The Role of Inflammation and Neuroplasticity in Irritable Bowel Syndrome

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Table of Contents

Abstract——————————————————————————————————————————2
Introduction————————————————————————————————————————-3
Methods——————————————————————————————————————————3
Discussion————————————————————————————————————————–4
Low-Grade Inflammation in IBS————————————————————————————–4
Innate Immune Response———————————————————————————————4
Adaptive Immune Response——————————————————————————————6
Gut-Brain Axis————————————————————————————————————8
Alterations in Brain Activity——————————————————————————————–9
Interventions————————————————————————————————————-10
Limitations and Conclusion————————————————————————————————-13
References (AMA format used)——————————————————————————————–14

The Role of Inflammation and Neuroplasticity in Irritable Bowel Syndrome

(Date)

Abstract
Objective: The purpose of this review is to analyze the immunological factors associated with the perpetuation of irritable bowel syndrome (IBS). The innate and adaptive immune response and alterations in brain function will be explored. Considerations for therapeutic interventions will be based on establishing immunological homeostasis, minimizing systemic inflammation, and regulating brain activity.
Methods: A literature search in the Allied and Complementary Medicine Database, Cochrane Database of Systematic Reviews, DynaMed, MEDLINE, and PubMed was conducted using the terms, “Immune cells and IBS,” “T-helper cells and IBS,” “Cytokines and IBS,” “Mast cell activation and IBS,” “Histamine and IBS,” “Gut-Brain Axis and IBS,” “Neural plasticity and IBS,” “Visceral hypersensitivity and IBS,” and “Neuro-inflammation and IBS.” Systematic reviews, meta-analyses, epidemiological, and randomized-controlled trials with full-text published between 2000 and 2019 are included. Human, animal, and in-vitro studies are referenced. Narrative reviews were excluded.
Conclusion: The etiology of IBS is multi-factorial and its presentation is unique to each individual. Persistent low-grade inflammation is a potential mediator involved in promoting the chronicity of this condition. Abnormalities seem to exist in the expression of innate and adaptive immune cells, and in the communication between the gut and the brain. These alterations are associated with impairments in gastrointestinal motility, changes in stool consistency, and visceral hypersensitivity. Promoting inflammation resolution and restoring activity of the parasympathetic nervous system may be necessary to maintain IBS in a state of remission.

Introduction
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by unresolved changes in bowel habits. The condition is divided into the following four categories depending on symptoms: diarrhea (IBS-D), constipation (IBS-C), a mixture of diarrhea and constipation (IBS-M), or abdominal pain with unspecified stool formation (IBS-U). The criteria for a positive diagnosis include a 6-month history of the following symptoms: abdominal pain, frequent changes in stool frequency, and changes in stool form. It is estimated that 5-15% of the population experience IBS, with the prevalence being higher in women than in men. Consequences of IBS may include decrements in quality of life, depression, anxiety, and reduced work productivity 1-3.
It is reasonable to consider the etiology of IBS to be multifactorial. Possible triggers include childhood adversity, experiencing a traumatic event, or gastrointestinal infection. The effects of broad-spectrum antibiotic treatment have been considered for its impact on intestinal pH, reduced gastrointestinal (GI) motility, and bacterial or yeast overgrowth 4-6. Bashashati et al. investigated the role of genetic polymorphisms leading to an up-regulation of inflammatory cytokines, interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α), and a down-regulation in anti-inflammatory cytokines such as IL-10 7.
Diet, food sensitivities, and intolerances may be involved in the development or persistence of IBS. Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates not easily absorbed in the intestine. Unabsorbed FODMAPs are fermented by intestinal microbiota, leading to increased osmotic pressure. Water retention in the small intestine and damage to the intestinal mucosa may result 8.
Bohn et al. conducted a study in which 197 IBS patients were asked to complete questionnaires related to consumption of a variety of food items. Two-thirds of the participants reported worsening symptoms of IBS after consuming histamine-containing foods or foods that stimulate the release of histamine from mast cells 9. Biogenic amines (BAs) such as histamine and tyramine are created by microbial decarboxylation of amino acids. Examples of BA-containing foods are wine, beer, fish, cheese, and other fermented foods 10. Lectin-containing foods such as beans, lentils, peas, peanuts, soy beans, and spicy capsaicin-containing foods such as chili pepper, red pepper, and cayenne were listed as foods that may activate mast cells to secrete histamine 9,11.
There is an abundance of published research on the many possible triggers (i.e. genetics, stress, infection, diet, and others) of IBS. The focus in this review will be on physiological mediators associated with the perpetuation of IBS. The innate and adaptive immune response in IBS will be investigated. The communication occurring between the immune system and the brain will then be explored. To conclude, therapeutic interventions focused on reversing immune imbalance, minimizing systemic inflammation, and inhibiting damage to brain tissue will be considered.
Methods
A literature search in the Allied and Complementary Medicine Database, Cochrane Database of Systematic Reviews, DynaMed, MEDLINE, and PubMed was conducted using the terms, “Immune cells and IBS,” “T-helper cells and IBS,” “Cytokines and IBS,” “Mast cell activation and IBS,” “Histamine and IBS,” “Gut-Brain Axis and IBS,” “Neural plasticity and IBS,” “Visceral hypersensitivity and IBS,” and “Neuro-inflammation and IBS.” Systematic reviews, meta-analyses, epidemiological, and randomized-controlled trials with full-text published between 2000 and 2019 are included. Human, animal, and in-vitro [CR15] [SS16] [SS17] studies are referenced. Narrative reviews were excluded.

Discussion
Low-Grade Inflammation in IBS
Patients with IBS do not present with overt signs of inflammation like the ulcerations found in inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s. However, there are signs to indicate the presence of a low-grade chronic level of inflammation. To begin, the risk of developing IBS is significantly increased in people who have experienced an acute GI infection 12,13.
Halvorson et al. conducted a meta-analysis which included eight studies and almost 600,000 human subjects. Using the Mantel-Haenszel fixed effects calculation, the odds of developing IBS increased more than 7-fold in participants who experienced an acute infectious gastroenteritis (95% CI 4.7–11.1). There was no significant heterogeneity (p=0.41). Independent evaluators report the weighted quality score of the included studies to be very good (weighted κ = 0.80) with a median score of 10.25 out of 18 and there was no obvious publication bias on a funnel plot or Egger’s test (p=0.35) 13.
One possibility is that the inflammation associated with gastroenteritis has long-term effects on visceral hypersensitivity and GI motility. Alternatively, and as mentioned above, the persistence of low-grade inflammation may explain the pathology of IBS.
IBS develops in approximately 25% of people who are infected with Campylobacter jejuni. Spiller et al. aimed to measure the number of inflammatory cells that remain in patients one year after being infected by Campylobacter enteritis. Rectal biopsies, intestinal permeability tests (i.e. lactulose/mannose test), and symptoms questionnaires were regularly performed for up to one year post-infection. In the experimental group, enteroendocrine cells (ECs) (p<0.001) and T-lymphocytes (p<0.001) both remained significantly higher compared to controls at 12 weeks post-infection. To provide perspective on the magnitude of effect, cluster of differentiation 3 (CD3+) T-cells in patients post-infection were 5 times higher than in controls at the initial visit. At 12 weeks, CD3+ T-cells in subjects post-infection were 3 times greater than in controls. A small percentage of participants remained symptomatic for one year post-infection; ECs remained 5 times that of controls (p<0.001) and T-cells were >2.5 times more numerous than in controls (p<0.01). Low-grade inflammation correlated with continued complaints of IBS symptoms 14. The presence of low-grade inflammation has also been observed in IBS patients without a history of GI infection. Chadwick et al. assessed colonic biopsy specimens taken from 77 IBS patients and 38 healthy asymptomatic controls (HCs). Eight subjects had biopsies consistent with lymphocytic colitis which is classified as IBD. Only 36% of the remaining 69 participants describe the onset of IBS symptoms as “sudden,” which may or may not correlate to GI infection. There was no apparent history of infection in the other 64% of subjects. It was concluded that intraepithelial lymphocytes (IELs) and CD3+ cells were 1.8 times higher in IBS subjects than in controls (p<0.05; p<0.001 respectively), and CD25+ cells were 6.5 times higher (p>0.001) 15.
Innate Immune Response
NK cells, Neutrophils, Eosinophils
To explore the innate immune response, it is useful to assess the activity of cells that respond to the site of infection or tissue damage immediately upon insult. To date, research on NK cells, neutrophils, and eosinophils is limited, and results are mixed. In the study described above, Chadwick et al. observed increased numbers of NK cells and neutrophils in the 31 IBS patients who were classified as having non-specific microscopic colitis (NSMC). Individuals in the NSMC group had an enlarged lamina propria, more populated with neutrophils 15. In 2004, Elsenbruch et al. observed significantly fewer NK cells in women with IBS versus healthy controls, and in a subsequent study, the same investigators found no difference in NK cells in IBS patients 16,17.
These types of innate immune cells are predominantly responsible for responding to acute sources of stress. A possible explanation for discrepancies in study results is that NK cells, and neutrophils may only increase immediately following a recent infection, damage to the epithelial lining, stress, or after bowel preparation in those who are sensitive 15. Fewer NK cells may be present in a chronic state of low-grade inflammation in the absence of an acute stress. In fact, the major role of these cells is to destroy and remove pathogens or tissue debris. Insufficient levels of NK cells may lead to inadequate pathogen removal. This deficiency may ultimately trigger macrophages to activate T-lymphocytes and can potentially promote the chronicity of inflammation 18.
Monocytes, Macrophages
In contrast to NK cells, monocytes and macrophages are less involved in clearance. Monocytes and macrophages play a more important role in releasing pro-inflammatory cytokines and promoting the activation of the adaptive immune response. Researchers can gain insight into monocyte and macrophage activity by observing the presence of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8. IL-10 is associated with reduced inflammation 19.
A variety of different strategies have been deployed by researchers to evaluate cytokine response in IBS patients. Bashashati and colleagues were interested in the genetic component of IBS and conducted a meta-analysis to investigate the influence of single nucleotide polymorphisms on cytokine expression in IBS 20. Dinan et al. stimulated IBS and healthy patients with corticol-releasing hormone (CRH) to assess cytokine release as it relates to stress 21. Liebregts et al. retrieved peripheral blood mononuclear cells (PBMCs) from IBS patients and healthy controls and assessed the cytokine response after inoculating the PBMCs with Escherichia coli lipopolysaccharide (LPS) 19.
In these studies the evidence suggests that IL-6 is higher in IBS patients compared to controls both at baseline, and following protocol interventions (i.e. CRH stimulation, LPS inoculation) 19,21-23. To provide perspective on effect size, 8 studies were included in a meta-analysis, each with a quality score of > 6 according to the Newcastle-Ottawa scale. IL-6 was increased in IBS with a standardized mean difference (SMD) of 2.40 (95% CI, p=0.01) 24. In contrast, in a study conducted by Ohman et al., there was no difference in IL-6 expression in PBMCs of IBS subjects compared to healthy controls 25.
Data from randomized controlled trials and meta-analyses suggests that TNF-α is also higher in IBS patients versus healthy controls 7,19,23,26. Conversely, Dinan et al. found no difference in TNF-α in IBS patients versus controls 21.
Evidence is suggestive of a decreased expression of the anti-inflammatory cytokine IL-10 mRNA and/or a predominance of a low-producer IL-10 genotype in IBS 7,26. O’Mahony et al. observed reduced IL-10 in PBMCs of IBS patients at baseline versus healthy volunteers with a difference of approximately 393 pg/mL and a small increase in the pro-inflammatory IL-12 (approximately 9 pg/mL). The result was a significantly dysregulated IL-10/IL-12 ratio in IBS versus control (p=0.003) 27. In disagreement, Ohman and colleagues report a tendency toward increased IL-10 in IBS patients 25.
In total, there is predominantly more evidence to suggest an increased expression of pro-inflammatory cytokines IL-6, IL-1β, IL-8, and TNF-α and decreased expression of IL-10 in IBS 28. Discrepancies may exist because of study design, small sample sizes, and the potential for type 1 and type 2 errors. Additionally, the presence of cytokines in unstimulated or stimulated PBMCs may or may not be representative of internal cytokine production in GI mucosal tissue 25. Publication bias must also be considered for its role in the skewing of published results towards positive findings.
Mast Cells
Mast cells (MCs) release histamine, prostaglandins (PG), leukotrienes, and proteases such as tryptase, and chymase, which play a role in destroying pathogens and tissue debris. Via cell signaling, proteases activate proteinase activated receptors (PARs) and histamine binds to histamine receptors (H1 and H2) 29. Over time, MCs begin to secrete inflammatory cytokines, TNF-α, IL-4, IL-6, IL-13, and IL-33 30. Evidence from animal studies suggests that stimulation of PAR2 may alter chloride secretion, increasing intestinal permeability 31. A pain sensation is stimulated when PAR2 and prostaglandin E2 (PGE2) receptors are activated. Voltage-gated calcium channels open, which innervates cholinergic motor neurons and induces a pain sensation 31,32. The result is visceral hypersensitivity and continuous neuronal activation.
In addition to their potential impact on intestinal permeability, and pain sensation, MC mediated effects on cholinergic neurons may be implicated in the GI motility disturbances observed in IBS. Balestra et al. found the same inflammatory mediators in both IBS-D and IBS-C and suggest there are many influences involved in determining which subset of IBS (i.e. IBS-D, IBS-C, IBS-U, IBS-M) that ultimately manifests 29. The gut-brain axis and the role of neuroplasticity and GI motility will be further explored later on in this review.
Twenty-two studies with over 1000 human subjects (706 people with IBS and 401 healthy controls) were reviewed in a meta-analysis conducted by Bashashati et al. The objective was to measure the density of intestinal immune cells in IBS patients versus HCs. MCs were found to be significantly increased in the rectosigmoid colon with a SMD of 0.38 (p=0.02) and in the descending colon with a SMD of 1.69 (p=0.001) 33. It was mentioned that MC increases were not observed in all studies on IBS 34. The number of MC cells may be a less relevant biomarker than a measure of MC activity. MC activity can be evaluated by observing the presence of MC mediators such as histamine, prostaglandins, proteases, and cytokines such as IL-33.
Barbara et al. studied MC activity in IBS patients versus HCs and report that the number of degranulating MC’s was increased by a factor of 150% (p=0.026). Tryptase was observed to be 2.35 pmol/min/mg higher than control (p=0.015) and histamine was measured to be approximately 170 ng/g greater than control (p=0.015). The number of MCs located in close proximity to nerves was 223% more than in IBS patients (P<0.001) and these MCs nearest to nerves degranulated most actively (r=0.72, p=0.002). Finally, there was a significant and positive association between the proximity of mast cells to nerves and the level (r=0.75, p=0.001) and frequency (r=0.70, p=0.003) of GI distress and abdominal pain 29. Several other researchers report observing an upregulation of MC mediators in IBS 31,32,34.
Adaptive immune response
T-lymphocytes are involved in adaptive immunity and they are divided into subsets classified by the type of cytokines they secrete. T-helper cell type 1 (Th1) cells are involved with cell-mediated immunity. They secrete cytokines interferon gamma (IFN-γ), IL-12, and IL-2, which are associated with fighting bacterial and viral infections. T-helper 2 (Th2) cells increase the expression of IL-4, IL-5, IL-13, and IL-6, which are responsible for destroying parasites, and the proliferation of B-lymphocytes in humoral immunity. Th17 up-regulates IL-17, which has been studied for its involvement in autoimmunity. Other known subsets are Th9 and Th22. T-regulatory cells (Tregs) secrete anti-inflammatory cytokines IL-10 and tumor growth factor-β (TGF-β) 14,35,36. (Figure 1) 37.

Figure 1: Schematic of cytokines, transcription factors, T-cell formation, and function.

Chen et al. compared cytokine expression in mucosal tissue from patients with post-infectious IBS (PI-IBS) versus non-PI-IBS versus healthy controls. IFN-γ was approximately 0.47 a.u. higher in PI-IBS than in patients with non-PI-IBS (p<0.05), and IL-10 was approximately 0.15 a.u. lower in PI-IBS than non-PI-IBS (p<0.05) 35.
Th1 cytokines have historically been considered pro-inflammatory, and while it may be accurate that they stimulate proliferation of other immune cells, they may also promote inflammation resolution by scavenging and removing infectious material or tissue debris. It would be premature to assume that the mere presence of Th1 cytokines in PI-IBS indicates they are a cause of the inflammation in PI-IBS. IFN-γ up-regulation and anti-inflammatory IL-10 down-regulation may be a defense mechanism by which the body fights an infection to ultimately diminish inflammation. An important question to ask about both non-PI-IBS and PI-IBS is why do inflammatory cells such as MCs, IL-6, IL-1β, IL-8, and TNF-α remain persistently up-regulated as observed in many of the studies referenced above 23,24,28,33 ?
Kindt et al. suggest that the increased expression of IL-5 and IL-13 they observed in IBS patients, and the proliferation of IL-6 reported by others such as Liebregts et al., are associated with a Th2 dominance 19,38. Increased MC activation may also indicate a shift toward Th2 because MCs attach to receptors on Immunoglobulin E (IgE) antibodies, and produce Th2 cytokines IL-4, IL-5, and IL-13 39.
Th17 cells are gaining more attention in recent years for their influence in chronic inflammation, and have been studied in chronic lung disease and autoimmunity40-42. Emerging evidence suggests that the combined effects of Th17 and Th2 along with MC activation yield continuous inflammation 40,43.
An alternative theory about some Treg cytokines, traditionally considered to be anti-inflammatory, is also developing. In an animal study, Mangan et al. demonstrate that while TGF-β inhibits the Th1 cytokine IFN-γ, TGF-β simultaneously promotes the proliferation of Th17 cytokines, IL-17 and IL-23 44. It might therefore be more appropriate to suggest that while TGF-β has anti-inflammatory properties whereby it inhibits IFN-γ, it may also act in a manner which is pro-inflammatory by stimulating secretion of IL-17 and IL-23 via up-regulation of retinoic-acid-receptor-related orphan nuclear receptor gamma t (RORγt). Interestingly, IFN-γ and IL-4 were capable of inhibiting the further development of pro-inflammatory Th17 cytokines 44,45. IFN-γ is being used in the treatment of the autoimmune condition multiple sclerosis (MS). Using an individualized approach, clinicians may consider the promotion of IFN-γ in the treatment of autoimmune diseases 42,46.
Research on the involvement of Th17 in IBS is limited. Using colonic subepithelial myofibroblasts, Hata et al. demonstrated the secretion of IL-6, IL-8, TNF-α, and monocyte chemoattractant protein (MCP-1) by IL-17. MCP-1 is a chemokine and may play an important role in the chronicity of inflammation because chemokines function to prolong the recruitment of other immune cells such as monocytes, eosinophils, T cells, and basophils 47. IL-17 has been studied in relation to IBD. Fujino et al. report IL-17 was highly expressed in active IBD colonic tissue and serum whereas neither serum nor colonic tissue from HCs had expression of IL-1748. In IBS, Choghakhori et al. report increased IL-17 in serum of the IBS-D subset (8.46 ± 3.32 vs. 5.63 ± 3.15 pg/mL, p<0.001) 49. Further investigation on the role of Th17 in IBS may answer some unresolved questions about the development, perpetuation, and treatment of IBS.
T-helper cells are involved with the proliferation of antibody-producing B-lymphocytes and in turn, B-lymphocytes are antigen-presenting cells, which can stimulate T-cell activation50. Cytokines are used by T-helper cells to stimulate a B-cell class switch. Th2 cytokine IL-4 promotes B-cells to switch production of the non-specific immunoglobulin M (IgM) to the production of IgE. IgE is the antibody associated with an immediate immune response to food or pathogen, sometimes resulting in an anaphylactic reaction 51. Th1 cytokines, IL-12 and IFN-γ are associated with the B-cell class switch to immunoglobulin G (IgG). IgG antibodies are responsible for a delayed and less severe response to antigen often associated with food intolerances. T-reg cytokine TGF-β induces a class switch to immunoglobulin A (IgA) which has immune suppressing properties 52,53.
It has yet to be clearly determined if there is a type of B-lymphocyte characteristic of IBS. As mentioned above, MCs can exacerbate the production of IgE because of their ability to provoke the secretion of IL-4. Asthma is characteristically a Th2-dominant condition with increased expression of MCs and IL-4. In a large nested case-control study, Cole et al. report a 20% increased incidence of IBS in people with asthma (standardized morbidity ratio = 1.2; 95% CI, 1.0–1.5) 54. This could indicate a similar cytokine and antibody profile between the two conditions. Ohman et al. observed increased expression of IgG in the blood of IBS patients. Following administration with lipopolysaccharides or probiotic bacteria, blood samples from IBS patients had reduced expression of the co-stimulatory molecule CD80 compared to HC. The researchers postulate that reduced CD80 is indicative of an impaired ability of IBS patients to elicit tolerance 50.
Forshammer et al. did not find a difference in IgG or IgE expression in segments of ascending and sigmoid colonic tissue between IBS patients and HCs. However, IgA levels in IBS colonic tissue was significantly lower than that found in HCs (p=0.039). Insufficient IgA could prolong an immune response and promote the chronicity of inflammation 53.
Up-regulation of IgE and/or IgG or down-regulation of IgA can be associated with IBS. It is also possible that symptoms related to IBS such as dysbiosis and intestinal permeability increase systemic exposure to endotoxins and provoke an antibody response.
Gut-Brain Axis
An investigation of the symptoms associated with IBS (i.e., GI distress, abdominal pain, changes in gastric motility, depression, and anxiety) may provide further insight into the involvement of low-grade inflammation in the perpetuation of IBS.
Cenac et al. used rectal biopsy samples from humans with IBS and healthy controls to demonstrate that colonic tissue from IBS patients had a 5-fold increase in proteolytic activity in vitro compared to healthy controls. MC secretions of trypsin and tryptase were the predominant proteases observed. The supernatant cells activated PAR2 and mobilized calcium in cultured mouse dorsal root ganglion (DRG) neurons, whereas cells from HCs did not have an effect on PAR2 or sensory neurons. The investigators considered this part of their experiment as proof of mechanistic concept that proteases are excitatory to nociceptors via PAR2 activation. As a next step, rectal biopsy samples were injected into mice. The recipients of IBS tissue experienced thermal and mechanical hyperalgesia (decreased threshold to heat and pain) not observed in controls. IBS tissue significantly increased nociceptive score (p<0.05) while mice in the control group maintained a nociceptive score of zero. IBS recipients experienced allodynia (abnormal pain felt from repetitive stimulus), and significantly increased high-intensity abdominal contractions in response to colorectal distension (p<0.005) 55.
Wouters et al. sought to confirm this manifestation of visceral hypersensitivity in a human experiment. Transient reporter potential channel V1 (TRPV1) is a receptor that is stimulated by sensations such as heat and capsaicin. As proof of concept, the researchers exposed rectal tissue taken from patients with IBS to capsaicin in-vitro. Compared to healthy rectal biopsy specimens, supernatants taken from IBS patients resulted in significantly higher amounts of calcium firing to stimulate neurons via TRPV1 activation. Next, 51 patients with IBS completed a double-blind randomized trial in which they were instructed to either take a histamine receptor (HR) antagonist, or a placebo for 12 weeks. At the end of 12 weeks, subjects who took the HR antagonist experienced significantly diminished abdominal pain (mean change, -17 ± 25 vs. +3 ± 23; p=0.0004), reduced flatulence (p<0.03) and less bloating (p<0.007), significantly improved sleep, diet, social, and emotional roles (p<0.05), and decreased sensation of urge (placebo -1 [-30 to +32] vs HR antagonist -18 [-65 to +27]; p=0.046) 56.
These results suggest that the GI distress, pain, and changes in bowel habits experienced by IBS sufferers may be a manifestation of MC-induced visceral hypersensitivity and neuronal activation.
Balestra et al. explain that although bowel habits vary between IBS-D and IBS-C patients, immune cell patterns are similar. IBD patients also experience alternating symptoms of diarrhea and constipation while inflammatory cell profiles remain the same. The question of why IBS patients experience contrasting bowel habits has yet to be elucidated. Diet and the microbiome play a role. Interestingly, MCs have also been implicated. Serotonin, which is released by MCs, ECs, and intestinal bacteria, stimulates gastric motility. The type of IBS a person experiences may be determined by the combined effects of diet, differing intestinal bacteria species, and a serotonin/dopamine imbalance 32,57.
With changes in GI transit time and increased inflammation, IBS patients are at increased risk of developing small intestinal bacterial overgrowth (SIBO), changes in gastric acid secretions, and intestinal hyperpermeability 58,59. In a meta-analysis involving 50 studies, 8398 IBS patients and 1432 healthy volunteers, Chen et al. found that IBS patients had a 5-fold increased risk of developing small intestinal bacterial overgrowth (SIBO) (p<0.00001) 59.
Dinan et al. demonstrate an association between increased IL-6 levels and severity of symptoms such as depression, abdominal pain, gas, and bloating in IBS. In a human study, pyridostigmine was used as an acetylcholinesterase inhibitor, which stimulates the release of growth hormone (GH). Procyclidine was used as an anti-muscarinic agent. IBS patients experienced an exaggerated release of GH (p<0.03) and IL-6 (p<0.001) when challenged with pyridostigmine compared to either healthy volunteers or depressed non-IBS patients. Increases in IL-6 significantly correlated with worsening symptoms of IBS (p<0.001). Inhibiting muscarinic receptors with procyclidine prior to treatment with pyridostigmine prevented the IL-6 rise. In summation, muscarinic stimulation in IBS patients may provoke the production of the Th2 cytokine IL-6. The muscarinic system and its inflammatory effects may be dominant in IBS patients with diminished activity of the anti-inflammatory nicotinic system. Furthermore, low-grade inflammation and altered gut-brain signaling may mediate IBS 22.
Alterations in Brain Activity
Using magnetic resonance imaging (MRI) technology, several researchers have observed significant changes in the brain structure and function in IBS patients 60-63. Aizawa et al. used the Wisconsin Card Sorting Test (WCST) to assess cognitive flexibility in IBS patients compared to healthy controls. The WCST evaluates executive function, sustained attention, and the ability to appropriately switch from one task to another. MRI revealed that compared to healthy controls, IBS patients experienced significant differences in activity of the dorsolateral prefrontal cortex, the right hippocampus, and the left posterior insula (p<0.001 for all three). These changes were associated with significantly more Nelson perseverative errors (IBS: 4.5+3.1, HC: 3.0+2.7 p=0.049) and significantly more set-maintenance errors (IBS: 4.8+2.8, HC: 3.1+2.1 p=0.012). Perseverance errors are associated with an inability to ignore distractions and set-maintenance errors indicate impairments in memory and attention. These results suggest that IBS patients may have cognitive dysfunction. A reduced capacity to ignore irrelevant distractions could manifest into a hypersensitivity to pain (visceral hypersensitivity) and an altered perception of reality (anxiety and depression) 62,64.
Chen et al. conducted a large epidemiological study that included 32,298 IBS patients and 129,192 matched non-IBS controls all taken from the Taiwan National Health Insurance Database. The incidence of dementia in the IBS patients older than 50 was 4.86 for every 1000 years versus 3.41 in the non-IBS cohort. The significantly increased risk for developing dementia was found in IBS patients aged 50 or more. Several co-morbidities such as diabetes, hypertension, stroke, and others, tended to be higher in IBS patients. These co-morbidities were controlled for when calculating the odds ratio for dementia, but the impact of confounding factors cannot be ignored. However, there may be a connection between systemic inflammation, neuro-inflammation, subsequent changes in brain structure, and ultimately, cognitive deficits 65.
It is difficult to discern whether the chronic low-grade inflammation and neuronal excitation characteristic of IBS causes brain alterations or if abnormal brain activity causes IBS. However, it is imperative to consider the gut-brain connection in order to gain a better understanding of IBS and optimize clinical care.
Intervention
IBS manifests itself in a manner that is multifactorial and diverse. It remains unclear as to whether inflammation is the underlying cause of IBS or if immune imbalance and inflammation are the results of another trigger (i.e. genetics, infection, trauma, etc.). Nevertheless, it seems evident that chronic inflammation is involved in the perpetuation of IBS. Several types of interventions can and should be considered for the treatment of up-stream symptoms of IBS such as SIBO, intestinal hyperpermeability, impaired gastric motility, and depression. However, addressing chronic low-grade inflammation and promoting optimal brain function may be essential components needed to maintain IBS in a state of remission long-term.
Probiotics can be considered for the treatment of dysbiosis or SIBO 66. The amino acid glutamine is an energy source used by intestinal epithelial cells and can be taken to aid in reducing intestinal permeability. By improving intestinal health, glutamine plays a role in minimizing translocation of endotoxins into circulation 58. Ginger has been suggested for its antimicrobial and prokinetic effects 67. The elimination of foods that are tested to elicit an IgE or IgG response is recommended 8,68. These interventions can be appropriately chosen on a case-by-case basis to treat acute manifestations of IBS, reduce symptoms, and improve quality of life.
For long-term resolution, treatment of the down-stream features of IBS such as inflammation and the gut-brain axis can be considered. It may be clinically useful to assess a patient’s cytokine and immunoglobulin profile in addition to the symptoms they experience. Evaluation of the following biomarkers may be valuable: MCs, MC mediators (i.e. histamine, tryptase, PG, and serotonin), cytokines (i.e. TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17, IL-23, IFN-γ, and TGF-β), and immunoglobulins (i.e. IgE, IgG, and IgA) 15.
In addition to the traditionally observed symptoms of diarrhea, constipation, abdominal pain, and depression, analysis of a patient’s immune response may provide useful information. For example, if a person has seasonal allergies, asthma, hives, or repeated bouts of bacterial, viral, or sinus infections, this could be indicative of insufficient Th1 cytokine activity. Hu et al. used a mouse model to demonstrate that asthma is characteristic of reduced expression of Th1 cytokines combined with a more dominant Th2 response 69. This type of Th1/Th2 imbalance was also observed in a human study in people with interstitial pneumonia 70. Treatment strategies can be used more effectively if the underlying immune imbalance (i.e. Th2 dominance, MC activation, and Th1 repression) is accurately assessed.
The objective is to promote inflammation resolution and balance the immune system. Clinical intervention may differ between individuals based on their unique immunological pattern. For some patients, this objective may be acquired by minimizing MC activation and increasing expression of Tregs. In chronically infected patients, resolution may require the promotion of NK cells and a Th1 response 71,72 . Suppression of TNF-α, IL-6, IL-17, IL-23 and oxidative stress may be the priority in other cases 73.
Novel Considerations for Addressing IBS-Associated Low-grade Inflammation
Flavonoids such as quercetin and luteolin are compounds found in fruits, vegetables, grains, nuts, seeds, herbs, and spices. Researchers have examined the effects of these flavonoids on the inhibition of MC activation. Weng et al. used LAD2 cells, which resemble human MCs in culture. The LAD2 cells were activated with IgE and the neuropeptide, substance P (known MC activators). The lipid soluble analogue of luteolin, methoxyluteolin was a potent inhibitor of MC activation. The researchers report that methoxyluteolin prevented MC secretion of histamine, TNF-α, and chemokines by inhibiting the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer of B-cell inhibitor, alpha (IkBα), thereby inhibiting the stimulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB). NF-kB is a transcription factor which triggers gene expression of inflammatory cells such as TNF-α and IL-1β. Methoxyluteolin also blocked intracellular calcium secretion, which is what provokes MC degranulation 74.
In a small human trial, skin response was observed in nickel-sensitive dermatitis patients after being exposed to nickel-containing patches. After a 1-week washout period, the volunteers were given 2g of a water-soluble quercetin (WSQ) for 3 days before and after another exposure to nickel. There was a greater than 50% reduction in skin dermatitis in 8 out of the 10 participants and 100% elimination of dermatitis in the other 2 subjects (p=0.039 for 48 hr post nickel exposure; p=0.031 for 120-hr post-nickel exposure) 75. Similarly, a skin lotion containing tetramethoxyluteolin was applied topically and had significant improvements in patients with mastocytosis, atopic dermatitis, or psoriasis 76.
MC activation is also implicated in the GI and brain inflammation experienced by children with autism. Two human studies have been conducted in which quercetin and luteolin were effective in reducing symptoms of GI distress and allergy, and improved communication skills, eye contact, and sustained attention. Inflammation characteristic of autism can be MC mediated and the researchers suggest the positive outcomes observed in these studies were largely due to MC inhibition. However, this cannot be proven 77,78. This is a novel therapy for consideration in IBS. To date, there are no published human studies on the use of these flavonoids in IBS, however, it may offer therapeutic potential in the subset of patients experiencing excessive MC activation.
Berberine is an alkaloid found in plants and has been traditionally used in Chinese medicine to treat GI distress. It has antioxidant, antimicrobial, anticarcinogenic, neuroprotective, and blood sugar regulating effects. In an animal model of colitis, berberine significantly inhibited Th17 and Th1 cytokines along with their corresponding transcription factors (i.e. RORγt and T-box transcription factor, T-bet) and pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Expression of the anti-inflammatory cytokine IL-10 was significantly increased 79. IL-33 is associated with MC activation and in another animal study, Li et al. report that berberine inhibits IL-33, MC activation, and reduces expression of TNF-α, IL-6, IL-13, and MCP-1 30.
In a randomized, double-blind, placebo-controlled trial, 132 IBS-D patients were randomly assigned to receive 400 mg berberine hydrochloride twice daily or placebo for 8 weeks. Study subjects who received berberine hydrochloride had significantly reduced frequency of diarrhea (p=0.032), frequency of abdominal pain (p<0.01), and urgency of defecation (p<0.01). Overall IBS score reduced by approximately 16.5 points in the experimental group and by approximately 6.75 in the control group (p<0.05), and quality of life increased by approximately 36 points in the experimental group and by 5 points in the control group (p<0.05). There is also evidence to suggest that berberine has antidepressant and anti-nociceptive effects whereby, it promotes the secretion of dopamine, serotonin, and norepinephrine 80.
In another randomized, placebo-controlled trial, 85 patients with IBS-D were randomly assigned to either receive 50,000 IU vitamin D3 per day or placebo for 6 months. IL-17 and TNF-α were significantly reduced (p<0.05) and IL-10 was significantly increased (p<0.05). The researchers concluded that vitamin D3 is an effective anti-inflammatory and anti-oxidant reagent in IBS-D 73. However, clinical outcomes were not assessed, and further research is necessary to confirm clinical relevancy.
As mentioned previously, stimulation of nicotinic receptors of the cholinergic system are suggested to be anti-inflammatory. They are densely populated in the brain, and researchers suggest that when nicotinic receptors (in particular, nicotinic acetylcholine receptor α7, α7-nAChRs) are stimulated by acetylcholine, expression of TNF-α, IL-1β, and IL-6 is inhibited. The use of positive allosteric modulators of α7-nAChRs have been studied for their anti-inflammatory, neuroprotective, and antinociceptive effects. There is therapeutic potential in brain injury, neurodegenerative diseases, and inflammatory diseases such as IBD and rheumatoid arthritis 81-83.
For IBS, evidence from animal studies suggest administration of a choline uptake enhancer in IBS reduces visceral pain and hyperalgesia 84. The potential benefits are intriguing to consider and future research in humans would provide valuable insight. To provide perspective on dosing, 2 grams per day of phosphatidylcholine in divided doses was given to UC patients being weaned from steroids. In a randomized, double-blind, placebo-controlled trial, 24 of the 30 participants who supplemented with phosphatidylcholine successfully discontinued steroid use without recurrence of disease symptoms, and only 3 of the 30 placebo-taking subjects were successfully weaned (p<0.001) 85. In another randomized, double-blind, placebo-controlled, multi-centered study, 231 patients with dementia were randomly assigned to receive 1200 mg of L-α-glycerylphosphorylcholine, a phosphatidylcholine derivative in divided doses, or placebo for 180 days. According to the Alzheimer’s Disease Assessment Scale, choline recipients showed a 3.2-point decrease in cognitive impairment (p<0.001), and the placebo recipients had a 2.9-point increase in cognitive impairment compared to baseline (p<0.001) 86.
Interventions Related to Neuro-Plasticity
Melatonin can have anti-inflammatory, anxiolytic, and antinociceptive effects. As an up-regulator of α7-nAChR, it may help mediate nicotinic cholinergic activity and promote neuroprotection 87. Song et al. report efficacy in a dose of 3 mg per day in significantly reducing abdominal pain scores (2.35 v 0.70; p<0.001) and rectal pain sensitivity (8.9 v 21.2 mm Hg; p<0.01) 88. However, further research is needed to assess inflammatory biomarkers and appropriate dosing for reduction of inflammation.
Vagal nerve stimulation is a technique used to enhance the parasympathetic nervous system. Strategies include deep breathing with full expiration and the use of electrical impulses to stimulate the vagal nerve. There is human evidence to suggest that these strategies reduce pain and improve gastric motility in IBS patients 89.
Docohexanoic Acid (DHA) and Eicosapentaenoic acid (EPA) are poly-unsaturated fatty acids that have been suggested to have anti-inflammatory and neuroprotective effects. Chua et al. found a positive and significant association between depression scores in a group of Asian females with IBS, reduced serum levels of omega-3 fatty acids, and higher serum levels of saturated fatty acids compared to HCs 90. In vitro, DHA has been demonstrated to inhibit the secretion of several inflammatory markers in endothelial cells such as TNF-α, IL-1β, IL-6, IL-8, prostaglandins, and leukotrienes 91. Woods et al. report that in vitro, nAChRs preferentially bind to DHA and subsequently block the binding of cholesterol and saturated fats. DHA has been extensively studied in connection with improved brain function, but, in this study, a connection to the cholinergic system was highlighted. There are no human studies published on the topic of DHA and IBS and some researchers have relayed complaints of GI disturbances associated with fish oil supplementation. It may be best to start at low doses of 300 mg DHA + EPA per day and increase as tolerated to 1-2 grams per day 92,93.
Limitations and Conclusion
IBS cannot be classified by any singular phenotype or genotype. It manifests itself in a variety of ways and differs from person-to-person. In fact, for any given individual, it may change its presentation over time. Low-grade inflammation is a clear mediator of this condition and may be associated with its perpetuation. The intention of this review was not to underscore the importance of treating the obvious symptoms of IBS, which may include some combination of GI infection, dysbiosis, SIBO, intestinal hyperpermeability, and others. Interventions designed to treat these acute impairments are a necessary part of the healing process. However, the immunology of IBS and the various ways in which the immune system responds in different individuals should be deeply considered and addressed as a means of promoting long-term remission.
There are several limitations to this review. No generalizations can be made regarding any specific subset of the innate or adaptive immune system in association with IBS. Throughout the entire analysis, studies with contrasting results were referenced and this makes it difficult to form a definitive conclusion. As previously mentioned, discrepancies may be the result of small sample sizes, study designs, or differing assessment tools.
Publication bias is a factor which increases the chances that a specific set of results have been more highly publicized. The opposing, less noteworthy result cannot be ruled out. In-vitro and animal studies were used to showcase possible underlying mechanisms. Results from these studies cannot be generalized to humans, however a strong effort was made to include human studies to support each argument. Finally, the suggestions listed for therapeutic consideration are novel ideas based on the immunology of IBS highlighted in this review. Many of these compounds have yet to be studied in relation to IBS. The interventions described may offer therapeutic advantages and are suggestions for further investigation.

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