imbalanced Gut on Gluten

Gluten allergies and intolerances have been in the headlines recently. Awareness and caution surrounding consumption of gluten, a protein found in grains like wheat, barley and rye, has skyrocketed for various reasons, and as a result, gluten-free foods are selling remarkably well. We are now finding foods that have always been gluten free (such as potatoes and vodka) with new “gluten-free” labels on them, driving sales in a demand-driven market. Consumers are afraid of gluten, but why?

Much of this fear comes from the symptoms of celiac disease, an immune response to gluten involving both innate and adaptive immunity in the small intestine. Common symptoms include diarrhea, weight loss, anemia, and bloating. But unlike other food allergies, continued exposure to gluten damages your small intestine’s lining and prevents absorption of nutrients, leading to malnutrition and associated complications. on top of all the nasty symptoms adults experience, children with celiac disease are at risk of nutrient malabsorption that can adversely affect their growth and development. This scary and uncomfortable disease can only be managed by following a strict gluten-free diet that may be, if caught early enough, able to heal and reverse the intestinal damage caused by the disease.

So how do gut microbes influence this disease? As I previously mentioned, intestinal microbiota aids in immune system maturation and the body’s ability to identify “self” vs “other.” However, gut microflora also assist  in maintaining intestinal barrier function by stimulating the proliferation of epithelial cells and help maintain the physical structure of the intestinal epithelium by transcriptionally activating the genes involved in desmosomes. On top of that, the microbiota of the intestine is extremely important in regulating the development of villi, or small invaginations of the intestinal epithelium.

However, in celiac disease patients, the makeup of gut microflora differs significantly from that of healthy control subjects. Many human studies have been conducted using a variety of methods and most seem to agree that celiac disease is associated with low levels of Lactobacilli and Bifidobacteria in the gut and with an increase in gram-negative bacterial species. Furthermore, pathogenic proteobacterial genera, which on their own have been linked to gastrointestinal symptoms, are prevalent in celiac disease patients.

Yet, celiac patients may still have hope! Studies have shown that supplementing a gluten-free diet with probiotics such as Bifidobacterium and Lactobacilli can be useful in restoring balance and diversity to gut microflora and reducing immune response to gluten. Probiotics may even increase the daily dietary gluten limit in celiac disease patients. These have the potential to also be used as a preventative therapy for those patients at high risk for the disease.

 

It’s a Micro World, After All

From digestion to food allergens, microbes clearly play a role in our interactions with food. Scientists  are continually discovering how microbes influence our metabolisms, from finding that viruses increase the chances of developing diabetes, to identifying microbiome shifts that increase our chances of developing food allergies and over-active immune responses to proteins like gluten. We still need to learn how the composition of our microbiome influences these diseases, not only through the various species compositions involved, but also through the metabolites and biomolecules in these environments. If the microbiome tickles your fancy, be sure to check out next month’s posts in ASM’s Microbial Sciences blog to learn more about the human microbiome and microbial communities!

 

Further Reading

Björkstén, Bengt. "Effects of Intestinal Microflora and the Environment on the Development of Asthma and Allergy." Springer Seminars in Immunopathology 25.3-4 (2004): 257-70. Web.

H., Hyöty, and Taylor K. "The Role of Viruses in Human Diabetes." Diabetologia 45.10 (2002): 1353-361. Web.

Marasco, Giovanni, Anna Biase Rita Di, Ramona Schiumerini, Leonardo Eusebi Henry, Lorenzo Lughetti, Federico Ravaioli, Eleonora Scaioli, Antonio Colecchia, and Davide Festi. "Gut Microbiota and Celiac Disease." Dig Dis Sci Digestive Diseases and Sciences 61.6 (2016): 1461-472. Web.

Last modified on Wednesday, 28 September 2016 12:23
Monika Buczek

Monika Buczek is a Ph.D. candidate in the Molecular, Cellular and Developmental Biology Department at the City University of New York Graduate Center. She is a member of Dr. Anu­rad­ha Janakiraman's lab at the CCNY Center for Discovery and Innovation, and her thesis research focuses on the proteolytic regulation of E.coli cytokinesis. She also teaches as an adjunct lecturer in Molecular Biology and Microbiology at the City College of New York. 

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