Inflammatory Bowel Disease (IBD)

inflammatory-bowel-diseaseInflammatory Bowel Disease

Inflammatory bowel disease (IBD), which primarily consists of Crohn’s disease and ulcerative colitis, are chronic inflammatory conditions of the gastrointestinal tract. Most people who have chronic IBD actually have autoimmunity as the culprit. Both Crohn’s disease and ulcerative colitis are directly linked to autoimmunity to specific structures of the GI tract. In genetically susceptible individuals, the interaction between environmental factors and normal intestinal commensal flora is believed to lead to an inappropriate immune response that results in autoimmunity and chronic inflammation of the GI tract.[541] IBD is also known to be associated with a substantial increase in the risk of colorectal cancer, especially after 8–10 years of active disease.[542]

IBDAffected GI Organs

Ulcerative colitis (UC) is an autoimmune condition that involves only the colon and is primarily confined to the superficial mucosal and submucosal layers of the colon, with a tendency toward involving the distal part. In contrast, Crohn’s disease (CD) can involve any component of the gastrointestinal tract from the oral cavity to the anus and may involve all layers of the gut.  CD can involve perineal disease, fistulas, histologic granulomas, and full-thickness lesions as opposed to largely mucosal and submucosal limited disease observed in UC.[542] CD usually has a clinical presentation of diarrhea, abdominal pain, and malnutrition.[543]

extraintestinal-manifestationsOther Organ Systems Affected

Patients who suffer from IBD often have diseases that affect multiple other organ systems as well, such as the joints, skin, mouth, eyes, biliary tract, kidneys, liver, stomach and bone.[543,544] These are called extraintestinal manifestations and can be just as, if not more debilitating than the intestinal inflammation itself. The skin is one of the most commonly affected organ systems in patients who suffer from IBD. The scientific literature suggests that a disturbance of the equilibrium between host defense and tolerance, and the subsequent over-activity of certain immune pathways are responsible for the cutaneous disorders seen so frequently in IBD patients.[545]

“Ultimately, it is important for healthcare providers to understand that skin manifestations should always be checked and evaluated for in patients with IBD. Furthermore, skin disorders can predate gastrointestinal symptoms and thus may serve as important clinical indicators leading physicians to earlier diagnosis of IBD.”[545]

prevalence-IBDPrevalence

It is now clear that the incidence of IBD is increasing worldwide and has become a global emergence disease.[542] IBD currently affects over 3.6 million people worldwide.[546] IBD is considered a problem in industrial-urbanized societies and attributed largely to a Westernized diet, lifestyle and other associated environmental factors.[542] The fact that incidence of the disease has been on the rise over the past few decades, highlights the role of environmental factors in this disease. IBD was once a very rare disorder, and only began to rise dramatically in incidence in the second half of the 20th century in North America and Europe, at times doubling every decade.[547] Recent data suggest that children and adolescents show the highest incidence of IBD, as approximately 25 to 30% of patients with CD and 20% of patients with UC present with symptoms before the age of 20 years.[542]

“The rising trend in the disease’s incidence in developing nations suggests that its epidemiological evolution is linked to industrialization and modern Westernized lifestyles.”[548]

pathogenesis-IBDPathogenesis

Extensive studies in the past decades have suggested that the pathogenesis of IBD involves environmental and genetic factors that lead to dysfunction of the epithelial intestinal barrier (intestinal permeability/leaky gut) with consequent dysfunction of the mucosal immune system and abnormal responses to gut microbiota.[549,550] One of the explanations for the onset of IBD suggests a three-step scenario, in which bacteria penetrate the epithelial barrier, provoking a weak inflammatory response with impaired clearance, which in turn causes chronic inflammation, culminating in IBD.[549]

“Available evidence indicates that IBD is the result of dysregulated immunogenetic parameters that depends on impaired coordination between luminal microorganisms, gut epithelium, and the host immune system in genetically susceptible individuals.”[551]

pathogenesis-IBD-2Various components of the mucosal immune system are implicated in the pathogenesis of IBD. These include luminal antigens (components of the GI tract that the immune system may target for destruction), intestinal epithelial cells (IECs), cells of the innate and adaptive immune systems, and their secreted mediators. Either a mucosal susceptibility or defect in sampling of gut luminal antigen leads to activation of innate immune response.[551] Keep in mind that imbalances in Th-1 and Th-2 responses by the immune system, and upregulation of Th-17 responses, have been associated with autoimmune disease, chronic inflammation and tissue destruction. In fact, many autoimmune diseases, including IBD, are classified in the literature by their T-helper dominance.

“Crohn’s disease (CD) is predominately a Th-1 and Th-17 mediated process, while ulcerative colitis (UC) appears to be predominately mediated through Th-2 and NK (natural killer) T-cells.”[551]

oxidative-stress-IBDOxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells’ inflammatory responses to food antigens and to the commensal bacteria of the gut.[552] During the active disease phase, activated leukocytes (white blood cells) generate not only a wide spectrum of pro-inflammatory cytokines (inflammatory mediators), but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, leading to excessive intestinal tissue damage.[552]

“The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease.”[552] 

causative-factors-IBDCausal Factors

As discussed, IBD is thought to result from the interaction between a genetically-susceptible host and environmental factors which influence the normal gut flora and trigger an inappropriate mucosal immune system response. Genetics appears to play a role in susceptibility to IBD. However, as described above, environmental factors, such as diet and lifestyle, appear to be driving the increasing incidence of IBD and therefore probably play a much larger role.[542] Let’s take a brief look at the role of these causal factors in IBD development.

DNAGenetic Factors

Although IBD susceptibility genes (such as NOD2 gene variants) have been identified, presence of these genes do not determine disease onset and risk of IBD probably involves a number of different genes.[542]   Multiple lines of evidence suggest that genetics appear to play a relatively minor role in the risk of developing IBD compared to environmental factors. Several twin studies have now shown that the rate for IBD between identical (monozygotic) twin pairs is significantly less than 50%, with an even smaller risk in CD.[547]

“Only approximately 10% of patients with IBD report a family history of IBD. It is therefore evident that there is a partial complex relationship between genetic susceptibility and environment and that this heritability is likely to be polygenic in nature in most patients with IBD.”[542]

“Genetic predisposition…cannot be solely responsible for disease etiology. The lack of complete penetrance must be accounted for by additional factors in disease etiology. Additionally, genetics cannot account for the rapid rise of IBD incidence in certain geographic regions.”[553]

antibiotic-medicationEnvironmental Factors

There are a number of environmental factors that appear to increase risk of IBD. Although these risk factors have been associated with the development of IBD, none of these environmental factors show causation of IBD and most studies report inconsistent observations.[542]

“There is abundant indirect evidence suggesting that smoking, oral contraceptives, diet, appendectomy, breast feeding, antibiotics, vaccination, infections, and childhood hygiene may be involved in the development of IBD.”[542]

“Childhood anti-anaerobic antibiotic exposure is associated with IBD development.”[554]

However, one environmental factor that is gaining increasing attention in the research literature as a significant risk factor for IBD is the status of the intestinal microbiome (intestinal bacteria).

microbiome-cover-nature-2Intestinal Microbiome

“Studies of the roles of microbial communities in the development of inflammatory bowel diseases (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota.”[547]

“There is direct evidence that the pathogenesis of inflammatory bowel disease (IBD) involves the gastrointestinal microbiota and some evidence that the microbiota might also play a similar role in irritable bowel syndrome (IBS).”[555]

“IBD has emerged as one of the most studied human conditions linked to the gut microbiota.”[547]

gut-microbiome-nature-magDietary alterations in the Western population over recent decades have resulted in a shift in the composite gut microbiota. Gut microbiota, which outnumber human cells by nearly ten-fold and contain more than one million genes, (approximately 100 times more genes than in human DNA), have been shown to play an important role in complex disorders such as IBD.[549] Recent studies of the intestinal microbiome have associated the development of IBD with characteristic shifts in the composition of the intestinal microbiota. These studies reinforce the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system.[547] One of the differences in the microbiota between healthy and IBD subjects is that there is a decreased biodiversity in IBD subjects compared to healthy subjects by 30%-50%.[551]

microbes-maketh-manThe reduction in diversity of the microbiota in IBD is due to loss of normal anaerobic bacteria such as BacteroidesEubacterium, and Lactobacillus species[556] and there are fewer Firmicutes species in IBD compared to healthy subjects (P < 0.025)[557]. Diversity is generally thought to be desirable to the host by conferring resiliency to an ecosystem and decreasing risk of chronic disease.[558] Diversity of bacteria is also important to ensure that key metabolic processes occur in the body such as the breakdown of nutrients and prevention of random chaotic fluctuations of bacterial subpopulations. Restriction of biodiversity in the human gut may lead to dysbiosis (imbalance of gut flora) and result in GI mucosal insult. Additionally, there are pathogens that are found in increasing frequency in IBD and have been implicated in the development of IBD.[559]

The host immune system is tolerant toward the antigens of commensal (beneficial) gut microbiota believed to be essential for normal healthy gut function. Any deregulation in immune response toward gut bacteria is thought to be an underlying factor in the development of IBD.

The hypothesis that intestinal bacterial flora contributes to IBD pathogenesis is supported by several experimental as well as clinical studies.[560]  The importance of the microflora in the induction and maintenance of IBD has been demonstrated in animal models of colitis. These studies have shown that supplementation with certain microflora prevent recurrence of colitis in mice genetically predisposed to developing IBD.[561,562]

microscope-examinationAssessment

A diagnosis of IBD is complex and based on a combination of clinical examination, imaging, endoscopy with histopathology, and laboratory testing. Ileocolonoscopy (scoping of the ileum and colon) and histopathological evaluation of tissue taken in biopsy remains the gold standard for assessment of possible IBD.[563] But there are a number of other techniques that offer additional information in the diagnosis of IBD.

Diagnostic Imaging

diagnostic-imagingRecent advances in diagnostic imaging, such as magnetic resonance (MR) imaging and computed tomographic enterography (CTE), as well as in endoscopic imaging, such as small bowel enteroscopy (SBE), constitute additional diagnostic techniques to standard ileocolonoscopy. Both MR and CTE are currently considered key investigational techniques in the diagnosis, follow-up of disease activity, and identification of complications.[543] Diagnostic imaging has the advantages of simultaneously examining different parts of the GI tract, assessing areas of the bowel that are beyond the reach of the conventional ileocolonoscopy, detecting extraluminal involvement and complications of IBD, and potentially helping in the differentiation between UC and CD.[543] However, thus far, no single imaging modality has effectively replaced a detailed endoscopic evaluation and histopathologic evaluation of GI tissue.[543]

serological-testingSerological Markers

In cases where the diagnosis is uncertain, serological markers can provide adjunctive information. Antibodies such as anti- Saccharomyces cerevisiae antibody (ASCA) and anti-neutrophil cytoplasmic antibody, perinuclear pattern (pAN-CA), are considered specific serological markers in patients with IBD.[564] ASCA is detected mainly in patients with CD. pANCA is more common in patients with UC, although it is also associated with UC-like CD.[564] Other serological markers provide additional diagnostic information. These include antibodies to the bacterial protein OmpC and to the bacterial flagellins, including CBir1 and more recently, FlaX and Fla2.[564] Several other markers associated with chronic inflammation, angiogenesis, and cell adhesion have been reported to be upregulated in the serum and intestinal mucosa of patients with IBD, such as ICAM-1, VCAM-1 and VEGF.[564]

antigen-antibody-bindingPredicting the Development of IBD with Serological Markers

Data from the international European Prospective Investigation into Cancer and Nutrition (EPIC) study that enrolled more than 520,000 individuals demonstrated that the combination of the serological markers pANCA, ASCA, anti-CBir1, and anti-OmpC was able to predict the development of CD and UC in individuals who were considered to be at low risk approximately 4.5 years prior to diagnosis.[565] Additionally, the predictive value of these markers increased as the time to the diagnosis of IBD was shorter.[565]

inflammatory-chemicals-markersNon-Invasive Inflammatory Markers

Non-invasive markers of inflammation have become an important part of the daily assessment of patients with IBD. The use of these markers has expanded to include making initial diagnosis and differentiating between IBD and other diseases, evaluating the symptoms of active IBD to rule out flare-ups, postoperative evaluation, monitoring the response to therapy, and predicting relapse.[543] Historically, inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were used for these indications, but have since fallen out of favor as they are generally non-specific. More recently, markers of inflammation that are specific to the GI tract, such as fecal calprotectin (FC) and stool lactoferrin (SL), have been introduced.[543]

Stool Lactoferrin (SL)

SL is a stool marker has been proven to be a useful tool to diagnose IBD in patients presenting with lower GI symptoms and to differentiate between active and inactive disease, especially in the pediatric population.[543] Furthermore, SL has been found to correlate well with the endoscopic severity of colonic IBD (Pearson’s r = 0.9, P = 0.001) and to have high positive predictive value (PPV; 100%) and negative predictive value (NPV; 83%) for diagnosing small bowel CD.[543]

fecal-calprotectinFecal Calprotectin (FC)

Calprotectin is a protein released by white blood cells and squamous cells in response to inflammation. FC is a sensitive marker of gut inflammation as it correlates well with fecal excretion of a compound called indium-111–labeled neutrophilic granulocytes, the gold standard of disease activity.[543] It also accurately predicts the disease severity as well as clinical relapse after infliximab treatment in UC patients, and has been used as a monitoring tool in clinical trials.[543] Since FC is easy to perform and results can be rapidly provided, it serves as a useful and reliable tool for screening symptomatic patients and managing them accordingly.[543]

man-facing-mazeThe Challenge of Early Diagnosis

The diagnosis of CD can be challenging, particularly if the disease is limited to the small bowel. In practice, it is not uncommon that patients report having complained of GI symptoms for months to years prior to their diagnosis. This delay can be explained by patient-centered factors as well as lack of available resources and incomplete diagnostic evaluation.[543] CD is often mistaken for irritable bowel syndrome (IBS) or food intolerances because of the vague and overlapping symptoms occurring mainly at a young age.[543] Furthermore, the limited access to a gastroenterologist and resources results in a deferral of several months until a diagnosis is reached and this potentially leads to earlier disease-related complications.[543]

Conventional Treatment of IBD

The current treatment of IBD consists of long-term conven-tional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients’ quality of life.[566]  For patients with moderate to severely active disease, the most commonly used classes of medications include cortico-steroids, immune modulators (6-mercaptopurine, azathioprine, methotrexate), and biologics, which primarily block TNF-α (adalimumab, certolizumab pegol, infliximab, natalizumab).[567]

corticosteroidsStandard corticosteroids, while probably effective in inducing remission in UC, and may be of benefit in CD, carry substantial risk of side effects. Studies show if corticosteroids are used daily and long-term, even at low doses, there is an increase in the occurrence of several wide- ranging adverse effects such as osteoporosis, metabolic syndrome, cardiovascular disease, infections, osteonecrosis, and cataracts.[568]

“In summary, corticosteroid therapy has long been used to treat IBD and is one of the best choices to treat acute exacerbation. However, the presentation of adverse effects, especially with systemic administration, coupled with the unresponsiveness observed in some patients, presents an important barrier to their continuous use.”[569]

immunomodulatorsNewer medications such as immune modulators or biologics, including anti-tumor necrosis factor-α (TNF-α) antibodies all carry the risk of significant side effects and a poor treatment response.[566] Known side-effects associated with immunomodulators such as 6-mercapto-purine and azathioprine include allergic reactions (2%), nausea (2%), hepatitis/ abnormal liver tests (2%), pancreatitis (3%), and serious infections (5%). Important side-effects associated with biologics, including anti-TNF agents, include infusion or injection site reactions (3%-21%), drug related lupus-like reaction (1%), serious infections (3%), and non-hodgkin’s lymphoma (0.06%).[567]

In the U.S., biological agents are the fastest-growing segment of the prescription drug market. These agents cost thousands of dollars per patient per year. The need for biological therapy will inevitably increase dramatically with the increasing prevalence of IBD, and the pharmaceutical industry will continue to reap substantial profits from this new class of pharmaceutical drugs.[542]

essential-fatty-acidsRecent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids (such as omega-3 fatty acids) to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-κB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling.[566] However, as we will see shortly, there are a number of herbal and plant compounds as well as fish oils which have already been shown in the literature to affect these target molecules in a positive way.[570,571]

Functional Medicine Approach to Management of IBD

GI-Effects-Stool-ProfileThe FM Assessment Phase: Comprehensive Stool Analysis

Following appropriate diagnostic evaluation by a physician, assessment of IBD should include a comprehensive stool analysis, looking for signs of dysbiosis and/or chronic GI infection, digestive abnormalities, inflammatory markers associated with IBD, including stool lactoferrin and/or calprotectin, and short chain fatty acid balance, including butyric acid levels, now considered a risk factor for colon cancer.[572] Eliminating any signs of GI infection present and normalizing the intestinal microbiome with the use of probiotics should be made a priority. Supporting any digestive abnormalities with stomach or pancreatic enzyme supplementation and normalizing butyric acid levels with increased fiber and/or prebiotic supplementation should also be considered.

Cyrex-Array-5-Multiple-Autoimmune-Reactivity-screenComprehensive Antibody Screening

Assessment of related organs should also be considered, such as the joints, skin, mouth, eyes, biliary tract, kidneys, liver, stomach and bone since studies have shown that all these organs may be affected in IBD.[543] Since both UC and CD are inflammatory intestinal conditions and are usually autoimmune in origin, assessing for risk of autoimmunity to these related organs via the assessment of antibodies to these organs is a thoughtful and forward-thinking approach. Remember that when the immune system begins targeting any tissue/organ for destruction, it is likely to target other tissue and related organs of the body as well. Cyrex Labs offers a comprehensive antibody test (Array 5) which assesses for antibodies to most of these organs in one simple screen which is very useful in ruling out autoimmunity to other organs.[573]

leaky-gut-progression-to-autoimmunity Intestinal Permeability

Recall that extensive studies in the past decades have suggested that the pathogenesis of IBD involves environmental and genetic factors that lead to dysfunction of the epithelial intestinal barrier (leaky gut) with consequent dysfunction of the mucosal immune system and abnormal responses to gut microbiota.[549] A recent article published in a well-respected medical journal hypothesized that intestinal permeability is a necessary pre-condition for the development of autoimmunity:

“There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases. Therefore, we hypothesize that loss of intestinal barrier function is necessary to develop autoimmunity.”[574]

Cyrex-Array-2-Intestinal-Antigenic-Screen-2Given that the literature supports the view that intestinal permeability (leaky gut) is the “gateway” for the development of environmentally-induced autoimmunity, including IBD, it is important to assess the integrity of the intestinal barrier and provide nutritional support to improve the integrity of this barrier when necessary. Assessment of the intestinal barrier can be done with Cyrex Labs Array 2 Intestinal Antigenic Screen.

The Cyrex intestinal barrier function test is the most accurate intestinal barrier permeability test available and is currently the only lab that measures the immunological response against the tight junctions of the intestinal barrier and accepted markers of permeability.  The profile includes actin/myosin network IgG, occludin/zonulin IgG, IgA, IgM and lipopolysaccharides (LPS) IgG, IgA, and IgM.  Measurements of these antibodies can be used as markers for intestinal permeability.[575]

anti-inflammatory-herbs-5FM Management of IBD: Immune-Modulating Herbal Compounds

The focus of management of IBD should be to prioritize decreasing immune responses and oxidative stress resulting in excess inflammation and supporting balance between the Th-1 and Th-2 systems. There are a number of herbal/botanical compounds which have shown promise in reducing inflammatory responses and oxidative stress, supporting the T regulatory cells and balancing Th-1 and Th-2 responses, inhibiting leukotrienes and nuclear factor-kappa B (NF-kB), and having antiplatelet activity.[570,571]

Some of the herbal compounds that have been studied and found to have beneficial effects on targeted inflammatory molecules and mediators involved in IBD, some of which have shown comparable or superior effects to standard medical treatment, include:

  • Curcuminanti-inflammatory-3
  • Resveratrol
  • Pineapple Juice (Bromelain)
  • Green Tea
  • Pomegranate
  • Rutin
  • Aloe vera (Xanthorrhoeaceae)
  • Andrographis paniculata (Acanthaceae)
  • Boswellia serrata (Burseraceae)
  • Anthocyanin-rich bilberry preparation (Vaccinium myrtillus)
  • Plantago ovata (Plantaginaceae)
  • Evening primrose (Oenothera biennis)
  • Wormwood herb (Artemisia absinthium-Asteraceae)
  • Tripterygium wilfordii [570,571]

Some of these compounds, such as curcumin and resveratrol, have been found in various studies to have powerful anti-inflammatory effects by inhibiting NF-kB, a key trigger of inflammatory responses.

NF-kB-signalling-2Natural NF-kB Inhibitors

NF-kB is a protein complex that controls the transcription of DNA inside each cell of the body. It is found in all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, and antigens. NF-kB controls the expression of genes encoding the proinflammatory cytokines, chemokines, adhesion molecules, inducible enzymes (COX-2 and iNOS) and growth factors involved in inflammation. Chronically activated NF-kB has been linked to cancer, inflammatory conditions and autoimmune diseases.[576-580]

“An increasing number of studies indicate that NF-kB plays an important role in controlling expression of genes relevant to the pathogenesis of autoimmunity”[579]

“NF-kB is a key signaling component in autoimmunity and an attractive target for autoimmune disease therapy”[580]

Curcumin and resveratrol have been found to modulate inflammation and mediate inflammatory effects by targeting the NF-kB signaling system.[581-583]

curcumin-resveratrol“Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the NF-kB signaling pathway. Treatment with curcumin or resveratrol suppressed NF-kB-regulated gene products involved in inflammation.”[584]

“The anti-inflammatory effects of curcumin included down-regulation of gene products that mediate matrix degradation…prostanoid production…apoptosis…and stimulation of cell survival…all known to be regulated by NF-kB”[585]

curcumin-3“…curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as NF-kB)…”[586]

“Our data suggest that the suppression of TRIF and TBK1, which mediates transcriptional activation of NF-kB, AP-1 and IRF-3, contributes to resveratrol’s broad-spectrum inhibitory activity, and that this compound can be further developed as a lead anti-inflammatory compound”[587]

resveratrolThis study confirms the NF-kB inhibitory activity and anti-inflammatory activity of resveratrol, which may contribute to neuroprotection in diabetic neuropathy apart from its antioxidant effect”[588]

“Data at our disposal on resveratrol clearly suggest that it has great potential to effectively modulate colon inflammation and it is already in clinical trial.”[570] 

The therapeutic value of plant and herbal compounds, such as turmeric, resveratrol and others, have recently gained the interest of researchers in the field of gastroenterology. A very recent study published in the Annals of Gastroenterology concluded the following:

“The available data concerning the administration of extracts derived from plants and herbals give the gastroenterologist the excuse to explain to our patients the benefits of this therapy, concurrently providing evidence-based information about their use.”

cut-cost“It is true that the cost of treatment of IBD patients is continuously rising and herbal treatment might represent a new effective and cheap treatment method. Doctors must become more tolerant and open-minded about the benefits of alternative medicine.”

“Large, double-blind clinical studies assessing the most commonly used natural substances should urgently be conducted.”[571]

Glutathione

glutathione-4Glutathione (GSH) is an important antioxidant that quenches reactive oxygen species (ROS) compounds before they cause oxidative damage and helps protect the intestinal barrier.[589-593] In general, high oxidant burdens are a common feature in many immune dysfunctions and GSH plays a major role in quenching these oxidant species, and hence protecting the cell from damage.  Therefore, any decrease in GSH may influence the immune system through perpetuating reactive species signaling events and increasing ROS-related damage.[594] Glutathione helps support regulatory T cells, and differentiation of T-cells into their specific types by reducing damage from oxidative stress.  Studies suggest that intracellular GSH levels in macrophages (important white blood cells in immune responses), influence the TH1/TH2 cytokine response patterns which are associated with immune dysregulation and autoimmunity and suggest that supporting glutathione levels in these cells is an effective strategy to support immune health.[589,595]

“Accumulation of evidence suggests that intracellular GSH levels in antigen-presenting cells such as macrophages, influence the TH1/TH2 cytokine response pattern.  The observations reported herein show that pro-GSH molecules represent new therapeutic agents to support immune modulation.”[594]

glutathione-benefits-2Low GSH levels have been associated with many autoimmune and inflammatory diseases, including IBD. [594,596] Elevated tissue GSSG (oxidized glutathione) has been correlated with severity of intestinal mucosal inflammation.[597,598] Significantly lower levels of GSH were found in inflamed ileal mucosa from patients with CD [597], and in the colonic mucosa of patients in active UC disease states.[599]

“Intracellular and extracellular thiol-disulfide (GSH/GSSG) redox homeostasis is central to intestinal function and integrity. Maintenance of the intestinal epithelial redox environment is essential for the activities of key physiological processes that include digestion and absorption, cell proliferation and apoptosis, and immune response.”[600]

glutathione-needed-by-cellsGiven that the glutathione recycling system (system that supports GSH/GSSG conversion) is critical for overall modulation of autoimmunity and intestinal function and integrity in particular, supplementation with compounds to support glutathione levels should be considered in management of IBD. In addition to glutathione supplementation, this includes compounds which support glutathione recycling such as n-acetyl-cysteine[601-603], alpha-lipoic acid (ALA)[604-606], l-glutamine[607-609], selenium[610-615], cordyceps[616-617], centella asiatica[618-620], silybum marianum[621-623] and broccoli seed extract[624-626].

Omega-3 Fatty Acids

fish-oilsThe anti-inflammatory effects of omega-3 (n-3) fatty acids found in fish oils are well-established in the research literature.[627-631]  These fatty acids have been found to inhibit a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression, leucocyte‐endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from arachidonic acid, production of inflammatory cytokines and T cell reactivity.[627-631]  These fatty acids appear to exert their clinical effects via their capacity to regulate the expression of genes for proinflammatory cytokines.[632] Animal models demonstrate benefit from n‐3 fatty acids in various inflammatory conditions including rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma.[627]

“N-3 fatty acids from fish oil decrease the production of inflammatory cytokines and eicosanoids. They act both directly (by replacing arachidonic acid as an eicosanoid precursor) and indirectly (by altering the expression of inflammatory genes through effects on transcription factor activation). Thus, these fatty acids are potentially useful anti-inflammatory agents and may be of benefit in patients with chronic inflammatory diseases or at risk of hyperinflammation and sepsis.”[629] 

cell-membrane-3“Thus, the fatty acid composition of human immune cells influences their function and the cell membrane contents of arachidonic acid, EPA and DHA are important. Fatty acids influence immune cell function through a variety of complex mechanisms and these mechanisms are now beginning to be unraveled.”[630]

Past literature reviews conclude that there is therapeutic benefit from fish oils in the treatment of IBD. [633,634]

inflammation…these studies point to the therapeutic potential for these lipids in the therapy of IBD. It is possible that these fatty acids act by reducing low-grade active inflammation rather than by preventing reinitiation of the inflammatory process from a truly quiescent state.  Nevertheless, taken together, all these studies suggest the effectiveness of these new therapeutic approaches (omega-3 fatty acid therapy), not only when conventional treatment fails or when it is not possible to treat chronically, but also, in some instances, as first choice.”[633]

In most of these studies, fish oil supplementation in IBD improved outcomes related to clinical score, gut mucosal histology score, induced remission, and relapse [635]. A few studies show that fish oil has an apparent ability to maintain remission in CD patients.[636]

“These results suggest that dietary lipids and curcumin interact to regulate mucosal homeostasis and the resolution of chronic inflammation in the colon.”[637]

colon-7The beneficial and protective effects of omega-3 fatty acids in colon health extend beyond inflammatory bowel disease and have been shown to protect against cancer of the colon as well.

“Compelling data indicate a functional link between chronic inflammation and colon cancer. With respect to environmental risk factors, there is growing evidence that long-chain n-3 polyunsaturated fatty acids found in fish oil suppress inflammatory bowel diseases and colon cancer risk in humans.”[638]

The consumption of dietary fish oil may prove to be an effective adjuvant therapy in colon cancer. Therefore, it is both appropriate and timely to determine precisely how n-3 polyunsaturated fatty acids modulate cell signaling networks, and reduce the risk of developing colon cancer and inflammatory disorders of the intestine.”[638]

fish-oils-2These results suggest that the anti-tumorigenic effect of n-3 PUFA may be mediated in part via its anti-inflammatory properties.[639]

Given the evidence for the beneficial effects of omega-3 fatty acids in IBD, consideration of omega-3 status and supplementation should be considered in inflammatory conditions such as IBD.

vitamin-DVitamin D

Vitamin D deficiency is commonly diagnosed among patients with inflammatory bowel disease (IBD).[640] Patients with IBD are at risk of low bone density and increased fractures due to low vitamin D levels, long standing disease, and frequent steroid exposures. Therefore, vitamin D supplementation is essential in this high-risk group.[640] It is well-established in the literature that vitamin D supplementation in this population is important.[640] Additionally, there is increasing evidence for the role of vitamin D in strengthening the innate immune system by acting as an immunomodulator and reducing inflammation in experimental and human IBD.[640] Vitamin D modulates T regulatory cell function, resulting in more balanced Th-1/Th-2 immune responses, and decreases destructive Th-17 responses resulting in decreased inflammation and destruction of tissue.

“The active form of vitamin D, 1,25(OH)D3, acts on T cells to promote T helper (Th)2/regulatory T cell responses over Th1/Th17 responses; suppresses dendritic cell inflammatory activity; induces antibacterial activity; and regulates cytokine production in favor of an anti-inflammatory response.”[640]

conductor-of-orchestraImmunomodulatory Effects of Vitamin D

Vitamin D is important in both the innate and adaptive immune systems.[641] Like a conductor of an orchestra, vitamin D can modulate the adaptive immune responses by altering the actions of activated T and B cells, and it can modulate the innate immune responses by regulating macrophages and dendritic cells.[642] It has been established that vitamin D is an immune system regulator through its role in targeting T lymphocytes to suppress T helper type 1 (Th1) cell driven immune responses.[643-645]. Vitamin D works to inhibit the over production of pro-inflammatory cytokines, such as IFN-γ, interleukin (IL)-2, and tumour necrosis factor-alpha (TNF-α).[645]

Th1-Th2-balanceOverall, the main action of vitamin D on T-cells is mediating T helper type 1 (Th1)/T helper type 2 (Th2) development and differentiation.[643,644]  Vitamin D reduces inflammatory tissue damage by suppressing Th17 development and in doing so, reduces IL-17 production.[641] Additionally, vitamin D increases the development of T regulatory cells by acting on naïve T lymphocyte cells. Regulatory T cells are a group of T lymphocyte white blood cells that have immunosuppressive properties by depressing the proliferation of other T lymphocytes.[641]

Role of Vitamin D in IBD

Increasing studies have demonstrated the role vitamin D plays in reducing gastrointestinal inflammation and suggest deficiency is associated with IBD.[640] Vitamin D reduces the impact of cytokine-induced apoptosis (cell death) and cytokine disruption of epithelial barrier function, which prevents the proinflammatory profile seen in IBD.[640] inflammatory-cytokinesThere is evidence to suggest that there are distinct cytokine profiles in Crohn’s disease and ulcerative colitis.[651] Specific pro-inflammatory cytokines have been identified in the inflamed mucosa of Crohn’s disease and ulcerative colitis patients such as IL-1, IL-6, IL-8, and TNF-α.[651] Each of these cytokines upregulate the inflammatory cascade leading to more inflammation and tissue damage in the inflamed mucosa.[651] Vitamin D has been shown to target each of these inflammatory pathways.[640]

vitamin-D-2Animal and human IBD studies support a therapeutic role of vitamin D in IBD.[640] Normalization of vitamin D levels is associated with reduced risk of relapse, reduced risk of IBD-related surgeries, and improvement in quality of life.[640] One randomized placebo-controlled study assessed the effectiveness of vitamin D supplementation in improving Crohn’s disease activity. In comparison to the placebo, oral vitamin D supplementation of 1200 IU in adult patients with Crohn’s disease in remission was shown to increase the serum vitamin D levels and reduce the risk of relapse from 29% to 13% at 1 year (P = 0.06).[652]

vitamin-D-3Recent advances in the understanding of the effects and mechanism of action of vitamin D on the mucosal and systemic immune system and subsequently on intestinal inflammation suggests it has a role to play in the therapeutic management of IBD. Furthermore, both epidemiologic and emerging retrospective and prospective clinical evidence supports a significant beneficial role of vitamin D supplementation in patients with IBD.”[640]

Vitamin D is an inexpensive supplement which has been shown to have various beneficial anti-inflammatory and immune-regulating effects and improve IBD outcomes.[640] Vitamin D status should be assessed and supplementation should be strongly considered in IBD patients. However, there are still unanswered questions regarding the optimal levels of serum vitamin D to achieve optimal effects in IBD patients.IBD-vitamin-D-algorithm

“While the precise level of 25(OH)D3 (serum vitamin D) that needs to be achieved for these therapeutic effects is unknown, it has been established that levels of 75 nmol/L or higher are generally adequate. Given the safety profile and low cost of vitamin D, its addition to the therapeutic armamentarium as a supplement to induction and maintenance therapy should be strongly considered.”[640]

probioticsProbiotics

Probiotics have been shown to have anti-inflammatory effects in patients with inflammatory bowel disease and appear to regulate mucosal immune response through reductions in proinflammatory cytokines.[654]  Studies have shown that some types of probiotic gut bacteria prevent and/or improve symptoms of IBD and have been proposed as a suitable treatment for mild to moderate IBD.[655,656] The beneficial probiotic activity has been associated mainly with Lactobacilli, BifidobacterE. coli, and Saccharomyces boulardii [657].

“Our results suggest that Saccharomyces boulardii may represent a useful tool in the maintenance treatment of Crohn’s disease.”[658]

microbiome-cover-nature“These results demonstrate that L. plantarum can attenuate immune-mediated colitis and suggest a potential therapeutic role for this agent in clinical inflammatory bowel diseases.”[659]

Several studies suggest that probiotics can improve the health condition of UC, pouchitis, and CD patients.[658-662]. Taken together, these studies clearly indicate that probiotics show great promise in decreasing symptoms of IBD, but the current consensus warrants a large number of controlled clinical trials before the use of probiotics as a routine medical treatment for IBD.[560] Let’s take a brief look at a few of these studies.

VSL#3The efficacy of VSL#3 (a combination of Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, and Streptococcus thermophilus) in UC patients has been proven in several papers. One study showed this probiotic led to remission of mild-moderate UC in 34 adult patients without any adverse events [663]. Another study showed positive effects of VSL #3 on 20 UC patients intolerant or allergic to 5-ASA (a standard treatment in IBD).[664]. Efficacy of VSL#3 leading to remission and maintenance of remission of UC was shown in a study conducted on 29 children with newly diagnosed UC.[665].

Other probiotics have been shown to be effective in studies as well. A study from 2004 showed that the probiotic E. coli Nissle 1917 was just as effective as mesalazine (5-ASA) in the maintenance of remission in UC patients.[666] Another study demonstrated the efficacy of the probiotic BIFICO (bifidobacteria) in preventing flares in UC patients.[667]

microbiome-7‘These results suggest that oral administration of this new probiotic preparation is effective in preventing flare-ups of chronic UC. It may become a prophylactic drug to decrease the relapse of UC.”[667]

Another large study showed equivalent efficacy of Lactobacillus GG to the mesalazine (5-ASA) treatment group in maintenance of remission in 187 patients with UC. However, the Lactobacillus GG seemed to be more effective than standard treatment with mesalazine in prolonging the time until relapse (P < 0.05). [668]

microbiome-13“Lactobacillus GG seems to be effective and safe for maintaining remission in patients with ulcerative colitis, and it could represent a good therapeutic option for preventing relapse in this group of patients.”[668]

In 2007, a Cochrane review [669] concluded that probiotics could provide efficacy in the maintenance of remission in patients with mild-moderate UC, while limited efficacy could be predicted for moderate-severe disease.[670]

“Clearly, some probiotics have considerable potential in the management of IBS and IBD; however, the benefits are strain specific.”[671]

“Probiotics and prebiotics definitely have great potential for future therapeutic approaches in inflammatory bowel disease.”[672] 

vitamin-EVitamin E and Selenium

There is a strong relationship between the levels of certain vitamins and minerals, such as vitamin E and selenium and IBD.[560] In IBD, increases in oxidative damage accompanied by production of free oxygen radicals characterize the progression and severity of the disease. It has been shown that selenium (Se) and vitamin E are two natural antioxidants, which quench reactive oxygen species leading to improvement in IBD conditions.[673,674]

seleniumSe and essential co-factors, may play an important role in binding active sites of glutathione peroxidase and affecting glutathione levels (see previous section on glutathione and IBD). Vitamin E is an effective chain-breaking lipid soluble antioxidant likely to quench oxidants and reduce oxidative damage produced mainly by infiltrating macrophages and neutrophils within the inflamed colon. Recently it has been shown that Se and vitamin E in combination provide protective effects in experimental colitis.[675] There are other antioxidants, such as lycopene, which have also been shown to decrease the oxidative stress and inflammation induced by iron in rats with colitis.[676] Therefore, supplementation with vitamin E, selenium and other antioxidants such as lycopene, should be considered in IBD conditions.

anti-inflammatory-dietDiet and Nutrition

Dietary intervention is a critical component in managing any autoimmune condition, but particularly in IBD. Avoidance of common food allergens, such as wheat and dairy, is recommended even after celiac disease has been ruled out. As we will learn in the next section, non-celiac gluten sensitivity is extremely common in autoimmune conditions, including IBD. Assessing for food sensitivity and avoidance of these foods that provoke immune responses is important in IBD. Adherence to a diet to support intestinal permeability is also recommended given the close association between intestinal permeability and IBD. Refer to the Intestinal Permeability Dietary Restrictions for more information.

“In pediatric or adolescent CD patients, nutritional therapy is well established as a way to maintain remission of CD. It has been shown that exclusive enteral nutrition (EEN) alleviates clinical symptoms, improves quality of life, and rapidly decreases CD activity by influencing the underlying mucosal inflammatory process.”[570]

Related Articles

 

Intestinal Permeability/Leaky Gut

Celiac Disease

Non-Celiac Gluten Sensitivity

Autoimmune Disease

Introduction to autoimmune disease: What is it? How common is it? How is it diagnosed? How is it managed?

What are the different types of autoimmune disease? How common is Hashimoto’s hypothyroidism? What is involved in the development of AI disease?

What are the mechanisms and mediators involved in autoimmunity? Intestinal permeability promotes autoimmunity. Gluten sensitivity and autoimmunity connection.

What role do chronic bacterial and viral infections play in autoimmunity?  What role do environmental toxins play?  The role of the glutathione and nitric oxide synthase (NOS) systems and development of autoimmunity.

How do we modulate the autoimmune response? What role do the glutathione and nitric oxide synthase (NOS) systems play in preventing and modulating AI disease?  What role does vitamin D play?

 

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