In anticipation of the upcoming Crohn’s and Colitis Summit, I want to share more about inflammatory bowel disease, Crohn’s disease, and ulcerative colitis. This two-part series will be a deep-dive into the root cause of inflammatory bowel disease, along with a comprehensive look at lifestyle changes and functional therapies that may provide relief. This free summit, hosted by Ravi Jandhyala and Mallika Allu of Gut Heal Protocol, will be held September 21st-27th. I will be speaking at the summit, and I encourage you to sign up if you or a loved one has Crohn’s disease or ulcerative colitis.
Inflammatory bowel disease (IBD) comprises a number of different medical conditions. The most significant of these are Crohn’s disease (CD) and ulcerative colitis (UC). These are chronic, immunologically mediated diseases with periods of relapse and remission, in addition to marked variations in mucosal inflammation from near normal in remission to severe ulceration in relapse.
UC affects only the colon with superficial inflammation, whereas CD affects the entire gastrointestinal tract and leads to transmural inflammation, strictures, fistulas, and abscess formation.
The etiology of IBD is complex, but intricate dynamic interactions between the intestinal microbiome, host genetics, and external environmental factors all play an interrelated role in the development of IBD and its subsequent outcomes.
The key mechanisms underlying the pathogenesis of these diseases are a genetically susceptible host exposed to external environmental factors, affecting gut microbiome and commensal flora. This results in a dysregulated immune response to different aspects of the gut microflora and increased intestinal permeability.
In this article, you will learn:
- The etiology (root causes) of IBD, CD, and UC,
- How the intestinal microbiome and your body’s immune response lead to IBD,
- And the risk factors that may make you more susceptible to developing CD or UC, or having more severe flare-ups.
In Part 2, I will discuss our current strategies for diagnosing and treating CD and UC.
What causes IBD?
The health of the intestinal microbiome plays a key role in the pathogenesis of CD and UC. In particular, this is related to dysbiosis and reduced diversity of the gut microbiome. It also relates to protective bacteria subpopulations, such as Firmicutes, and an increased representation of potentially pathogenic bacteria, such as enteroinvasive Escherichia coli in subsets of ileal CD. In these conditions, species richness decreases, although some species seem to overgrow and increase in number.
Both CD and UC are defined by an abnormal immune response, in which the immune system mistakes benign or beneficial cells and bacteria for harmful foreign substances. When this happens, the immune system, through a process known as molecular mimicry, can damage the gastrointestinal tract and produce symptoms of IBD. UC is primarily a T-helper 2 (Th2) immune cell response, while CD is primarily T-helper 1 (Th1) cell mediated.
Starting at birth, the cumulative effects of different environmental exposures, combined with a predetermined genetic susceptibility, is thought to cause IBD. It appears that continuous exposure to the collective effect of dynamic environmental factors, referred to as ‘exposome’ by Christopher Wild, affects the incidence of IBD. Infancy and early childhood influence the formation of the immune system, whereas adult exposures to environmental factors alter established pathways.
Western lifestyles also seem to play a role, indicated by higher number of cases of IBD in Europe and the USA. The condition affects 1.5 million US citizens and 2.2 million people in Europe. There has been a significant increase in the last five years that’s consistent across several distinct ethnic groups and geographic locations. This increase parallels the Westernization or industrialization of an area’s lifestyle
Immigrants moving from low risk to high risk areas tend to assume the qualities of the high-risk areas within a generation or two. In their new location, the risks are much higher than in their low-risk country of origin. There has also been an increase in the number of cases in developing countries in Asia, Eastern Europe, and Northern Africa, as their lifestyles and living environments change. Onset of IBD in young adulthood is characterized by a relapsing and remitting course with frequent hospitalizations or surgery.
- Is irritable bowel syndrome a type of IBD?
Irritable Bowel Syndrome (IBS) is considered non-inflammatory and a syndrome, or a group of symptoms, rather than a specific disease. Symptoms of IBS typically include chronic abdominal pain, diarrhea, constipation, or alternating bouts of both of these. People with IBS are also more likely to have other functional disorders such as fibromyalgia and chronic fatigue syndrome (CFS). IBS doesn’t produce the destructive inflammation found in IBD, so it may be considered a less serious condition. However, it can still cause chronic discomfort and affect quality of life. Research suggests that IBS can be caused by stress and the manner in which the brain and gut interact.
Risk factors of IBD
Well known risk factors for IBD include:
- Cigarette smoking: reduced risk of UC, increased risk of CD
- Appendectomy: reduced risk
- Western diet: increased risk
- Stress: increased risk
- Depression: increased risk
- Low vitamin D levels: increased risk
- Estrogen replacement therapy: increased risk of UC
- Left-handedness: increased risk
- Mycobacterium paratuberculosis infection: increased risk of CD
Breast-feeding, appendectomy, and smoking, surprisingly, are all associated with reduced risk of UC.
The effects of some of the risk factors outlined above appear to differ between CD and UC. Despite shared genetic and immunologic mechanisms, distinct pathways of pathogenesis exist.
There’s a substantial body of research that’s available regarding risk factors, but limited evidence for the treatment of these environmental triggers to modify disease outcomes or prevent relapse. There have only been a few controlled clinical trials for modification of risk factors resulting in an improvement in patient outcomes.
Risk loci, or specific gene locations within your chromosomes that appear to alter IBD risk, highlight several key pathways in pathogenesis. These include the following:
- Innate immunity
- Adaptive immune responses
- Abnormal glycosaminoglycan (GAG) content of the mucosa
- Maintenance of intestinal barrier function with increased intestinal permeability
- Pathogen sensing
- Endoplasmic reticulum stress
- Response to oxidative stress
- Decreased oxidation of short chain fatty acids
- Increased inflammatory mediators
- Increased sulfide production
- Decreased methylation
Everyone is born with a certain genetic susceptibility to IBD. Following exposure to a Western lifestyle, diet, and certain environmental triggers, a specific threshold is reached and IBD may develop. This explains the low concordance rate in twins, suggesting that genetic influence, while important, is only one piece of the IBD puzzle. The exposome, or the total coherent effect of all environmental factors from birth to death, plays the determining role.
A positive family history of IBD is the most important risk factor for the development of the condition. Whole genome scans have found susceptibility genes for UC on chromosomes 1 and 4. A concordance rate of 19 percent for UC and 50 percent for CD in monozygotic twins has also been established.
Genetics have shown 204 distinct genetic risk loci for IBD, with the majority of risk alleles being shared between both diseases. However, 37 CD-specific and 27 UC-specific loci have been identified. Known loci account for only a third of the risk for either disease.
- Childhood exposures
Breast-feeding appears to confer a protective effect on both UC (1.8-fold) and CD (2.2-fold), in keeping with known protective effects for other immune-mediated diseases such as eczema and asthma, allergic rhinitis, and type 1 diabetes. This is thought to be due to protective maternal antibodies and the induction of immune tolerance to specific food antigens and gut microbes.
Antibiotic exposure is associated with an increased risk of adult and pediatric-onset IBD. Exposure during infancy or early childhood is associated with the greatest increase in risk. Use of antibiotics between the ages of five and sixteen, through the effect on the microbiome, appears to increase the incidence 1.6-fold. If antibiotics are used in the first year of life, the risk of CD increases 5.3-fold.
The strongest risk increase is linked to the use of broad-spectrum penicillin (3.1-fold), pen V (2.9-fold), then cephalosporin (1.9-fold).
It’s been hypothesized that by altering the gut microbiome composition, pathogenic bacteria colonize while the normal process of tolerance, which is crucial for immune development, is disrupted. This leads to an aberrant response of the host immune system to its microflora.
On the other hand, early childhood Helicobacter pylori infection is associated with a decreased risk of CD of 1.7-fold and UC of 1.3-fold. H. pylori increases Fox-3, the transcription factor of T-regulatory cells, which down-regulates the inflammatory response.
A high hygiene level increases the risk of IBD. Living in an urban environment increases risk by 1.2-fold.
Having a smaller number of siblings increases risk 2.6-fold. The more siblings you have, the lower your risk for IBD.
Sharing a bedroom decreases risk of UC by 2.1-fold and CD by 2.3-fold, while a hot water tap in the home increases the risk of CD by 5-fold.
Animal contact decreases risk of UC and CD, with similar effects seen regarding asthma and eczema.
The implication is that the more hygiene measures employed, the fewer helminths (worms and parasites) you’re exposed to, and therefore less induction of dendritic cells maturation and ability to drive the T-cell immune system occurs. This results in decreased protection against autoimmunity.
In simpler terms, “germophobes” may be at an increased risk of developing IBD.
There have been several reports of a link between autism spectrum disorder (ASD) and chronic gastrointestinal (GI) symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia, and focally enhanced gastritis in people with ASD compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability, and unfavourable gut microflora.
Wakefield et al conducted one of the earliest studies investigating gastrointestinal anomalies in autistic children in 1998. In this study, twelve children with regressive developmental disorders, nine of whom were autistic, were all reported to have abnormal colonoscopies. The most consistent finding was lymphoid nodular hyperplasia (LNH), which was present in nine of the twelve children. This mild to moderate colitis was deemed nonspecific on the basis of not fulfilling criteria for either Crohn’s disease or ulcerative colitis.
Criticism regarding the ‘normalcy’ of LNH in children prompted Wakefield, et al. to perform ileocolonoscopies in 60 children with regressive developmental disorders and compare them with 37 developmentally normal controls. In this trial, ileal LNH was present in 93 percent of affected children in comparison to 14.3 percent of controls (P<0.001). Chronic colitis was detected in 88% of affected children compared with 4.5% of controls.
Torrente et al. compared the gastric biopsies of 25 autistic children with those of ten normal controls, ten CD patients, and ten children with H. pylori infection. Eleven of the 25 autistic children had a focally enhanced gastritis, while two had mild diffuse gastritis. Immunohistochemistry results demonstrated the pattern of lymphocyte infiltration was most similar to Crohn’s disease, with the exception of a striking predominance of CD8-positive over CD4-positive cells and a marked increase in intra-epithelial lymphocytes. Another highly specific finding among autistic children was a dense, sub-epithelial basement membrane immunoglobulin G deposition, which was absent in the other subgroups.
ASD patients and their caregivers often report improvement in the patient’s condition after following elimination diets. Improvements occur not only in the GI symptoms, but also in behavioural and cognitive problems such as hyperactivity, communication skills, and attentiveness. Interestingly, 36% of children with ASD have a history of cow’s milk and/or soy protein intolerance in infancy. In addition, while studies haven’t indicated an increased incidence of Celiac disease in these individuals, parents have often reported an improvement in their child’s behavioural disturbances when following a gluten-free diet. These benefits haven’t been seen consistently in randomized trials, although a Cochrane review did report a significant reduction in autistic traits on a gluten-free, casein-free diet.
One hypothesis is that ASD may be accompanied by aberrant innate immune responses to dietary proteins, leading to GI inflammation and aggravation of behavioural problems. One study, measuring pro-inflammatory cytokines in response to common dietary proteins, showed a greater than two standard deviations (SD) excess in tumour necrosis factor-alpha and interferon-gamma production in response to gluten and cow’s milk protein among ASD children, when compared with controls.
A subsequent study confirmed a higher prevalence of elevated tumour necrosis factor-alpha and interleukin-12 production with beta-lactoglobin and alpha-lactoglobin, but not casein, in autistic children and children with non-allergic food hypersensitivity, compared with normal controls.
Another theory suggests that abnormal intestinal permeability in children with ASD causes them to absorb fragments of incompletely broken-down peptides such as gluten or casein, which cross the blood-brain barrier and act as endogenous opioids.
The gut microflora has also been targeted as a potential player. There have been anecdotal reports of the onset of autism following broad-spectrum antibiotics, suggesting that disruption of the indigenous flora may lead to colonization by neurotoxin-producing bacteria. Autistic children have been shown to have higher counts and more species of Clostridia than controls matched by age or gender. A small prospective trial demonstrated a significant but transient improvement in autistic features following a course of vancomycin (antibiotic) therapy, with relapses presumed to occur because of persistent spores that proliferate upon discontinuing the medication.
The ratios of yeasts in the gut, such as Saccharomyces cerevisiae and Candida albicans, may be significantly altered by IBD. Normally, yeasts and fungi account for less than 0.1% of the total microbiota population. However, there is often a decreased population of S. cerevisiae and increased populations of C. albicans and other Candida yeasts in the guts of people with IBD.
Antibiotic use can result in fungal overgrowth, especially of the Candida yeasts, which may then compete with the bacteria in the gut for survival and growth. This fungal overgrowth can make the host more susceptible to mold illness, paving the way for an immune response that may invoke chronic inflammation, autoimmunity, or IBD.
It appears also that certain components of the cell walls of fungi can trigger immune responses, which may add to the overall exposomeXI.
- Gut microbiome
Recent studies have highlighted the association between the gut microbiome and the pathogenesis of IBD.
Reduced biodiversity of the gut microbiome is apparent even at the onset of diagnosis, before treatment is initiated. CD, especially ileal CD, has been associated with increased frequency of pathogenic bacteria such as enteroinvasive E. coli. There can also be a reduction in the frequency of anti-inflammatory bacterial subgroups, particularly Faecalibacterium prausnitzii. Giving strains of this specific bacteria has resulted in improved outcomes and amelioration of colitis in animal models.
By the time someone reaches adulthood, the immune system has matured and lifestyle factors become more apparent as choices are increased. Adult exposures seem to be involved in changing the already developed immune system. Several environmental factors have been identified as playing a role in IBD development independent of stage of life, previous development of acute bacterial gastroenteritis, geographical location, and vitamin D.
Bacterial gastroenteritis as a result of Clostridium difficile, Campylobacter, and/or Salmonella infections can increase risk of IBD. The risk of developing IBD increases significantly after bacterial gastroenteritis, especially within the first year. The largest effect is seen with CD, for which there is a 2.9-fold increase, rather than the 2.1-fold for UC. This may be explained by the increase in interleukin-6 (IL6), blockage of T-reg cells, and the activation of self-reactive T-cells, leading to a chronic inflammatory response.
- Mycobacterium avium infection
M. avium subspecies paratuberculosis (MAP) infection rates are higher in CD, although a causative link hasn’t been established. Meta-analysis has shown a 7-fold increase in CD in MAP infections, but the timing of this infection couldn’t be ascertained to be a cause of CD and is perhaps merely a bystander.
- Tap water
Drinking tap water lowers the risk of CD 2-fold. It’s been proposed that this might be due to harmless microorganisms triggering regulatory T-cells.
Individuals have an increased risk of disease flare following high-altitude flights or after travelling more than 2,000 metres above sea level. Mild hypoxia leads to an increase in IL6 and C-reactive protein (CRP), which are markers of inflammation.
An American cohort study showed a 2.5-fold increase in CD in obese women with a body mass index (BMI) greater than 30 kg/m2.
Smoking confers a 2-fold increase in risk of CD, which is somewhat lessened when stopping smoking, although the pathogenic mechanism remains unknown.
Smoking is associated with a more aggressive form of CD, more surgery, and an earlier risk of recurrence and re-operation following a bowel resection. Stopping smoking prior to the diagnosis can result in a reduced likelihood of progressing to complicated disease behaviour or the need for surgery. Smoking cessation is also associated with a reduced rate of relapse regarding CD.
With UC, current but not former smokers appear to have some protection, with half the risk of UC in current smokers compared to individuals that have never smoked. Smoking confers a 1.7-fold reduction in risk for UC.
For former smokers, the risk for both UC and for CD increases by the same amount.
For patients with UC, smoking leads to a more benign disease course with fewer flares, a reduced need for steroids, and lower colectomy rates. Smoking cessation increases the risk, with the effect lasting for up to ten years after quitting smoking. This suggests that smoking only defers the development of UC. Quitting smoking is also associated with flare-ups.
Passive, or second-hand, smoking has a weaker beneficial effect. The mechanism of this different effect between CD and UC is unknown, but is thought to be influenced by the constituents of cigarette smoke having different effects on oxidative stress in mononuclear cells.
Smoking is known to affect the immune system through both cellular and humeral pathways by transforming the synthesis of pro-inflammatory cytokines, altering gut permeability, reducing smooth muscle tone and contractility due to nitrous oxide, and effecting changes in the gut microflora.
There’s also an interaction between smoking and genetic variants in the CYP2A6/EGLN 2 locus and glutathione transferase enzymes (GSTP1) and risk of CD and UC. Snips in these genes showed significantly different outcomes.
There are divergent effects between UC and CD following appendectomy.
When performed before the age of twenty, there’s an increased risk of UC with no effect or only a slightly increased risk of CD. The mechanisms remain unclear, and appendectomy may result in intestinal microbiome alteration with a protective effect on UC. The microbiome composition in the appendix also appears to confer protective effects against UC
The role of diet has been problematic to determine. This is due to difficulty in tracking it through the course of a lifetime, different recall between controls and cases, and potential restrictions on diet choices pre-diagnosis based on the nature of the disease.
Increased fibre of approximately 24 grams was associated with a significant reduction in risk of CD but not UC. This was related to fruit fibre and not that of vegetables, including cruciferous ones. No association was found between fibre from cereals, whole grains, or legumes.
Fibre may confer epithelial integrity and reduce translocation of potentially pathogenic bacteria such as enterovirus E. Coli, which may play a role in CD. Fibre activates the aryl hydrocarbon receptor (AhR) expressed in intestinal lymphocytes, which offers protection against environmental antigens.
A diet high in long-chain n-3 polyunsaturated fatty acids (PUFA) was associated with a reduced risk of UC. CD had no modifiable fat intake risk factors for CD. One large study found omega-3 supplements had no beneficial effects, while a high intake of animal protein revealed a potential association with IBD. Sugar and a high-carbohydrate diet are associated with an increased risk of IBD, while fruits and vegetables seem to have a protective effect.
Alteration of diet can trigger flares in many different types of disease. High fat diets result in expansion of specific bacterial subpopulations that are associated with a pro-inflammatory response, particularly diets high in meats, as well as polyunsaturated omega-6 fats (like those found in industrial seed oils such as soybean oil, corn oil, and canola oil).XVI Elemental diets show improved outcomes in CD, whereas partial and complete enteral nutrition show effects superior to placebo but lower than steroids.
Elimination diets, such as the specific carbohydrate diet, lectin-free diet, autoimmune paleo, and Whole30, are of particular interest as well, but there is still a lack of strong evidence regarding their efficacy for IBD treatment.
Childhood diet and antibiotic exposure is an important determinant of microbiome composition. Breastfeeding appears to reduce UC risk, but it doesn’t appear that formula-feeding necessarily increases UC risk. Researchers have found that the gut microbiome of both breastfed and formula-fed children changes significantly after the introduction of foods. Therefore, the first foods a child receives (other than breastmilk or formula), and the foods they eat throughout their early childhood, may profoundly affect their gut microbiota composition and affect their IBD risk level.
Glyphosate is the world’s most widely produced herbicide. It’s the primary toxic chemical in Roundup™ and many other herbicides. As a broad-spectrum herbicide, glyphosate is present in more than 700 different products and used in industries such as agriculture and forestry, and even in the home.
Glyphosate was introduced in the 1970s to kill weeds by targeting the enzymes that produce the amino acids tyrosine, tryptophan, and phenylalanine. However, the enzymes of many bacteria are susceptible to inhibition by this chemical, so it can also alter the gut flora of many animals.
Usage of glyphosate significantly increased after the introduction of genetically modified (GMO), glyphosate-resistant crops that grow well despite the presence of this chemical in the soil. In addition, the toxicity of the surfactant polyoxyethyleneamine (POEA), which is commonly mixed with glyphosate, is greater than the toxicity of glyphosate alone.
In addition, Enlist Duo™, a herbicide product containing a 2,4-dichlorophenoxyacetic acid (2,4-D) salt and glyphosate, was approved for use in Canada and the United States in 2014. This was for use on GMO soybeans and maize, both of which were designed to be resistant to both 2,4-D and glyphosate. 2,4-D has many toxic effects of its own.
Research has shown that glyphosate disrupts the microbiome in the intestine, causing a decrease in the ratio of beneficial to harmful bacteria. Highly pathogenic bacteria such as Salmonella entritidis, Salmonella gallinarum, Salmonella typhimurium, Clostridium perfringens, and Clostridium botulinum are highly resistant to glyphosate. Unfortunately, however, most beneficial bacteria such as Enterococcus faecalis, Enterococcus faecium, Bacillus badius, Bifidobacterium adolescentis, and Lactobacillus ssp. were found to be moderately to highly susceptible.
The relationship between the microbiome of the intestine and overall human health is still unclear.
However, current research indicates that disruption of the microbiome could lead to conditions such as metabolic disorder, diabetes, depression, autism, cardiovascular disease, and autoimmune diseases such as IBD.
- Celiac disease, IBD, and the glyphosate connection
Researchers have found that people with Celiac disease are about 10 times as likely as a control group to have IBD. Conversely, the prevalence of Celiac disease in IBD appears to be comparable with that indicated in controls.
Celiac disease, and more generally, gluten intolerance, is a growing problem worldwide. It’s particularly serious in North America and Europe, where an estimated 5% of the population now suffers from this condition. It’s a multi-factorial disease associated with numerous nutritional deficiencies, as well as reproductive issues and an increased risk of thyroid disease, kidney failure, and cancer.
It has been proposed by researchers Samsel and Seneff that glyphosate is the most important causal factor in this epidemic. Fish exposed to glyphosate develop digestive problems that are reminiscent of Celiac disease. The condition is associated with imbalances in gut bacteria that can be fully explained by the known effects of glyphosate on these particular types of bacteria.
Characteristics of celiac disease point to impairment in many cytochrome P450 (CYP450) enzymes, which are involved with detoxifying environmental toxins, activating vitamin D3, catabolizing vitamin A, and maintaining bile acid production and sulfate supplies to the gut. Glyphosate is known to inhibit CYP450 enzymes.
Deficiencies in iron, cobalt, molybdenum, copper, and other rare metals associated with Celiac disease can also be attributed to glyphosate’s strong ability to chelate these elements. Deficiencies in tryptophan, tyrosine, methionine, and selenomethionine associated with Celiac disease also match glyphosate’s known depletion of these amino acids.
Celiac disease patients have an increased risk of developing non-Hodgkin’s lymphoma, which has also been implicated in glyphosate exposure. Reproductive issues associated with Celiac disease, such as infertility, miscarriages, and birth defects, can similarly be linked to glyphosate.
Glyphosate residues in wheat and other crops have been increasing recently due to the growing practice of crop desiccation just prior to the harvest. The practice of ‘ripening’ sugar cane with glyphosate may also explain the recent surge in cases of kidney failure among agricultural workers in Central America.
- Mast Cell Activation Syndrome (MCAS)
As early as 1980, Dvorak and colleagues reported that mast cells were markedly increased in the ileum of patients with CD. In 1990, Nolte et al. showed the same findings in patients with UC. There were increased numbers of mast cells with associated degranulation products of histamine and tryptase, along with associated increases in cytokines and leukotrienes IL-16. TNF-alpha and substance P have also been found in the mucosa of patients with IBD, particularly when stained with the CD 117 stain.
According to the latest literature research conducted by Dr. Lawrence Afrin, one of the key researchers in MCAS, mast cells release at least 1,000 mediators of inflammation. This includes, but isn’t limited, to histamine, proteoglycans (heparin and chondroitin sulfate), proteases (tryptase, chymase and carboxypeptidase), eicosanoids, and platelet activating factor (PAF).
Activation of mast cells leads to the release of the eicosanoid arachidonic acid from the phospholipids on the cell membrane. This 20-carbon fatty acid is then rapidly oxidised, along either the cyclooxygenase pathway to form prostaglandin D2 (PGD2) or the lipoxygenase pathway to form leukotriene C4 (LTC4). Histamine triggers the histamine H1 receptor and tryptase, the protease-activated receptor 2 (PAR2).
Therapies aimed at down-regulation of mast cell activity may be important in the treatment of IBD.
Mast cell cytokines constitute a third category in that they may be both preformed and newly synthesized. These include IL-4, IL-5, IL-6 and TNF-alpha in the nasal mucosa and bronchi, as well as IL-1B, IL-3, IL-8, IL-9, IL-10, IL-13, IL-16, IL-18, IL-25, granulocyte -macrophage colony stimulating factor (GM-CSF), and stem cell factor macrophage chemotactic peptide (MCP)-1, MCP-3, and MCP-4.
Many factors are known to activate mast cells, and their activation is a crucial step involving pathophysiological changes. These factors include antigens, anti-IgE, substance P, VIP, C5a, C3a, somatostatin, morphine, very low-density lipoprotein, stem cell factor, tryptase, and eosinophil cationic protein, all of which are known to activate mast cells.
It should be noted that mechanisms of mast cell activation differ with different classes of triggers.
- Nutrient deficiencies
UC patients were found to have lower levels of vitamin A, vitamin E, and carotenoids than those in controls. This implies that certain nutrient deficiencies may either play a role in the development of UC, or, conversely, are a complication of UC.
- Vitamin D
Vitamin D intake is inversely associated with UC risk, meaning that higher vitamin D intake is linked to a lower UC risk. Additionally, higher blood levels of vitamin D are associated with reduced risk of CD.
Patients who increased their blood vitamin D levels had a 1.9-fold protective effect for CD, but not for UC. They also had a lower risk of surgery compared to those who remained vitamin D deficient. Low vitamin D levels are also associated with a higher rate of colon cancer and C. difficile infections.
Vitamin D administration may reduce the risk of IBD relapses. Vitamin D is also known to play a role in the regulation of the innate immune system by activating the TH1 lymphocytes and monocytes. This causes the inflammatory response to be down-regulated.
- Weather and latitude
Incidence of IBD is higher in northern latitudes where people have reduced exposure to ultraviolet (UV) light. The Women’s Health Initiative (WHI) study noted a lower risk for both UC and CD in women in southern latitudes (1.6-fold for UC) compared to those at higher latitudes. Living in southern latitudes appears to be protective, likely due to increased UV light and subsequently higher vitamin D levels.
Warm summers have a protective effect for UC and possibly for CD as well. This is also the case for other inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). This is thought to be due to an increase in microbial diversity, which in turn confers benefit.
- Psychological behaviours
IBD has long been associated with neuroticism, dependency, anxiety, and perfectionism. Recent well-designed studies have confirmed that adverse life events, chronic stress, and depression increase the likelihood of relapse in patients with quiescent (dormant) IBD.
The evolving science of psychoneuroimmunology has outlined the mechanisms by which the nervous system can affect immune function at both the systemic and gut mucosal levels. These mechanisms are thought to be due to changes in the hypothalamic-pituitary-adrenal (HPA) axis and alterations in the bacterial mucosal barrier. These occur via mucosal mast cells and mediators, such as corticotrophin releasing factor (CRF).
To maintain homeostasis, a living organism must constantly adapt at a mental, emotional, molecular, cellular, physiological, and environmental level. Stress is defined as a threat to an organism’s homeostasis. The function of the stress response is to maintain homeostasis through behavioural and biological or physiological adaptations. The stress response involves the complex integration between a series of interconnected regions within the brain. These are the hypothalamus, the amygdala, and the hippocampus. This hub receives inputs from viscera and somatic afferents and from higher cortical structures, including the internal dialogue and mental perceptions of the patient. This in turn, affects the neuroendocrine stress response via two interconnected effector pathways, namely the HPA axis and the autonomic nervous system (ANS).
Stress stimulates the release of CRF from the hypothalamus, causing the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. This in turn causes the release of cortisol from the adrenal cortex. Stress also activates the descending neural pathways from the hypothalamus to pontomedullary nuclei, which control the autonomic nervous system response. Stimulation of the sympathetic nervous system (fight/flight) causes the release of adrenaline and noradrenaline from the adrenal medulla. This is in addition to supplying the entire gut directly. The parasympathetic vagus nerve and sacral nerves provide parasympathetic input to the upper gut and to the distal colon and rectum.
The gut has its own nervous supply called the enteric nervous system (ENS), which is innervated by both sympathetic and parasympathetic fibres. This network has been termed the gut-brain axis. The ENS contains 100 million neurons and regulates the motility, the exocrine and endocrine functions, and the microcirculation of the gut. These axes (HPA, ANS, ENS) can then interact directly with the immune system. Psychoneuroimmunology is the study of how behavioural factors and CNS function can influence the immune system, and hence inflammation, at both systemic and local tissue levels.
Nerve fibres of the ANS form close effector junctions with lymphocytes and macrophages in lymph glands, bone marrow, the thymus, the spleen, and mucosa associated lymph tissue. These nerve fibres also release a number of chemicals called neurotransmitters, such as catecholamines, vasoactive intestinal peptides, angiotensin II, neurotensin, somatostatin, and substance P. These are capable of affecting lymphocytes, macrophages, neutrophils, and other inflammatory cells at the neuro-immune cell junction. Lymphocytes and other inflammatory cells also carry receptors for the hormones and neuropeptides of the HPA axis, such as growth hormone, ACTH, corticosteroids, and CRF.
At high concentrations, cortisol has an immunosuppressive effect, increasing the release of anti-inflammatory proteins and IL-10. Transcription of inflammatory signalling molecules such as IL-6, IL-1, and TNF-α are reduced through transcription factors AP-1 and nuclear factor kappa beta. At lower doses, cortisol has an immune stimulating effect.
Similarly, adrenaline and noradrenaline have mixed effects at different doses on immunity and inflammation. Adrenaline causes an increase in serum IL-6, an increase in lipopolysaccharide (LPS) induced IL-8 and IL-10, and an increase in cytotoxic (cell-killing) T-cells and natural killer (NK) cells.
Chronic sustained stress due to adverse life events, such as bereavement, divorce, and depression, have been shown to reduce the numbers of cluster of differentiation 8 (CD8, a glycoprotein) lymphocytes, NK cells, and macrophages in the blood. However, in addition to immunosuppression, chronic stress with reduced heart rate variability, which is a sign of increased sympathetic tone, has been shown to increase inflammation, showing raised CRP.
Acute stress causes stimulation of the sympathetic nervous system with a rise in adrenaline and noradrenaline, followed a little later by a rise in cortisol. This leads to an acute episode of immune enhancement with an increase in inflammatory cytokines that are known to be associated with flares of IBD. This includes a rise in cytotoxic CD8 T lymphocytes and NK cells and an increase in their cytolytic activity, in addition to platelet activation and thrombin generation, producing effects of microcirculation ischemia causing thrombosis and microinfarction. This effect is lowered with beta blockers rather than aspirin, suggesting that a stress response or sympathetic activation is at the root of it.
Psycho-social stressors have long been associated with triggers. Recent and remote stress is associated with an increased incidence of IBD, with recent stress being more significant. When questioned, patients indicated that stress was the trigger for 70% of their flares. Depression feelings were associated with a 2.4-fold increased risk of CD, but not UC. Depression, anxiety, and stress are also associated with increased rates of relapse and surgery for IBD.
The inflammatory response to stress through elevation of IL-6 levels can be changed in mice by administrating antibiotics, suggesting antibiotics exerts their effects through changes in the gut microbiota.
Using medications to treat these conditions appears to have variable effects. People referred for therapy following increased stress due to the diagnosis have reduced rates of relapse, outpatient attendance, and use of steroids or other medications for IBD.
In summary, stress can play a significant role in immune system dysfunction leading to an inflammatory response, which may trigger new-onset IBD or a flare of existing disease.
Both increased and reduced amounts of sleep have been associated with negative health outcomes. Reduced sleep quality was associated with an increased risk of relapse at six months post-remission in CD, supporting an association between poor sleep and gut inflammation. Sleep disturbances in IBD may lead to a 2-fold increase of disease flare. Sleep deprivation also leads to activation of the immune cascade.
- Nonsteroidal anti-inflammatory drugs
The use of nonsteroidal anti-inflammatory drugs (NSAIDS) for fifteen days per month increases the risk of UC 1.9-fold and CD 1.6-fold. These figures are increased by greater weekly dosage, and a higher frequency or longer duration of use. NSAIDS lead to inhibition of cyclooxygenase (COX), resulting in a decrease in protective prostaglandins in the gut mucosa, increasing gut permeability.
- Oral contraceptives
Current use of oral contraceptives (OCP) leads to 1.3-fold increased risk of UC. The risk of developing CD with current use of OCP is increased by 1.5-fold.
- Post -menopausal HRT
Post menopausal HRT increases the risk of UC by 1.7-fold, but not CD. It’s been proposed that estrogen modulates gut inflammation by acting on estrogen receptors that are found on gastrointestinal epithelial and immune cells.
UC is a Th2 mediated illness, and estrogen promotes Th2 cytokines. The same holds true for other Th2 mediated diseases, such as RA and SLE. However, this is not the case with CD, which is a Th1 mediated illness.
A prospective cohort study (the Women’s Health Study) followed 108,844 postmenopausal American women, with a median age of 54, without a prior history of CD or UC in 1976. The risk of UC appeared to increase with longer duration of hormone use and decrease depending on the time since discontinuation. There was no difference in risk according to the type of hormone therapy used, such as estrogen as opposed to estrogen and progestin. No association was noted between the current use of hormones and the risk of CD. The effect of hormones on the risk of UC and CD was also not modified by age, BMI, or smoking.
- Ambient air pollution
On the whole, air pollution exposure wasn’t associated with the incidence of IBD. However, residential exposure to sulfur dioxide and nitrous dioxide gases found in industrialized regions may increase the risk of early-onset UC and CD respectively.
Living in regions with high sulfur dioxide emissions before the age of 25 increases the chances of UC 2-fold. A high nitrogen dioxide exposure before the age of 23 increases the chance of CD 2.3-fold. Total pollutant emissions correlate significantly with an increased risk of hospitalization in established IBD. Pollutants may also be absorbed and incite the inflammatory process that’s characteristic of IBD.
- Physical activity
Researchers have found that women engaging in active physical activity have a 44% reduction in CD risk compared with sedentary women. Physical activity was not associated with risk of UC.
The absolute risk of UC and CD among women in the highest fifth of physical activity levels was at just 8 and 6 events per 100,000 person years. This compares to 11 and 16 events per 100,000 person years among women in the lowest fifth of physical activity.
Age, smoking, BMI, and cohort didn’t significantly modify the association between physical activity and the risk of UC or CD in these findings. The pathway appears to be mediated through the autophagy (clearing out or recycling of damaged cells) pathway or cell senescence (cell aging).
There’s a rich body of research showing potential environmental risk factors for the development of IBD. However, there aren’t many high-quality studies showing that environmental changes may have a large effect on disease outcomes. For a large number of possible environmental factors, meta-analyses are not yet available.
Many novel factors are identified by large cohort or case-control studies, but are yet to be reproduced by and validated by independent research groups. Consequently, the level of evidence is somewhat low and caution should be exercised when drawing firm conclusions or making recommendations.
However, individuals with a genetic susceptibility can be cognisant of environmental factors and do their best to lower or delay their genetic expression, as their exposure threshold may not be reached. Being aware of which environmental factors are involved in developmental phases as well as along the course of the disease to increase flares and development of complications, gives the treating physician and patient as advocate the opportunity to make the necessary adjustments along the patient’s timeline.
This has the effect of lowering the risk of disease expression with a more personalized treatment plan.
In Part 2, I will be reviewing the lab tests that are used to diagnose CD and UC, along with lifestyle changes and treatment options that are often successfully employed in IBD care.
Dr. Bruce Hoffman, MSc, MBChB, FAARM, IFMCP is a Calgary-based Integrative and Functional medicine practitioner. He is the medical director at the Hoffman Centre for Integrative Medicine and The Brain Centre of Alberta specializing in complex medical conditions. He was born in South Africa and obtained his medical degree from the University of Cape Town. He is a certified Functional Medicine Practitioner (IFM), is board certified with a fellowship in anti-aging (hormones) and regenerative medicine (A4M), a certified Shoemaker Mold Treatment Protocol Practitioner (CIRS) and ILADS trained in the treatment of Lyme disease and co-infections. He is the co-author of a recent paper published by Dr. Afrin’s group: Diagnosis of mast cell activation syndrome: a global “consensus-2”. Read more about Dr. Bruce Hoffman.