Genetic Susceptibility + Environmental Exposures + Gut Microbial Ecology + Stress Coping
There are few conditions that are better suited to the precision medicine approach than inflammatory disorders of the gastrointestinal (GI) tract. At the Harlin Center, we focus on genetic susceptibility and microbial ecology, as well as dietary and lifestyle choices and stress — each of which play important roles in modulating the molecular mechanisms at the root cause of disease. There are few diseases that better exemplify this relationship between environment and gene expression than those involving the GI tract.
Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD)
Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are two disorders that share some of the same symptoms, but they have distinct differences. Both can be chronic conditions, and it is possible to have both conditions at the same time. IBS is a syndrome, meaning it is a collection of symptoms and findings. A syndrome is an umbrella term for multiple diagnoses. As such, IBS lacks a single pathogenic mechanism. IBD causes more serious symptoms than IBS. Although the exact etiology of inflammatory bowel disease is not completely understood, research suggests that IBD begins with a genetic predisposition for an autoimmune-based attack against normal cells lining the intestinal tract. Any single autoimmune disease increases the likelihood of another and many patients with IBD have a concomitant autoimmune disorder. Although researchers do not know the exact cause of IBS or IBD, there is much we do know.
Irritable Bowel Syndrome
Irritable bowel syndrome is not a disease unto itself, but a collection of symptoms with many of possible causes. IBS is characterized by abdominal pain, bloating, and either constipation, diarrhea or both. Epidemiologic studies estimate that 20-30% of the population suffers from IBS.
Genetic predispositions manifest in clinical findings, treatment responses, and potential biomarkers of IBS. There is growing evidence that genetic contributions, inflammatory activation, and psychosocial factors may play important roles to the development of IBS. (1 Cheung)
Many IBS patients with diarrhea or chronic diarrhea have a condition known as bile acid malabsorption (BAM). Studies suggest that 30% or more of patients with previous unexplained chronic diarrhea have impaired BAM. (2 Smith). However, there are many potential explanations for what might cause IBS symptoms: fructose malabsorption, gluten sensitivity, poor diet, an eating disorder, diverticulosis, gallbladder dysfunction, motility disorder, parasites, bacterial or fungal overgrowth, leaky gut, microscopic colitis, thyroid disorders, reaction to a pharmaceutical, stress, and the list goes on. (3 Chutkan)
Differences in the Microbiota
Over the past decade, the majority of data support the notion that the composition of luminal and mucosal microbiota differs among specific subgroups of IBS patients and healthy individuals. The diversity of the microbial population is reduced, the proportion of specific bacterial groups is altered and the degree of variability in the microbiota composition is different in IBS patients when compared with healthy subjects. Examples of these modifications are a decreased amount of Lactobacilli and Bifidobacteria along with an increased amount of aerobes relatively to anaerobes in IBS patients. Finally, mucosal bacteria have been found to be more abundant in IBS patients than in healthy controls. (4 Distrutti)
Inflammatory Bowel Disease
Inflammatory bowel disease causes ulcers in the tissue lining the digestive tract. The two most common inflammatory bowel diseases are Crohn’s disease and ulcerative colitis. Crohn’s disease (CD) can affect any portion of the gastrointestinal (GI) tract, but mainly affects the small intestine. Ulcerative colitis (UC) can affect the small intestine, but more commonly affects the last segment of the colon. Arthritis, or inflammation of the joints, is the most common extraintestinal complication of IBD.
Approximately 1 in 200 people have IBD. The etiology and pathogenesis of IBD have been associated with the interaction of environmental factors, shifts in the intestinal microbiota, and genetic and immune factors — together which initiate an abnormal immune response and chronic inflammation. A cure for IBD would control inflammation and establish appropriate immunological tolerance.
Although Crohn’s disease and ulcerative colitis are chronic conditions, nutritional interventions show promise. A small 2012 Japanese study compared a semi-vegetarian diet (SVD) with an omnivore diet in 22 patients with Crohn’s disease. Remission (disease-free status) was maintained in 15 of 16 patients (94%) in the SVD group vs two of six (33%) in the omnivorous group. Remission rate with SVD was 100% at 1 year and 92% at 2 years. SVD showed significant prevention in the time to relapse compared to that in the omnivorous group. (Chiba)
The Rise of Inflammatory Diseases
The increasing incidence of inflammatory conditions, such as IBD, is creating an urgent need for a better understanding of disease progression, with the aim of developing effective and targeted treatments for inflammatory diseases. Since the 1950s, Western countries have seen a dramatic decrease in infectious diseases, while at the same time, a dramatic rise in inflammatory diseases.
Antibiotic use is implicated in both trends. We’ve long known about the effectiveness of antibiotics in treating infectious diseases. We have only recently begun to understand the ramifications of the widespread use of antibiotics. Antibiotic use changes gut microbiota composition and creates a lack of microbial diversity. This is believed to alter the immune response and predispose to a range of diseases, particularly inflammatory diseases. (5 Shen)
The second half of the 20th century transformed American eating habits, as well as those of other Western countries, and not in positive ways. Our modern diet, along with antibiotics, has also been implicated in the rise of inflammatory diseases. The “Western diet” increased consumption of refined carbohydrates and fats in highly processed foods, and decreased intake of dietary fiber. On average, we consume only about 15 grams of fiber daily — half of the daily recommended intake.
The Health Benefits of Fiber
The health benefits of fiber have long been appreciated, but our understanding of the different kinds of fiber didn’t come until the mid-1990s. Researchers and nutritionists discovered that inulin, oligofructose, and fructooligosaccharide (fibers labeled prebiotics) caused some remarkable changes in the bacterial composition of the colon. There is accumulating evidence to suggest that these soluble prebiotics promote health, strengthen immunity, and protect us from many inflammatory diseases. Soluble fiber resists digestion in the human small intestine and reaches the colon where it is fermented by the gut microflora. The fermentation of polysaccharide fiber creates byproducts, such as short-chain fatty acids (SCFAs) — namely acetate, propionate and butyrate. Bacterial fermentation of polysaccharides results in the production of acidic fermentation end products, primarily lactic acid and SCFAs, that reduce the colonic pH, which in turn impacts the composition of the microbial communities present in the gastrointestinal tract. (7 Holscher) The decrease in colonic pH promotes the growth of beneficial bacteria, such as lactobacilli and bifidobacteria. SCFAs can be absorbed into the circulation and have important systemic anti-inflammatory effects.
The mucus layer covering the gastrointestinal mucosa is considered the first line of defense against pathogens. MUC genes code for the protein backbone of mucins. Butyrate affects MUC genes and is able to upregulate colonic mucins. These findings suggest that butyrate influences the composition and properties of the mucus gel and thus has a protective function. (8 Gaundier)
Butyrate is an important SCFA. Besides being an energy source for the epithelial cells and improving mucosal barrier function, it also influences a wide array of cellular functions affecting health. Research suggests that butyrate also has an anti-carcinogenic and anti-inflammatory effect, decreases oxidative stress, and plays a role in our satiety.(9 Hamer)
The Distal Colon
The distal part of the colon (the lower end) is the predominant location of several gastrointestinal disorders, such as ulcerative colitis and colon cancer. The complex biological interactions that result in disease pathology are only recently starting to be unraveled.
It is hypothesized that the production of toxic metabolites, such as ammonia and sulfur-containing compounds, are involved in the pathogeneses of these diseases. High-protein diets increase delivery of protein to the colon and might promote oncogenesis through the generation of toxic products. (10 Le Leu) Toxic metabolites are also created from the breakdown of our own proteins (such as mucous, and sloughed epithelial cells) due to depletion of SCFAs at the distal colon. Most micro-organisms prefer to ferment carbohydrate over protein. Fermentation is usually a rapid process occurring in the proximal colon (the upper end) so that the luminal concentration of butyrate is lower in the distal colon than in the upper end. This may explain the higher risk of adenocarcinoma in the distal colon versus proximal colon and the localization of ulcerative colitis. This also underscores the interest for foods with a slow fermentation profile, potentially leading to increased concentrations of butyrate in the distal colon.
The Mucus Barrier Inhibits Inflammation
In the large intestine, the mucus barrier inhibits inflammation by preventing the passage of bacteria and food derived antigens. (An antigen is a toxin or other foreign substance that induces an immune response in the body, especially the production of antibodies.) If the bacteria get through that mucus layer and reach the intestinal walls, inflammation is the result. The main role of goblet cells is to secrete mucus in order to protect the mucous membranes. This mucus is a gel-like substance that is composed mainly of mucins, glycoproteins, and carbohydrates. Alterations in goblet cell function — composition and thickness of the intestinal mucous layer — have been found in several intestinal disorders. For example, a reduced mucous thickness and decreased mucin production have been reported in UC patients and hyperproduction of mucins is typical in CD patients. (15 Dorofeyev)
Replenishment of the Intestinal Mucosal Barrier
A 2017 mouse study found that the Gatm gene is required for the rapid replenishment of the intestinal mucosal barrier. According to researchers, the Gatm gene is needed for the synthesis of creatine, a substance made in the liver that travels to the barrier cells and allows them to utilize energy in an efficient manner. The study indicates that creatine is necessary for providing the energy needed for the rapid replenishment of the mucosal barrier. The researchers hypothesize that mutations in this gene and others needed for mobilization of energy in cells may account for some cases of IBD in humans. (16 Turer)
Another form of colitis, called microscopic colitis, is less severe than ulcerative colitis but is also an autoimmune disease. It is a type of inflammation of the colon. The disorder gets its name from the fact that it’s necessary to examine colon tissue under a microscope to identify it, since the tissue may appear normal with colonoscopy or flexible sigmoidoscopy. Studies show that it can be the cause of unexplained diarrhea, bloating, and cramping in up to 13 percent of people with these symptoms.
Common dietary triggers make the condition worse. These include dairy, caffeine, artificial sweeteners, and gluten. A wide variety of medications have been associated with microscopic colitis, including nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, certain kinds of antidepressants (selective serotonin reuptake inhibitors or SSRIs), acid-suppressive drugs (proton pump inhibitors), and cholesterol-lowering agents (statins).(3 Chutkan)
Over the last decade, remarkable progress has been made in the understanding of disease pathophysiology — the functional changes that accompany a disease. Several pathophysiologic mechanisms have been associated with gastrointestinal disorders, including altered gastrointestinal motility, impaired pathogen clearance, intestinal inflammation, immune activation, gut permeability, gut-brain dysregulation, sensitization after injury, central nervous system dysfunction, and changes in the gut microbiota.
Genetic Assessments Help Pinpoint the Root Cause
Polymorphisms in multiple genes appear to influence the frequency and severity of symptoms, as well as the therapeutic response to treatment. Genetic assessments help pinpoint the root cause of symptoms and can direct a treatment plan.
In 1975, Harvard cardiologist Herbert Benson, MD wrote a book titled The Relaxation Response. Dr. Benson introduced the concept that the mind and the body were not separate systems that functioned independently. He proved that transcendental meditation (TM) alone could lead to startling changes in heart rate, metabolic rate, and breathing rate and that as a group, people who practiced TM had much lower blood pressure. At the time, his findings were groundbreaking in Western medicine.
As Dr. Benson demonstrated, emotions such as fear and stress result in real and measurable physical changes. Feelings aren’t just in our minds; they’re also very much in our body, especially our guts.
The “gut-brain axis” is a two-way street; our digestive health and emotions affect one another. Psychological states such as anxiety or stress can wreak havoc on our digestive system: it increases cortisol production, speeds up colonic contractions, increases stomach acid production, causing heartburn and nausea, shunts blood away from the intestines, and decreases enzyme secretion — resulting in one major stomach ache. Conversely, the gut produces its own set of chemical messengers to the brain. Our GI tracts are lined with millions of nerve cells that have sometimes been called “the second brain.” Molecular-based microbial profiling has revealed compositional changes in the microbiota of at least a subset of IBS patients. Recent studies have shown that perturbation of the microbial composition of the gut alters brain chemistry and can induce anxiety. (Moser, Collins) When digestion is disrupted for whatever reason, these nerve cells set off alarms to the nervous system that exacerbate symptoms of anxiety.
We now also know that stress can have a negative impact on gut microbial diversity and composition, contributing to the progression of both IBS and IBD. Likewise, controlling our stress response, or inducing the relaxation response, can have a salutary effect on our gut health.
A Uniquely Individualized Programs for Optimal Health
Combined with an extensive review of symptoms, medical history, lifestyle, diet, and physical exam, we consider two genomes – your DNA genome and your gut microbiome – to identify the root cause of your gastrointestinal symptoms and create a uniquely individualized program to optimize your health.
- Cheung CK, Wu JC. Genetic polymorphism in pathogenesis of irritable bowel syndrome. World J Gastroenterol. 2014 Dec 21;20(47):17693-8.
- Smith MJ, Cherian P, Ruju GS, et al. Bile acid malabsorption in persistent diarrhea, J R Physicians Lond, 2000, vol. 34 (pg 448-451)
- Chutkan R, Gutbliss: A 10-Day Plan to Ban Bloat, Flush Toxins, and Dump Your Digestive Baggage. Penguin Publishing Group.
Neuman MG. Immune dysfunction in inflammatory bowel disease. Transl Res 2007; 149: 173–86.
- Distrutti E, Monaldi L, Ricci P, Fiorucci S, World J Gastroenterol. 2016 Feb 21; 22(7): 2219–2241. Published online 2016 Feb 21. doi: 10.3748/wjg.v22.i7.2219
- Shen SJ, Wong CHY. Bugging inflammation: role of the gut microbiota. Clinical & Translational Immunology (2016) 5, e72; doi:10.1038/cti.2016.12 Published online 15 April 2016
Brown K, DeCoffe D, Molcan E, Gibson DL, Diet-induced symbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012 Aug; 4(8): 1095–1119. Published online 2012 Aug 21. doi: 10.3390/nu4081095
- Holscher HD, Dietary fiber and probiotics and the gastrointestinal microbiota, Gut Microbes. 2017; 8(2): 172–184. Published online 2017 Feb 6. doi: 10.1080/19490976.2017.1290756
- Gaudier E, Jarry A, Blottiere HM, et al. Butyrate specifically modulates MUC gene expression in intestinal epithelial goblet cells deprived of glucose. Am J Physiol Gastrointest Liver Physiol 2004; 287: G1168–74.
- Hamer HM., Jonkers D, Venema K, Vanhoutvin S, Troost FJ, and Brummer RJ. (2008), Review article: the role of butyrate on colonic function. Alimentary Pharmacology & Therapeutics, 27: 104–119. doi:10.1111/j.1365-2036.2007.03562.x, January 2008
- Le Leu RK, Brown IL, Hu Y, et al. Effect of dietary resistant starch and protein on colonic fermentation and intestinal tumorigenesis in rats. Carcinogenesis 2007; 28: 240–5.
- Moser G, Fournier C, Peter J. Intestinal microbiome-gut-brain axis and irritable bowel syndrome. Wien Med Wochenschr. 2017 Sep 8.
- Collins SM, The intestinal microbial in the irritable bowel syndrome. Int. Rev. Neurobiol. 2016;131:247-261.
- Distrutti E, Monaldi L, Ricci P, Fiorucci S, World J Gastroenterol. 2016 Feb 21; 22(7): 2219–2241. Published online 2016 Feb 21. doi: 10.3748/wjg.v22.i7.2219
Kirsty Brown, Daniella DeCoffe, Erin Molcan, Deanna L. GibsonNutrients. 2012 Aug; 4(8): 1095–1119. Published online 2012 Aug 21. doi: 10.3390/nu4081095
- Dorofeyev AE, Vasilenko IV, Rassokhina OA, and Kondratiuk RB, “Mucosal Barrier in Ulcerative Colitis and Crohn’s Disease,” Gastroenterology Research and Practice, vol. 2013, Article ID 431231, 9 pages, 2013. doi:10.1155/2013/431231
- Turer E, McAlpine W, Wang K, Lu T, Li X, Tang M, Zhan X, Wang T, Zhan X, Bu C, Murray AR, Beutler B. Creatine maintains intestinal homeostasis and protects against colitis. Proceedings of the National Academy of Sciences, 2017; 201621400 DOI: 10.1073/pnas.1621400114
- Marteau P, Probiotics, prebiotics, synbiotics: ecological treatment for inflammatory bowel disease? Gut 2006; 55: 1692–3. (not referenced directly)
- Gendler SJ, Spicer AP. Epithelial mucin genes. Annu Rev Physiol 1995; 57: 607–34. (not ref directly)
- Henström M, Diekmann L2, Bonfiglio F et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2016 Nov 21. (not ref directly)
- Chiba M, Abe T, Tsuda H, Sugawara T, Tsuda S, Tozawa H, Fujiwara K, Imai H. Lifestyle-related disease in Chron’s disease: relapse prevention by a semi-vegetarian diet. World J Gastroenterol. 2010 May 28;16(20):2484-95.
- Haberman, Y rt al. Pediatric Crohn disease patients exhibit specific transcriptome and microbiome signature. J. Clin Invest. 2014 July 8; 124(8):3617-33.