Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a group of debilitating disorders affecting patient’s quality of life and with unknown aetiology. The collected evidence indicates that individuals can develop IBD as a result of genetic susceptibility, a dysregulated immune response and the influence of certain environmental factors. Common symptomatology includes abdominal pain, fever and bowel diarrhoea with blood and/or mucus excretion. The location and extent of disease differ between UC and CD, affecting the mucosal layer in the colon in UC patients, whereas in CD patients, a transmural inflammation is found anywhere in the gastrointestinal tract. Factors associated with IBD pathophysiology include alterations in immune responses, characterized by an atypically T helper (Th)-2 profile in UC, and a Th1/Th17 profile in CD, modifications in epithelial barrier function and alterations in the commensal microbiota composition with blooming of specific pathobionts, for example, adherent-invasive Escherichia coli (AIEC), and with diet. Recent research has uncovered that inflammation, per se, can activate the enteric nervous system inducing neurogenic inflammation and increasing visceral sensitivity, leading to pain. Similarly, alterations in the commensal microbiota composition/ligands have also led to modifications in intestinal nociceptive markers and in visceral pain. In this chapter, we aim to review the mechanisms implicated in microbial neuro-immune axis and its potential contribution to IBD pathophysiology and symptomatology. We focus on the findings identified in animal models and in IBD patients and on the prospective translation of targeting the microbial neuro-immune axis as future therapeutic treatment for intestinal inflammatory conditions.
- intestinal neuro-immune interaction
- visceral pain
- microbiota–gut–brain axis
1. Introduction IBD
Inflammatory bowel disease (IBD) is a group of diseases comprising mainly two entities, ulcerative colitis (UC) and Crohn’s disease (CD), of unknown aetiology. Ulcerative colitis was described in the late nineteenth century by Wilks and Moxon  and CD was described by Crohn et al. in the early 1930s as terminal ileitis . Since the beginning of the twenty-first century, the incidence of IBD is increasing worldwide, especially in Westernized areas such as the United States, Europe, Australia and New Zealand as well as in South America, Asia and the Middle East and in specific populations, for example, paediatric-onset IBD. The prevalence in the Western World is currently up to 0.5% of the population .
IBD affects the patients’ quality of life and is characterized by unpredictable flares of remission and relapses with symptoms of bloody diarrhoea, abdominal pain and rectal bleeding. The onset of IBD is at a young age ranging initially from 20 to 39 years and with a second onset in patients over 60 years of age . IBD affects both males and females, with a higher prevalence of CD in females and no major differences in UC patients . The inflammation in UC is localized to the colonic superficial mucosa while the inflammation in CD is transmural and can be found anywhere along the gastrointestinal (GI) tract, although the inflammation is predominantly located to the ileo-caecal area and the proximal colon [6, 7]. Ulcerative colitis is characterized by the formation of crypt abscesses, formed by extravasation of neutrophils through the intestinal epithelium while CD is characterized by the presence of skip lesions, granulomas, fibrosis and strictures. Extra-intestinal features in CD can result in major complications, for example, fibrotic strictures, and a subsequently need for surgery [8, 9]. To date, there is no cure for IBD, with most treatments primarily aiming to suppress disease severity and to keep the patient in remission by using biologics, anti-suppressants and steroids.
The cause of IBD is unknown but the collected evidence suggest that IBD can be manifested in genetically susceptible individuals who mount inappropriate local immune responses against microbial antigens after exposure to environmental factors [7, 10].
To date, genomewide association studies (GWAS) have identified at least 163 susceptible genes for IBD, with loci associated to bacterial recognition (NOD2) and autophagy (ATG16L1, IRGM) conferring a higher risk for CD. In contrast, genes involved in mucosal barrier function (e.g. HNF4a, CDH1, LAMB1, ECM1), IL-10 signalling and HLA haplotype DRB1*0103 have been associated with UC. Interestingly, genes linked with adaptive immune responses such as IL-23R, IL-12B and STAT3 confer a higher risk for both CD and UC. Despite the large number of loci identified, only approximately 20–25% of patients are linked to at least one of these loci suggesting that there are most likely other factors potentiating its development [11–13].
Alterations in barrier function, dysregulation in tight junction proteins and increased bacterial uptake has been reported in experimental models of colitis and in patients with UC and CD supporting the GWAS identified genes on barrier function [14, 15]. Others have also suggested that Peyer's patches are the sites of initial lesions in CD with M cells playing an important role in sampling microbes from the gut lumen and presenting to immune cells to mount inflammatory responses [16, 17]. Furthermore, unaffected relatives of CD patients have shown increased intestinal permeability [14, 15].
2. Intestinal immune mechanisms and IBD
The main function of the intestinal immune system is to protect the host from harmful signals, for example, pathogens, by mounting specific responses as well as to keep a tolerance against A myriad of food and microbial antigens. A robust immune response against invading pathogens is critical for their clearance but an excessive or uncontrolled inflammation can result in chronic inflammation and lead to the development of inflammatory conditions such as IBD (Figure 1). The collected evidence to date suggest that the aberrant immune response in IBD patients is attributed to the dysregulated adaptive and innate immune responses [7, 10]. The innate immune response is the first line of defence against harmful agents. Pattern recognition receptors (PRRs) detect microbial ‘pathogen-associated molecular patterns’ (PAMPs) or host-derived ‘damage-associated molecular patterns’ (DAMPs) inducing innate immune responses. Among PRRs, the intestinal Toll-like receptors (TLRs) are critical both in keeping intestinal homeostasis and in mounting innate immune responses. In humans, a total of 10 TLRs have been described, with the majority of them, except TLR3, signalling via the adaptor protein MyD88. Activation of TLRs via MyD88 induces several pathways including the transcription factor nuclear factor-kappa light-chain enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK) and AP1, while the MyD88-independent pathway activates the interferon regulatory factor 3/7 (IRF-3/-7) signalling pathway . In recent years, it has become evident that bacteria can penetrate/translocate through the intestinal barrier of IBD patients thereby inducing TLR-induced responses both by mucosal non-immune cells (e.g. epithelial cells) and innate immune cells (e.g. macrophages, dendritic cells). TLRs are expressed by both epithelial and immune cells, and alterations in TLRs expression have been reported in both UC and CD tissue including increase expression of TLR4, TLR2 and TLR5 . Activation of TLRs, for example, TLR4, leads to the activation of NF-
The intestine of IBD patients presents a chronic inflammation that differs in terms of immune cell subsets and cytokine profile. The colons of UC patients are heavily infiltrated with neutrophils, T and B cells with high levels of several pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α and an atypical T helper (Th2) profile (IL-5, IL-10 and IL-13) [7, 10, 19]. Other chemokines such as IL-8 and GRO-α are highly increased in UC mucosa, with IL-8 levels correlating with the degree of inflammation and disease activity [20, 21]. Although neutrophils are indispensable for eliminating pathogens, their excessive presence in the tissue and their resistance to apoptosis  can lead to extensive tissue damage in UC, which can be caused by the persistent release of cytokines (IL-17, IL-6), reactive oxygen species (ROS) and proteases, all of which highly associated with patients with active UC [7, 19, 23]. The intestinal wall of CD patients is highly infiltrated by macrophages and T cells. It is acknowledged that CD is primarily mediated by Th17/Th1 cells as well high levels of innate pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α [6, 10]. Further, the elevated levels of circulating and tissue B cells as well as their activity have also been reported in IBD patients [24, 25].
3. Intestinal neural pathways and visceral pain in IBD
A particular characteristic of the GI tract is the presence of an intrinsic nervous system, the enteric nervous system (ENS) also known as the second brain. Within the intestine, the ENS presents a clear distribution in two neuronal plexuses localized within the submucosa (submucosal or Meissner's plexus) and between the circular and longitudinal smooth muscle layers (myenteric or Auerbach's plexus). The ENS can maintain GI functions alone by the network around the gut wall formed by both plexi. It is composed by around 108 neurons consisting of intrinsic primary afferents, interneurons and motor neurons [26–28]. Enteric neurons are supported by glial cells (counterparts of the central nervous system (CNS) astrocytes), which can communicate with the mucosal immune system and the intestinal epithelium by producing different mediators including cytokines. The ENS controls intestinal motility, secretion and absorption, mucosal growth, local blood flow, the immune and barrier function and also carries nociceptive (painful) stimuli to the CNS [29–31] (Figure 2).
The gut receives also extrinsic innervation from the autonomic nervous system (ANS) and the spinal afferent nerve fibres that coordinate its activity. The ANS is composed of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). The extrinsic innervation consists of vagal and spinal sensory nerves, vagal and sacral parasympathetic motor neurons, and sympathetic neurons from prevertebral ganglia, and it plays a key role in maintaining the bidirectional communication with the CNS as well as it is the anatomical basis of the gut–brain–gut axis [32–34].
The vagus nerve (cranial nerve X interfacing with the PSNS) has a motor and a sensorial division and three different endings in the gut: the intraganglionic laminar endings within the myenteric plexus, the intramuscular arrays within the smooth muscle layers and the mucosal fibres within the mucosa . The SNS suppresses GI functions under vagus nerve’s activation, cell bodies arise from the paravertebral sympathetic chain ganglia, adjacent to the spinal column and innervating the GI vasculature, as well as the prevertebral (celiac and superior/inferior mesenteric) ganglia, which controls motility and secretomotor neurons. Axons extend to the gut by the mesenteric nerves but also by the vagus nerve, cranially, which also contacts with the ENS [32, 35]. The spinal innervation of the gut comes directly from the dorsal root ganglia (DRG) of the spinal cord, and it is less extensive when compared to the ANS. They extend to the gut by the splanchnic (cranially) and the parasympathetic pelvic nerves (distally). The colon, which harbours large amounts of bacteria, has specific DRG in their innervation .
4. Visceral hypersensitivity
Nociception is the neural processes of encoding and processing noxious stimuli that can be accompanied, or not, with pain [26, 36]. Visceral pain originates from the internal organs and is initiated by nociceptors, which can detect mechanical, thermal or chemical changes above a basal threshold . Perception of visceral pain relies mainly in spinal C and Aδ afferents fibres from DRG although vagal afferent stimulation can also mediate pain . The strong compression, as well as chemical stimuli or irritation, of the colon generates afferent signals that can hypersensitize afferent nerves and become nociceptive [39–41].
Although most of the intestinal functions can be carried out by the ENS, extrinsic innervation is necessary to maintain a coordinated activity with the rest of the body and for sensory functions related to visceral pain perception within the gut. This is particularly important because visceral pain and/or altered visceral sensitivity (hypersensitivity) are frequent symptoms in several GI diseases including irritable bowel syndrome (IBS) and IBD. Visceral hypersensitivity generally originates from a local inflammation leading to an enhanced response to a painful stimulus (hyperalgesia) as a result of activation of the immune system, stressful conditions and the intestinal microbiota [42–44] (Figures 1 and 2). Alterations in sympathetic neural activity have specifically been implicated in IBD [25, 45]. A decrease in noradrenaline release from sympathetic varicosities in inflamed and un-inflamed regions of the GI tract has consistently been reported in animal models of colitis, which appears to be due to the inhibition of N-type voltage-gated Ca2+ current in postganglionic sympathetic neurons . However, specific alterations of sympathetic function and its role in IBD remain unclear . In the last two decades, numerous morphological, pharmacological and molecular studies have characterized sensory-related systems within the gut, among them the serotonergic system, the endocannabinoid system, endogenous opiates and the vanilloid system have received particular attention due to their potential benefit as pharmacological targets for the treatment of visceral pain. A short description of each of these systems is outlined below.
4.1. The intestinal serotonergic system
The serotonergic system involves the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), which is mainly stored in mucosal enterochromaffin (EC) cells and in a lesser extent within the enteric neurons (up to 95% of body 5-HT is present in the gut). Tryptophan hydroxylase (TPH) is the limiting enzyme mediating 5-HT synthesis. Two TPH isoforms exist, namely TPH1, mainly expressed in EC cells, and TPH2, expressed in central and enteric neurons. TPH expression/activity is regarded as a reliable indicator of 5-HT availability, whereby high expression levels are indicative of a high rate of serotonin production and release [47–49]. Within the GI tract, 5-HT participates in motor, sensory and secretory functions modifying gut motility/sensation in several ways . For example, 5-HT present within the enteric nerves and acting on 5-HT3 receptors of the vagal afferent nerve fibres can stimulate intestinal secretion and motor reflexes. 5-HT can also act on the receptors 5-HT3, 5-HT4 and 5-HT1P present on enteric neurons, thereby contributing to peristalsis and stimulating intestinal transit . Expression of 5-HT7 receptor has been found on intestinal immune cells and demonstrated a key role in development of experimental colitis . Intestinal inflammation is accompanied by alterations in enteroendocrine cells, among which EC is the most abundant. These cells are distributed throughout the GI tract, with many of them concentrated in the small intestine and rectum and in between epithelial cells, where they act as sensors of the intraluminal milieu. 5-HT release from EC cells is mediated by luminal or neuronal stimuli including mucosal stroking and endogenous chemical stimuli such as adenosine. Changes in the content, release and reuptake of 5-HT as well as increase numbers of EC cells have been reported 8 in both inflamed and non-inflamed gut of IBD patients and in experimental models of IBD [53, 54]. Some studies have also shown that changes in the microbial composition or stressful conditions can induce 5-HT release from EC cells, leading to the initiation of intestinal inflammation and the generation of abnormal sensory-related responses (i.e. altered viscerosensitivity) [48, 55–57]. The sodium-dependent serotonin transporter (SERT), a member of the Na+/Cl− neurotransmitter transporter family, is expressed by epithelial cells and neurons in the gut  and is involved in the reuptake of 5-HT. SERT expression is reduced in the inflamed and in the healing colonic mucosa of UC patients, thereby increasing 5-HT levels [25, 58]. Furthermore, deletion of SERT increases the severity of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice  and mice treated with the SERT inhibitor paroxetine presented alterations in GI motility and sensitivity . Interestingly, the regulatory cytokine transforming growth factor-beta 1 (TGF-β1) was recently shown to stimulate SERT function suggesting a novel neuro-immune therapeutic strategy to treat GI disorders . These findings implicate that 5-HT signalling and its SERT-mediated termination can contribute to the symptoms associated with IBD pathophysiology and suggest that drugs targeting this pathway may benefit patients suffering from IBD and other inflammation-related gut disorders [25, 62].
4.2. The intestinal opioid system
The endogenous opioid system is composed by three G protein-coupled receptors: μ, δ and k opioid receptors. Within the GI tract, intestinal opioids, ligands and receptors are found in myenteric and submucosal neurons and in epithelial, endocrine and immune cells (including myeloid and CD4+ T and CD8+ T cells). Opioids have a well-characterized analgesic activity in visceral sensitivity [63, 64], which is mainly linked to the activation of μ and, to a lesser extent, k receptors. The expression of δ opioid receptor together with μ receptor is increased after administration of the inflammatory irritant mustard oil, thereby evoking allodynia and visceral hyperalgesia [25, 65]. μ-Opioid receptors (MOR) are overexpressed in active IBD mucosa, most likely as a compensatory analgesic mechanism generated in states of potentially increased sensitivity. MOR are also significantly enhanced by pro-inflammatory cytokines and repressed by NF-κB inhibitors in myeloid and lymphocytic cell lines . Increased numbers of β-endorphin immunoreactive CD4+ T cells and CD11b+ macrophages are found in murine colonic lamina propria in chronic dextran sodium sulphate (DSS)-induced colitis, where the release of endogenous opioids decreases nociceptive signalling through the activation of μ-opioid receptors . Therefore, it is speculated that the anti-nociceptive actions of peripheral opioids in colitis may indirectly result from a reduction of the neurogenic ‘pro-nociceptive’ components of inflammation, by decreasing CGRP and Substance P (SP) release that could counteract the pro-nociceptive effects of inflammatory mediators such as TNF-α during inflammation . Recent studies have suggested that probiotics and microbial-related products can also module the intestinal expression of MOR [66, 69–72].
4.3. The intestinal endocannabinoid system
The endocannabinoid (CB) system comprises of two main receptors, CB1 and CB2, their endogenous ligands and their metabolizing enzymes, Mainly the fatty acid amide hydrolase, FAAH. Because of their chemical characteristics, endocannabinoid ligands are difficult to determine; therefore, the expression of CB1, CB2 and the enzyme FAAH, are used to assess endocannabinoid functionality. Within the GI tract, the endocannabinoid system controls intestinal motility, nociception and intestinal inflammation. CB1 and CB2 receptors are expressed on intestinal ganglionic neural cells within the ENS, in epithelial cells and immune cells in the gut [73–76]. The CB1 receptor is predominantly found in neural and epithelial cells, whereas the CB2 receptors are predominantly expressed in immune cells . Upon activation, both receptors mediate analgesic effects and appear to have anti-inflammatory properties [75, 77–80]. Probiotics, bacterial products and stressful stimuli have been postulated to influence the endocannabinoid system [70, 81–83]. In IBD, an increased in CB1 expression has been identified in inflamed mucosa, while a reduction in the endocannabinoid agonist anandamide and no increase in CB2 expression were found. Ex vivo cultures of IBD biopsies and immune cells with the non-hydrolysable AEA analogue methanandamide (MAEA) resulted in a reduction in IFN-γ and TNF-α secretion . In animal models of colitis, the CB2 agonist JWH-133 attenuates colitis in IL-10−/− mice and in DSS-induced colitis by decreasing the number of mucosal immune cells (including CD4+ T cells, neutrophils, Mast cells and natural killer cells) . Recent studies in humans and animals have identified a new strategy for the endocannabinoid system, whereby targeting of the enzyme FAAH can prove to be a better approach due to the potentially less side effects when compared to the currently available CB compounds [86–88]. Overall, the preclinical findings indicate that manipulating the endocannabinoid system can have beneficial effects in IBD patients, and therefore, the use of
4.4. The intestinal vanilloid system
The vanilloid system consists of one of six subfamilies of the transient receptor potential (TRP) channel family, with six types of transient receptor potential vanilloid (TRPV1-6) . These receptors are calcium permeable, non-selective cation channels involved in thermo- and chemo-sensitive transduction . In the intestine, TRPV1, 3 and 4 have been linked to viscerosensitivity and are characterized as pro-algesic receptors [79, 92–94]. TRPV are mainly expressed in intestinal afferent nerves, although they can also be found in EC cells as well as epithelial and immune cells [95–97]. In agreement with their pro-algesic effects, TRPV are upregulated in states of intestinal inflammation and visceral hypersensitivity; for example, TRPV1 is highly increased in immunoreactive nerves in IBD tissue and in quiescent IBD with IBS-like symptoms such as pain [98–102]. TRPV1 deletion prevented the development of post-inflammatory visceral hypersensitivity and pain-associated behaviours, while SP can sensitize TRPV1 function leading to a pro-algesic state [101, 103]. TRPV1 has been linked to the crosstalk between the microbiota and the neuro-immune response in the gut, because TRPV1 and CGRP can modulate cytokine response to lipopolysaccharide (LPS) independently of the adaptive immune response. It has been proposed that TLR4 can activate TRPV1 via intracellular signalling thereby inducing the subsequent release of anti-inflammatory CGRP to maintain mucosal homeostasis . In addition, blocking of TRPV4 has also been shown to alleviate colitis and pain associated with the intestinal inflammation induced by TNBS in mice . Similarly, intrathecal injection of antisense oligonucleotides to TRPA1, another member of the transient receptor potential channel family, decrease its expression and attenuates visceral hyperalgesia in TNBS-induced colitis [25, 65].
4.5. Neurotransmitters, neuropeptides and neurotrophins
More than two dozens of putative neurotransmitters have been described to date, with neurons usually expressing a combination thereof. Most of these mediators have been implicated in the neuro-immune communication associated with gut homeostasis and in the pathophysiology of intestinal inflammation but their specific functions are still to be established . A short description of the most relevant mediators is outlined under this section.
Substance P (SP), an 11-amino acid peptide secreted by nerves and immune cells (including monocytes, macrophages, eosinophils and lymphocytes) belongs to the tachykinins family and acts by binding to the neurokinin-1 (NK-1) receptor. It functions in smooth muscle contraction, vasodilation and epithelial ion transport. It is a mediator of neurogenic inflammation due to stimulation of cytokine release from immune cells (e.g. macrophages, mast cells) and endothelium causing tissue damage and neurodegeneration [25, 107]. High expression of SP and NK-1 receptor was reported in the myenteric plexus and inflamed mucosa of patients with IBD. This is associated with a shift from mainly cholinergic innervation to a more extensive SP innervation, which correlates with the severity of UC and may be part of the neuronal basis for the observed altered motility disturbance seen in these patients [106, 108–110]. Antagonists of NK-1 receptors have been shown to ameliorate inflammation and protect from T-cell-induced colitis. Based on these findings, tachykinin antagonists have been proposed as potential anti-inflammatory treatment for IBD [25, 108, 111, 112].
Vasoactive intestinal polypeptide (VIP), a 28-amino acid peptide belonging to the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily, is highly expressed in the myenteric plexus of the colon. VIP inhibits the peristaltic reflex in the circular muscle layer, controls intestinal blood flow and modulates the immune system by binding to both G protein-coupled VIP receptors 1 and 2. VIP is released from nerve terminals that contain nitric oxide synthase (NOS). These two peptides are thought to be the primary intestinal components of non-adrenergic, non-cholinergic nerve transmission. VIP expression is increased in colonic neurons of CD patients but not in UC patients [25, 113–115]. Treatment with VIP in murine TNBS-induced colitis reduces colitis severity and Th1-cell response [116, 117]. In addition, glucagon-like peptide 2 (GLP-2), a regulator of absorption with anti-inflammatory properties, decreases mucosal inflammation in TNBS-induced colitis in rats by activating VIP neurons of the submucosal plexus . Neurotrophins are a family of proteins regulating neuronal activity in the CNS and PNS, belonging to a class of growth factors and playing a major role in visceral hypersensitivity in the inflamed gut. This is, partly linked to the effects of peripheral neurotrophic factors (NTFs) on local afferent neurons. Among these, nerve growth factor (NGF) is primarily involved in the regulation of growth, maintenance, proliferation and survival of certain target neurons and in innate and adaptive immune responses; brain-derived neurotrophic factor (BDNF) links the commensal microbiota and the CNS [119, 120]; and the family of glial cell line-derived NTFs (including GDNF, artemin and neurturin) are implicated in sensorial alterations observed in inflammatory and functional GI disorders .
5. Intestinal neuro-immune interactions
Intestinal inflammation, even if mild, causes significant alterations in neurally controlled gut functions including pain and altered motility. These symptoms are caused, in part, by persistent hyperexcitability of enteric neurons that can occur even after the resolution of colitis. Among cells generating inflammatory signals within the gut mucosa and affecting neural signalling in the ENS, mast cells and enterochromaffin cells seem to play a big role. Both of them are increased in the colonic mucosa of IBD patients . The ENS and the mucosal immune system have the ability to regulate each other functions. In the intestinal wall, nerve cells are localized in close proximity to immune cells and they share several chemical mediators. The collected evidence point towards a major role of inflammatory signals affecting the enteric neurons and most likely generating IBD-associated symptoms [25, 121, 122] (Figure 2).
Inflammation-related alterations in the ENS are divided into those that alter the structural morphology of neurons and glial cells of the ENS and those that modify enteric neurotransmitters [25, 122–124]. During intestinal inflammation, morphological and functional alterations, including remodelling of visceral afferents, are also observed outside the primary region affected by the insult . ENS structural changes are more marked in CD than in UC patients and are often associated with the extent of inflammatory infiltrate. In fact, it has been suggested that severe and extensive necrosis of gut axons may be a distinct feature in CD . In support of this notion is the ablation of myenteric neurons, accompanied by a high neutrophil infiltration and an excessive production of the Th1 cytokines IFN-γ, TNF-α and IL-12 present in models of colitis. Interestingly, neuronal loss persisted for up to 56 days, that is when the inflammation had resolved in these models [125–128]. Others proposed mechanisms implicated in neuron loss, arisen from animal models and IBD patients, Which involve an increase in immune cell infiltrates, including eosinophils, lymphocytes, plasma cells and mast cells, in myenteric ganglia [25, 123, 126, 128, 129] as well as the activation of apoptotic pathways . Furthermore, enteric glial cell ablation induces a significant decrease in the number of myenteric neurons, which appear to be associated with the loss of NOS-containing neurons in the myenteric plexus, likely underlying the alterations observed in smooth muscle relaxation and intestinal transit time [25, 131]. It is also believed that the reduced availability of neuroprotective factors due to neuronal cell loss may increase the susceptibility of enteric neurons to insults such as oxidative stress, which can have an important role in IBD pathophysiology. Overall, the collected data indicate that the loss of nerve cells is dependent on the time needed to develop inflammation, the type of inflammatory cells and the mediators profile required for nerve–immune interactions .
Immune cells found in the intestine, including dendritic and mast cells, lymphocytes and macrophages, express receptors for small molecule neurotransmitters and neuropeptides and produce cytokines targeting the enteric neurons . Neuro-immune regulation includes degranulation of mast cells and influx of neutrophils due to neuronal activation. Neuropeptides released by enteric nerves including SP and VP can stimulate lymphocytes to induce their differentiation and alter immunoglobulin production. Signalling between immune cells and enteric neurons can also evoke alterations in gut function. Hyperexcitability of intrinsic primary afferent neurons may be secondary to activation of cyclooxygenase (COX)-2 and production of prostaglandins (PGE2) from inflamed colon [25, 132]. Intestinal kinases have also been involved in intestinal inflammation. Protein kinase A activity in nerve terminals increases in previously inflamed colon and facilitates a fast synaptic transmission and the release-ready pool of synaptic vesicles [25, 133, 134]. There is also evidences that pro-inflammatory cytokines such as IL-1β and TNF-α exhibit pro-secretory effects in the human distal colon. Both IL-1β and IL-6 are reported to increase excitability in submucous and myenteric neurons and to mediate effects on cholinergic and non-cholinergic transmission [135–137].
Mast cells are a major player in the innate immune response. Apart from their prominent role in immunoglobulin E (IgE)-dependent hypersensitivity, mast cells can release and modulate the release of several mediators including cytokines, growth factors, chemokines as well as histamine, proteases, and probably serotonin 22 receptors that regulate multiple important biological processes including neural actions in the human ENS . Neuropeptides released from enteric and visceral afferent nerves regulate human intestinal mast cell mediator’s release. In healthy individuals, mast cells are generally located in the lamina propria, in fewer amounts in the submucosa and sporadically found in the muscle layers or in the serosa. An estimated 70% of intestinal mucosal mast cells are in direct contact with nerves, and another 20% are within a 2-μm distance. Mast cells respond to neurotransmitters and nerves and can thereby regulate their activation threshold [137, 138], submucous neurons would respond with a transient excitation mediated primarily by 5-HT3 receptors . Cytokines and chemokines can have different effect on mast cell functions. For example, the chemokine, macrophage inflammatory protein-1α (MIP-1α) is required for optimal mast cell degranulation in mice . In contrast, the regulatory cytokine TGF-β1 can dose dependently inhibits stem cell factor-dependent growth of human intestinal mast cells by both enhancing apoptosis and decreasing proliferation  as well as it can influence mediator secretion by reducing histamine, cysteinyl leukotrienes and TNF-α release while prostaglandin D2 (PGD2) generation and COX1 and 2 expressions are upregulated. Mucosal mast cells can also respond to other mediators including adenosine triphosphate (ATP), somatostatin, calcitonin gene-related peptide (CGRP) and SP. Colorectal biopsies from patients with active CD or UC incubated with SP induce mast cell degranulation and histamine release [30, 142].
Histamine, proteases and TNF-α are stored as granules in mast cells and can be released within seconds. Other mediators such as lipid mediators and most cytokines are synthesized once the mast cells are activated. The most important mast cell mediator identified so far is histamine. Histamine influences fluid and ion transport, which is partly nerve mediated and directly excites submucous extrinsic sensory neurons [137, 142, 143]. There are four histamine receptors (H1, H2, H3 and H4), which are found as receptor clusters on submucous neurons, with the most frequent clusters being H1/H3 (29%), H2 (27%) and H1/H2/H3 (20%), respectively. The implication of histamine on sensory neurons comes from studies in rodents . Rat dorsal root ganglion cells with projections to the viscera increased Ca2+ responses to a TRPV4 agonist and enhanced TRPV4 expression, when adding histamine or serotonin . The pathophysiological relevance of histamine in both allergic and non-allergic conditions including IBD and IBS is established [141, 145]. In IBD, it has been reported that histamine secretion is increased in the jejunum of active CD and in urine of UC patients , although in a recent study, no differences in serum levels of histamine were identified .
Proteases, in particular the serine protease tryptase, are prominent mediators released from mast cells. Tryptase is present in almost all human mast cells, comprising up to 25% of their total proteins . Proteases signal to nerves is mediated through protease-activated receptors (PARs), with four cloned PAR receptors identified in humans. PAR1, PAR3 and PAR4 are predominantly activated by thrombin, and PAR2 is activated by trypsin and mast cell tryptase . In patients with UC, tryptase induces the release of inflammatory cytokines and chemokines, some of which may exert their effects through nerve pathways as outlined above . Supernatants from stool of IBS and UC patients contain increased protease levels and when supernatants from UC patients were injected to mice, it promoted hypoalgesia, which was dependent on cathepsin-G-PAR4 activation . PAR2 activation in mice increases intestinal permeability, which is mediated by SP and capsaicin-sensitive spinal afferent nerves while in rats PAR2 evoked visceral hypersensitivity . Interestingly, PAR positive cells were increased in mucosa of UC patients and preferentially co-localized with tryptase+ cells suggesting that mast cells activation via PAR2 might be involved in the pathogenesis of UC . Similarly, mucosal biopsy supernatants from UC patients can activate mouse DRG neurons innervating the colon, via TNF-α regulation [137, 152].
6. Microbial alterations in IBD
The microbial community of the GI tract is composed by bacteria, virus, fungi, protozoa and yeasts. Gut colonization starts at birth and, when completed, it harbours about 100 trillion microbial commensals and symbionts belonging approximately to 5000 distinct species divided in the phyla Firmicutes, Bacteriodetes, Proteobacteria, Verrucomicrobia, Actinobacteria, Fusobacteria and Cyanobacteria [153–155]. The intestinal microbiota is not homogenously distributed along the GI tract. For example,
Overall, the commensal microbiota serves the host with protection against pathogens, metabolizing complex lipids and polysaccharides and neutralizing drugs and carcinogens; but it can also modulate intestinal motility, influence the maturation of the intestinal immune system and modulate visceral perception [33, 161]. Changes in the normal composition of the microbiota, termed generally in the literature as dysbiosis, have been associated with chronic inflammatory and functional GI disorders such as IBD and IBS [154, 162] (Figure 1). Dysbiosis can occur in parallel to intestinal pathogenesis and can be either a consequence or a cause of the disease . In fact, the causal effects of the microbiota in IBD are still a matter of discussion, with some authors considering that dysbiotic state a consequence and/or a perpetuating factor, rather than a cause of the disease [164, 165].
Many pathogenic organisms have been investigated as causing agents of IBD, including
Pathobionts have been identified and linked to intestinal pathology. For example,
In terms of commensals, a reduction in Firmicutes and a spatial reorganization of the Bacteroidetes has been described in patients with IBD [176–178]. For example,
Recent research has identified diet as a major factor influencing commensal microbiota composition. Dietary fibres are often associated with reducing the risk of IBD as well as alterations in bacterial carbohydrate metabolism . Fibres are metabolized to short-chain fatty acids (SCFA) by commensal microbiota in the distal GI tract. SCFA can influence the growth of pathogens, increase intestinal barrier function, influence visceral sensitivity and serve as energy source for colonocytes, and they can facilitate the generation and differentiation of intestinal regulatory T cells [198, 199]. Patients with CD and UC are associated with impairment in SCFA production , which is linked to a reduction in butyrate-producing bacteria, including
The composition of the gut microbiota has recently been linked to the uptake and signalling effects of bile acids. Some members of the
Apart from bacteria, there are also alterations in the commensal fungi composition as well as the virome. Fungal microbiota is skewed in IBD; for example, CD patients show reduced fungal diversity together with an increased
7. Microbiota–gut–brain axis and IBD
There is a bidirectional signalling pathway between the GI and the brain, mainly through the vagus nerve, in which the commensal microbiota have an active role, denoted as the ‘microbiota-gut-brain axis’. This axis is vital for maintaining homeostasis and it may be also involved in the aetiology of intestinal dysfunctions/disorders (Figures 1 and 2). There are evidences of the ability of the gut microbiota to communicate with the brain and thus modulate behaviour and pain and also transfer and eliminate micro-organisms for selecting the commensal profile. The proposal of a ‘microbiota-gut-brain’ implies that through a dynamic alignment, the microbiota inhabiting the intestinal lumen will affect the host’s superior functions by changing CNS activity and vice versa, that is the brain activity and will also impact on microbiota development and composition. Apart from cognitive and vegetative functions, the ‘microbiota-gut-brain axis’ has been studied in visceral pain [209–212]. Although it has been traditionally studied in the context of IBS pathology, some of those findings can be translated to IBD, since IBD shares some overlapping mechanisms with IBS [161, 213, 214]. This includes the dysfunction of the brain-gut axis, the implication of TNFSF gene, the abnormal microbial composition and altered host functions, the low-grade inflammation and the presence of IBS symptoms in patients with IBD in remission . Overall, there is evidence that host–microbe alterations might be not only divergent regarding the abundance of microbial community members but also in their metabolic activity.
The intestinal TLRs are critical for bacterial recognition and initiation of innate immune responses. In particular, TLR2, 4 and 7 have been directly implicated in the modulation of nociceptive markers and visceral hypersensitivity and pain [72, 104, 210, 216–221]. It has also been proposed that a neurochemical ‘delivery system’ exists whereby gut bacteria can send messages to the brain. This delivery system links the commensal gut microbiota to a number of neurotransmitters including GABA, serotonin, noradrenaline, dopamine, acetylcholine and melatonin, all of which are crucial for brain-regulated functions including visceral pain, brain development, anxiety or behaviour [33, 222, 223].
Some of the mechanisms described in the microbiota-gut-brain axis imply the activation of TLRs. Among them, TLR2, expressed in enteric neurons, glia and smooth muscle cells of the intestinal wall appear to regulate intestinal inflammation by controlling ENS structure and neurochemical coding, along with intestinal neuromuscular function. Colitis in Tlr2−/− mice is more severe compared to wild-type mice that is associated with altered ENS architecture and neurochemical profile, intestinal dysmotility, abnormal mucosal secretion, reduced levels of GDNF and impaired signalling via Ret-GFR-α1. Treatment with GDNF to Tlr2-/- mice led to improved colitis .
TLR4, increased in IBD patients, has also been associated with severe colitis with impaired epithelial barrier, altered expression of anti-microbial peptide genes and altered epithelial cell differentiation . A putative LPS–TLR4–TRPV1 axis has been described, directly implicating microbiota in changes of the nervous system by means of the innate immune system, that is the TLRs. In line with this notion, the local stimulation of TLR4 but also TLR7, both expressed in epithelial, immune and neural cells, can induce an immune activation that leads to changes in different nociceptive markers, implicating mainly the cannabinoid and the vanilloid system, without having an overt inflammatory response [216, 217]. These findings address some of the putative mechanisms associated with microbial neuro-immune responses, which can contribute to IBD pathophysiology (Figure 2).
8. Conclusions and perspectives
The intestinal immune system has as its main function to protect the host against invading pathogens as well as to tolerate the myriad of our commensal micro-organisms. If this crosstalk is altered due to genetic predisposition and/or environmental factors, the steady state will be broken and it will result in the development of chronic inflammation such as IBD. Recent research has also identified a third player, the nervous system consisting of both the ENS and the CNS, which can directly regulate the intestinal immune system (Figure 1). In this chapter, It is summarized the findings linking the intestinal neuronal pathways with the intestinal immune system and the microbiota in IBD patients. In several cases, the degree of inflammation appears to determine the alteration in neuronal pathways, for example, serotonin, the endocannabinoid system, the loss of neural axons, or the increase in EC and lía cell numbers [25, 26, 84, 106, 224–226]. However, it is worthy to note that an altered neuronal signalling can persist long after inflammation is apparently resolved in patients with inactive disease and in animal models after disease is resolved .
In conclusion, further studies addressing the triad gut microbiota nerves will be a major challenge in the future. Fundamental understanding of neuronal pathways in inflammatory conditions such as IBD is crucial for the discovery of future target strategies. These will in particular target the regulation of functional bowel symptoms such as abdominal pain, visceral sensitivity, which are prevalent in IBD patients with quiescent disease and are regulated by several of the outlined pathways. To date, the evidence on the gut–brain–microbiota axis in human IBD is scarce but future research will aim to delineate this axis in depth, with the goal to evolve our understanding on GI function, to elucidate the complex interaction of this axis with systemic organs and to cover new potential treatments.
This publication has emanated from the financial support of Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2273. The authors want to thank Dr Vicente Martinez for helpful discussions and valuable comments on the content of this chapter.
Wilks S. Lectures on Pathological Anatomy. London: Churchill; 1875.
Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. 1932. Mt Sinai J Med 2000;67:263–8.
Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol 2015;12:720–7.
Kelsen J, Baldassano RN. Inflammatory bowel disease: the difference between children and adults. Inflamm Bowel Dis 2008;14 Suppl 2:S9–11.
Betteridge JD, Armbruster SP, Maydonovitch C, Veerappan GR. Inflammatory bowel disease prevalence by age, gender, race, and geographic location in the U.S. military health care population. Inflamm Bowel Dis 2013;19:1421–7.
Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet 2012;380:1590–605.
Melgar S, Shanahan F. Inflammatory bowel disease—from mechanisms to treatment strategies. Autoimmunity 2010;43:463–77.
Parray FQ, Wani ML, Bijli AH, Thakur N, Irshad I. Crohn’s disease: a surgeon's perspective. Saudi J Gastroenterol 2011;17:6–15.
Loftus E V. Management of extraintestinal manifestations and other complications of inflammatory bowel disease. Curr Gastroenterol Rep 2004;6:506–13.
de Souza HSP, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2015;13:13–27.
Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011;43:246–52.
Lees CW, Satsangi J. Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. Expert Rev Gastroenterol Hepatol 2009;3:513–34.
Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 2011;43:1066–73.
Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009;9:799–809.
Atreya R, Neurath MF. IBD pathogenesis in 2014: Molecular pathways controlling barrier function in IBD. Nat Rev Gastroenterol Hepatol 2015;12:67–8.
Merga Y, Campbell BJ, Rhodes JM. Mucosal barrier, bacteria and inflammatory bowel disease: possibilities for therapy. Dig Dis 2014;32:475–83.
Keita A V, Söderholm JD. Barrier dysfunction and bacterial uptake in the follicle-associated epithelium of ileal Crohn’s disease. Ann N Y Acad Sci 2012;1258:125–34.
Walsh D, McCarthy J, O’Driscoll C, Melgar S. Pattern recognition receptors—molecular orchestrators of inflammation in inflammatory bowel disease. Cytokine Growth Factor Rev 2013;24:91–104.
Ordás I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet 2012;380:1606–19.
Mazzucchelli L, Hauser C, Zgraggen K, Wagner H, Hess M, Laissue JA, et al. Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation. Am J Pathol 1994;144:997–1007.
Daig R, Andus T, Aschenbrenner E, Falk W, Schölmerich J, Gross V. Increased interleukin 8 expression in the colon mucosa of patients with inflammatory bowel disease. Gut 1996;38:216–22.
Brannigan AE, O’Connell PR, Hurley H, O’Neill A, Brady HR, Fitzpatrick JM, et al. Neutrophil apoptosis is delayed in patients with inflammatory bowel disease. Shock 2000;13:361–6.
Naito Y, Takagi T, Yoshikawa T. Molecular fingerprints of neutrophil-dependent oxidative stress in inflammatory bowel disease. J Gastroenterol 2007;42:787–98.
Noronha AM, Liang Y, Hetzel JT, Hasturk H, Kantarci A, Stucchi A, et al. Hyperactivated B cells in human inflammatory bowel disease. J Leukoc Biol 2009;86:1007–16.
Lakhan SE, Kirchgessner A. Neuroinflammation in inflammatory bowel disease. J Neuroinflammation 2010;7:37.
Vermeulen W, De Man JG, Pelckmans PA, De Winter BY. Neuroanatomy of lower gastrointestinal pain disorders. World J Gastroenterol 2014;20:1005–20.
Sharkey K. Neuroimmune and epithelial interactions in intestinal inflammation. Curr Opin Pharmacol 2002;2:669–77.
Sharkey KA, Savidge TC. Role of enteric neurotransmission in host defense and protection of the gastrointestinal tract. Auton Neurosci 2014;181:94–106.
Costa M, Glise H, Sjodahl R. The enteric nervous system in health and disease. Gut 2000;47:iv1.
Kraneveld AD, Rijnierse A, Nijkamp FP, Garssen J. Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: future therapeutic targets. Eur J Pharmacol 2008;585:361–74.
Furness JB, Clerc N, Kunze WA. Memory in the enteric nervous system. Gut 2000;47 Suppl 4:iv60–2; discussion iv76.
Ratcliffe EM. Molecular development of the extrinsic sensory innervation of the gastrointestinal tract. Auton Neurosci 2011;161:1–5.
Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009;136:2003–14.
Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012;10:735–42.
Jänig W. Encyclopedia of Neuroscience. Berlin Heidelberg, Elsevier; 2009.
Loeser JD, Treede R-D. The Kyoto protocol of IASP Basic Pain Terminology. Pain 2008;137:473–7.
Sikandar S, Dickenson AH. Visceral pain: the ins and outs, the ups and downs. Curr Opin Support Palliat Care 2012;6:17–26.
Blackshaw LA, Brookes SJH, Grundy D, Schemann M. Sensory transmission in the gastrointestinal tract. Neurogastroenterol Motil 2007;19:1–19.
Sushil K. Sarna. Colonic Motility From Bench Side to Bedside. University of Texas Medical Branch. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.
Reigstad CS, Kashyap PC. Beyond phylotyping: understanding the impact of gut microbiota on host biology. Neurogastroenterol Motil 2013;25:358–72.
Spencer NJ. Control of migrating motor activity in the colon. Curr Opin Pharmacol 2001;1:604–10.
Fukudo S. Stress and visceral pain: focusing on irritable bowel syndrome. Pain 2013;154 Suppl :S63–70.
de Jonge WJ. The gut’s little brain in control of intestinal immunity. ISRN Gastroenterol 2013;2013:630159.
Srinath A, Young E, Szigethy E. Pain management in patients with inflammatory bowel disease: translational approaches from bench to bedside. Inflamm Bowel Dis 2014;20:2433–49.
Tougas G. The autonomic nervous system in functional bowel disorders. Gut 2000;47:78iv – 80.
Motagally MA, Neshat S, Lomax AE. Inhibition of sympathetic N-type voltage-gated Ca2+ current underlies the reduction in norepinephrine release during colitis. Am J Physiol Gastrointest Liver Physiol 2009;296:G1077–84.
Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132:397–414.
Ghia J-E, Li N, Wang H, Collins M, Deng Y, El-Sharkawy RT, et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 2009;137:1649–60.
Cremon C, Carini G, Wang B, Vasina V, Cogliandro RF, De Giorgio R, et al. Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am J Gastroenterol 2011;106:1290–8.
Camilleri M. Serotonin in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 2009;16:53–9.
Gershon MD. Enteric serotonergic neurones ... finally! J Physiol 2009;587:507.
Kim JJ, Khan WI. 5-HT7 receptor signaling: improved therapeutic strategy in gut disorders. Front Behav Neurosci 2014;8:396.
O’Hara JR, Ho W, Linden DR, Mawe GM, Sharkey KA. Enteroendocrine cells and 5-HT availability are altered in mucosa of guinea pigs with TNBS ileitis. Am J Physiol Gastrointest Liver Physiol 2004;287:G998–1007.
Spiller R. Serotonin and GI clinical disorders. Neuropharmacology 2008;55:1072–80.
Kidd M, Gustafsson BI, Drozdov I, Modlin IM. IL1beta- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn’s disease. Neurogastroenterol Motil 2009;21:439–50.
Julio-Pieper M, O’Mahony CM, Clarke G, Bravo JA, Dinan TG, Cryan JF. Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent. Stress 2012;15:218–26.
Margolis KG, Stevanovic K, Li Z, Yang QM, Oravecz T, Zambrowicz B, et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut 2014;63:928–37.
Bischoff SC. Physiological and pathophysiological functions of intestinal mast cells. Semin Immunopathol 2009;31:185–205.
Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, et al. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol 2009;296:G685–95.
Coates MD, Johnson AC, Greenwood-Van Meerveld B, Mawe GM. Effects of serotonin transporter inhibition on gastrointestinal motility and colonic sensitivity in the mouse. Neurogastroenterol Motil 2006;18:464–71.
Nazir S, Kumar A, Chatterjee I, Anbazhagan AN, Gujral T, Priyamvada S, et al. Mechanisms of intestinal serotonin transporter (SERT) upregulation by TGF-β1 induced non-Smad pathways. PLoS One 2015;10:e0120447.
Makharia GK. Understanding and treating abdominal pain and spasms in organic gastrointestinal diseases: inflammatory bowel disease and biliary diseases. J Clin Gastroenterol 2011;45 Suppl:S89–93.
Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept 2009;155:11–7.
Gray AC, Coupar IM, White PJ. Comparison of opioid receptor distributions in the rat ileum. Life Sci 2006;78:1610–6.
Yang J, Li Y, Zuo X, Zhen Y, Yu Y, Gao L. Transient receptor potential ankyrin-1 participates in visceral hyperalgesia following experimental colitis. Neurosci Lett 2008;440:237–41.
Philippe D, Chakass D, Thuru X, Zerbib P, Tsicopoulos A, Geboes K, et al. Mu opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation. Gut 2006;55:815–23.
Boué J, Basso L, Cenac N, Blanpied C, Rolli-Derkinderen M, Neunlist M, et al. Endogenous regulation of visceral pain via production of opioids by colitogenic CD4(+) T cells in mice. Gastroenterology 2014;146:166–75.
Valdez-Morales E, Guerrero-Alba R, Ochoa-Cortes F, Benson J, Spreadbury I, Hurlbut D, et al. Release of endogenous opioids during a chronic IBD model suppresses the excitability of colonic DRG neurons. Neurogastroenterol Motil 2013;25:39–46.e4.
Pol O, Alameda F, Puig MM. Inflammation enhances mu-opioid receptor transcription and expression in mice intestine. Mol Pharmacol 2001;60:894–9.
Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 2007;13:35–7.
Hutchinson MR, Lewis SS, Coats BD, Skyba DA, Crysdale NY, Berkelhammer DL, et al. Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain Behav Immun 2009;23:240–50.
Sauer R-S, Hackel D, Morschel L, Sahlbach H, Wang Y, Mousa SA, et al. Toll like receptor (TLR)-4 as a regulator of peripheral endogenous opioid-mediated analgesia in inflammation. Mol Pain 2014;10:10.
Storr MA, Yüce B, Andrews CN, Sharkey KA. The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome. Neurogastroenterol Motil 2008;20:857–68.
Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology 2005;129:437–53.
Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol 2008;153:263–70.
Aguilera M, Vergara P, Martínez V. Environment-related adaptive changes of gut commensal microbiota do not alter colonic toll-like receptors but modulate the local expression of sensory-related systems in rats. Microb Ecol 2013;66:232–43.
Brusberg M, Arvidsson S, Kang D, Larsson H, Lindström E, Martinez V. CB1 receptors mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in rodents. J Neurosci 2009;29:1554–64.
Petrella C, Agostini S, Alema’ GS, Casolini P, Carpino F, Giuli C, et al. Cannabinoid agonist WIN55,212 in vitro inhibits interleukin-6 (IL-6) and monocyte chemo-attractant protein-1 (MCP-1) release by rat pancreatic acini and in vivo induces dual effects on the course of acute pancreatitis. Neurogastroenterol Motil 2010;22:1248–56, e323.
De Petrocellis L, Orlando P, Moriello AS, Aviello G, Stott C, Izzo AA, et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf) 2012;204:255–66.
Zoppi S, Madrigal JLM, Pérez-Nievas BG, Marín-Jiménez I, Caso JR, Alou L, et al. Endogenous cannabinoid system regulates intestinal barrier function in vivo through cannabinoid type 1 receptor activation. Am J Physiol Gastrointest Liver Physiol 2012;302:G565–71.
Kuiken SD, Tytgat GN, Boeckxstaens GE. Review article: drugs interfering with visceral sensitivity for the treatment of functional gastrointestinal disorders—the clinical evidence. Aliment Pharmacol Ther 2005;21:633–51.
Alhouayek M, Muccioli GG. The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity. Trends Mol Med 2012;18:615–25.
Hong S, Fan J, Kemmerer ES, Evans S, Li Y, Wiley JW. Reciprocal changes in vanilloid (TRPV1) and endocannabinoid (CB1) receptors contribute to visceral hyperalgesia in the water avoidance stressed rat. Gut 2009;58:202–10.
Di Sabatino A, Battista N, Biancheri P, Rapino C, Rovedatti L, Astarita G, et al. The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease. Mucosal Immunol 2011;4:574–83.
Singh UP, Singh NP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(−/−) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol 2012;258:256–67.
Sałaga M, Sobczak M, Fichna J. Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract. Eur J Pharm Sci 2014;52:173–9.
Tourteau A, Leleu-Chavain N, Body-Malapel M, Andrzejak V, Barczyk A, Djouina M, et al. Switching cannabinoid response from CB(2) agonists to FAAH inhibitors. Bioorg Med Chem Lett 2014;24:1322–6.
Sałaga M, Mokrowiecka A, Zakrzewski PK, Cygankiewicz A, Leishman E, Sobczak M, et al. Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH). J Crohns Colitis 2014;8:998–1009.
Esposito G, Filippis D De, Cirillo C, Iuvone T, Capoccia E, Scuderi C, et al. Cannabidiol in inflammatory bowel diseases: a brief overview. Phytother Res 2013;27:633–6.
Naftali T, Mechulam R, Lev LB, Konikoff FM. Cannabis for inflammatory bowel disease. Dig Dis 2014;32:468–74.
Nilius B, Mahieu F. A road map for TR(I)Ps. Mol Cell 2006;22:297–307.
Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem 2007;76:387–417.
Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther 2010;126:21–38.
Phillis BD, Martin CM, Kang D, Larsson H, Lindström EA, Martinez V, et al. Role of TRPV1 in high-threshold rat colonic splanchnic afferents is revealed by inflammation. Neurosci Lett 2009;459:57–61.
Ueda T, Yamada T, Ugawa S, Ishida Y, Shimada S. TRPV3, a thermosensitive channel is expressed in mouse distal colon epithelium. Biochem Biophys Res Commun 2009;383:130–4.
Blackshaw LA. TRPs in visceral sensory pathways. Br J Pharmacol 2014;171:2528–36.
Blackshaw LA. Transient receptor potential cation channels in visceral sensory pathways. Br J Pharmacol 2014;171:2528–36.
Boesmans W, Owsianik G, Tack J, Voets T, Vanden Berghe P. TRP channels in neurogastroenterology: opportunities for therapeutic intervention. Br J Pharmacol 2011;162:18–37.
Vergnolle N. TRPV4: new therapeutic target for inflammatory bowel diseases. Biochem Pharmacol 2014;89:157–61.
Holzer P. TRPV1: a new target for treatment of visceral pain in IBS? Gut 2008;57:882–4.
Akbar A, Yiangou Y, Facer P, Brydon WG, Walters JRF, Anand P, et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut 2010;59:767–74.
de Fontgalland D, Brookes SJ, Gibbins I, Sia TC, Wattchow DA. The neurochemical changes in the innervation of human colonic mesenteric and submucosal blood vessels in ulcerative colitis and Crohn’s disease. Neurogastroenterol Motil 2014;26:731–44.
Lapointe TK, Basso L, Iftinca MC, Flynn R, Chapman K, Dietrich G, et al. TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis. Am J Physiol Gastrointest Liver Physiol 2015;309:G87–99.
Assas BM, Miyan JA, Pennock JL. Cross-talk between neural and immune receptors provides a potential mechanism of homeostatic regulation in the gut mucosa. Mucosal Immunol 2014.
Fichna J, Mokrowiecka A, Cygankiewicz AI, Zakrzewski PK, Małecka-Panas E, Janecka A, et al. Transient receptor potential vanilloid 4 blockade protects against experimental colitis in mice: a new strategy for inflammatory bowel diseases treatment? Neurogastroenterol Motil 2012;24:e557–60.
Margolis KG, Gershon MD. Neuropeptides and inflammatory bowel disease. Curr Opin Gastroenterol 2009;25:503–11.
Taylor CT, Keely SJ. The autonomic nervous system and inflammatory bowel disease. Auton Neurosci 2007;133:104–14.
Bernstein CN, Robert ME, Eysselein VE. Rectal substance P concentrations are increased in ulcerative colitis but not in Crohn’s disease. Am J Gastroenterol 1993;88:908–13.
ter Beek WP, Biemond I, Muller ESM, van den Berg M, Lamers CBHW. Substance P receptor expression in patients with inflammatory bowel disease. Determination by three different techniques, i.e., storage phosphor autoradiography, RT-PCR and immunohistochemistry. Neuropeptides 2007;41:301–6.
Neunlist M, Aubert P, Toquet C, Oreshkova T, Barouk J, Lehur PA, et al. Changes in chemical coding of myenteric neurones in ulcerative colitis. Gut 2003;52:84–90.
Gad M, Pedersen AE, Kristensen NN, Fernandez C de F, Claesson MH. Blockage of the neurokinin 1 receptor and capsaicin-induced ablation of the enteric afferent nerves protect SCID mice against T-cell-induced chronic colitis. Inflamm Bowel Dis 2009;15:1174–82.
Jardí F, Fernández-Blanco JA, Martínez V, Vergara P. Persistent alterations in colonic afferent innervation in a rat model of postinfectious gut dysfunction: Role for changes in peripheral neurotrophic factors. Neurogastroenterol Motil 2016.
Belai A, Boulos PB, Robson T, Burnstock G. Neurochemical coding in the small intestine of patients with Crohn’s disease. Gut 1997;40:767–74.
Mazumdar S, Das KM. Immunocytochemical localization of vasoactive intestinal peptide and substance P in the colon from normal subjects and patients with inflammatory bowel disease. Am J Gastroenterol 1992;87:176–81.
Schneider J, Jehle EC, Starlinger MJ, Neunlist M, Michel K, Hoppe S, et al. Neurotransmitter coding of enteric neurones in the submucous plexus is changed in non-inflamed rectum of patients with Crohn’s disease. Neurogastroenterol Motil 2001;13:255–64.
Arranz A, Juarranz Y, Leceta J, Gomariz RP, Martínez C. VIP balances innate and adaptive immune responses induced by specific stimulation of TLR2 and TLR4. Peptides 2008;29:948–56.
Arranz A, Abad C, Juarranz Y, Leceta J, Martinez C, Gomariz RP. Vasoactive intestinal peptide as a healing mediator in Crohn’s disease. Neuroimmunomodulation 2008;15:46–53.
Sigalet DL, Wallace LE, Holst JJ, Martin GR, Kaji T, Tanaka H, et al. Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2. Am J Physiol Gastrointest Liver Physiol 2007;293:G211–21.
Delafoy L, Gelot A, Ardid D, Eschalier A, Bertrand C, Doherty AM, et al. Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat. Gut 2006;55:940–5.
Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 2011;141:599–609, 609.e1–3.
Beyak MJ, Vanner S. Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels. Neurogastroenterol Motil 2005;17:175–86.
Geboes K, Collins S. Structural abnormalities of the nervous system in Crohn’s disease and ulcerative colitis. Neurogastroenterol Motil 1998;10:189–202.
De Giorgio R, Camilleri M. Human enteric neuropathies: morphology and molecular pathology. Neurogastroenterol Motil 2004;16:515–31.
Villanacci V, Bassotti G, Nascimbeni R, Antonelli E, Cadei M, Fisogni S, et al. Enteric nervous system abnormalities in inflammatory bowel diseases. Neurogastroenterol Motil 2008;20:1009–16.
Linden DR, Couvrette JM, Ciolino A, McQuoid C, Blaszyk H, Sharkey KA, et al. Indiscriminate loss of myenteric neurones in the TNBS-inflamed guinea-pig distal colon. Neurogastroenterol Motil 2005;17:751–60.
Sanovic S, Lamb DP, Blennerhassett MG. Damage to the enteric nervous system in experimental colitis. Am J Pathol 1999;155:1051–7.
Aulí M, Nasser Y, Ho W, Burgueño JF, Keenan CM, Romero C, et al. Neuromuscular changes in a rat model of colitis. Auton Neurosci 2008;141:10–21.
Wang X-Y, Vannucchi M-G, Nieuwmeyer F, Ye J, Faussone-Pellegrini M-S, Huizinga JD. Changes in interstitial cells of Cajal at the deep muscular plexus are associated with loss of distention-induced burst-type muscle activity in mice infected by Trichinella spiralis. Am J Pathol 2005;167:437–53.
Pontell L, Castelucci P, Bagyánszki M, Jovic T, Thacker M, Nurgali K, et al. Structural changes in the epithelium of the small intestine and immune cell infiltration of enteric ganglia following acute mucosal damage and local inflammation. Virchows Arch 2009;455:55–65.
Sarnelli G, De Giorgio R, Gentile F, Calì G, Grandone I, Rocco A, et al. Myenteric neuronal loss in rats with experimental colitis: role of tissue transglutaminase-induced apoptosis. Dig Liver Dis 2009;41:185–93.
Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L, et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 1998;93:189–201.
Linden DR, Sharkey KA, Ho W, Mawe GM. Cyclooxygenase-2 contributes to dysmotility and enhanced excitability of myenteric AH neurones in the inflamed guinea pig distal colon. J Physiol 2004;557:191–205.
Krauter EM, Strong DS, Brooks EM, Linden DR, Sharkey KA, Mawe GM. Changes in colonic motility and the electrophysiological properties of myenteric neurons persist following recovery from trinitrobenzene sulfonic acid colitis in the guinea pig. Neurogastroenterol Motil 2007;19:990–1000.
Chen Z, Suntres Z, Palmer J, Guzman J, Javed A, Xue J, et al. Cyclic AMP signaling contributes to neural plasticity and hyperexcitability in AH sensory neurons following intestinal Trichinella spiralis-induced inflammation. Int J Parasitol 2007;37:743–61.
Xia Y, Hu HZ, Liu S, Ren J, Zafirov DH, Wood JD. IL-1beta and IL-6 excite neurons and suppress nicotinic and noradrenergic neurotransmission in guinea pig enteric nervous system. J Clin Invest 1999;103:1309–16.
Kelles A, Janssens J, Tack J. IL-1beta and IL-6 excite neurones and suppress cholinergic neurotransmission in the myenteric plexus of the guinea pig. Neurogastroenterol Motil 2000;12:531–8.
Buhner S, Schemann M. Mast cell-nerve axis with a focus on the human gut. Biochim Biophys Acta 2012;1822:85–92.
Bienenstock J. From IgA to neuro-immunomodulation: a travelogue through immunology. Neth J Med 1991;39:183–7.
Michel K, Zeller F, Langer R, Nekarda H, Kruger D, Dover TJ, et al. Serotonin excites neurons in the human submucous plexus via 5-HT3 receptors. Gastroenterology 2005;128:1317–26.
Miyazaki D, Nakamura T, Toda M, Cheung-Chau K-W, Richardson RM, Ono SJ. Macrophage inflammatory protein-1alpha as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions. J Clin Invest 2005;115:434–42.
Gebhardt T, Lorentz A, Detmer F, Trautwein C, Bektas H, Manns MP, et al. Growth, phenotype, and function of human intestinal mast cells are tightly regulated by transforming growth factor beta1. Gut 2005;54:928–34.
Van Nassauw L, Adriaensen D, Timmermans J-P. The bidirectional communication between neurons and mast cells within the gastrointestinal tract. Auton Neurosci 2007;133:91–103.
Breunig E, Michel K, Zeller F, Seidl S, Weyhern CWH, Schemann M. Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors. J Physiol 2007;583:731–42.
Vergnolle N, Cenac N, Altier C, Cellars L, Chapman K, Zamponi GW, et al. A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation. Br J Pharmacol 2010;159:1161–73.
He S-H. Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol 2004;10:309–18.
Xie H, He S-H. Roles of histamine and its receptors in allergic and inflammatory bowel diseases. World J Gastroenterol 2005;11:2851–7.
Hagel AF, de Rossi T, Konturek PC, Albrecht H, Walker S, Hahn EG, et al. Plasma histamine and tumour necrosis factor-alpha levels in Crohn’s disease and ulcerative colitis at various stages of disease. J Physiol Pharmacol 2015;66:549–56.
Schwartz LB, Lewis RA, Austen KF. Tryptase from human pulmonary mast cells. Purification and characterization. J Biol Chem 1981;256:11939–43.
Kim J-A, Choi S-C, Yun K-J, Kim D-K, Han M-K, Seo G-S, et al. Expression of protease-activated receptor 2 in ulcerative colitis. Inflamm Bowel Dis 2003;9:224–9.
Annaházi A, Gecse K, Dabek M, Ait-Belgnaoui A, Rosztóczy A, Róka R, et al. Fecal proteases from diarrheic-IBS and ulcerative colitis patients exert opposite effect on visceral sensitivity in mice. Pain 2009;144:209–17.
Cenac N, Garcia-Villar R, Ferrier L, Larauche M, Vergnolle N, Bunnett NW, et al. Proteinase-activated receptor-2-induced colonic inflammation in mice: possible involvement of afferent neurons, nitric oxide, and paracellular permeability. J Immunol 2003;170:4296–300.
Ibeakanma C, Vanner S. TNFalpha is a key mediator of the pronociceptive effects of mucosal supernatant from human ulcerative colitis on colonic DRG neurons. Gut 2010;59:612–21.
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59–65.
Kamdar K, Nguyen V, DePaolo RW. Toll-like receptor signaling and regulation of intestinal immunity. Virulence 2013;4:207–12.
Sommer F, Bäckhed F. The gut microbiota – masters of host development and physiology. Nat Rev Microbiol 2013;11:227–38.
Swidsinski A, Loening-Baucke V, Lochs H, Hale L-P. Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J Gastroenterol 2005;11:1131–40.
Dinoto A, Suksomcheep A, Ishizuka S, Kimura H, Hanada S, Kamagata Y, et al. Modulation of rat cecal microbiota by administration of raffinose and encapsulated Bifidobacterium breve. Appl Environ Microbiol 2006;72:784–92.
Sekirov I, Russell SL, Antunes LCM, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010;90:859–904.
Kamada N, Chen GY, Inohara N, Núñez G. Control of pathogens and pathobionts by the gut microbiota. Nat Immunol 2013;14:685–90.
Ivanov II, Honda K. Intestinal commensal microbes as immune modulators. Cell Host Microbe 2012;12:496–508.
Montiel-Castro AJ, González-Cervantes RM, Bravo-Ruiseco G, Pacheco-López G. The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci 2013;7:70.
Simrén M, Barbara G, Flint HJ, Spiegel BMR, Spiller RC, Vanner S, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 2013;62:159–76.
Salzman NH, Bevins CL. Dysbiosis—a consequence of Paneth cell dysfunction. Semin Immunol 2013;25:334–41.
Comito D, Romano C. Dysbiosis in the pathogenesis of pediatric inflammatory bowel diseases. Int J Inflam 2012;2012:687143.
Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 2015;26:26191.
De Hertogh G, Aerssens J, Geboes KP, Geboes K. Evidence for the involvement of infectious agents in the pathogenesis of Crohn’s disease. World J Gastroenterol 2008;14:845–52.
Berg AM, Dam AN, Farraye FA. Environmental influences on the onset and clinical course of Crohn’s disease – part 2: infections and medication use. Gastroenterol Hepatol (N Y) 2013;9:803–10.
Sokol H. Probiotics and antibiotics in IBD. Dig Dis 2014;32 Suppl 1:10–7.
Buttó LF, Schaubeck M, Haller D. Mechanisms of microbe-host interaction in Crohn’s disease: dysbiosis vs. pathobiont selection. Front Immunol 2015;6:555.
Rath HC, Wilson KH, Sartor RB. Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus or Escherichia coli. Infect Immun 1999;67:2969–74.
Waidmann M, Bechtold O, Frick J-S, Lehr H-A, Schubert S, Dobrindt U, et al. Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology 2003;125:162–77.
Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. ISME J 2007;1:403–18.
Walters WA, Xu Z, Knight R. Meta-analyses of human gut microbes associated with obesity and IBD. FEBS Lett 2014;588:4223–33.
Boudeau J, Glasser AL, Masseret E, Joly B, Darfeuille-Michaud A. Invasive ability of an Escherichia coli strain isolated from the ileal mucosa of a patient with Crohn’s disease. Infect Immun 1999;67:4499–509.
Willot S, Gauthier C, Patey N, Faure C. Nerve growth factor content is increased in the rectal mucosa of children with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2012;24:734–9, e347.
Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 2008;3:417–27.
Marchesi JR, Adams DH, Fava F, Hermes GDA, Hirschfield GM, Hold G, et al. The gut microbiota and host health: a new clinical frontier. Gut 2015;65:330–9.
Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 2006;55:205–11.
Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A 2010;107:12204–9.
Barnes MJ, Powrie F. Immunology. The gut’s Clostridium cocktail. Science 2011;331:289–90.
Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol 2011;11:7.
Hansen R, Russell RK, Reiff C, Louis P, McIntosh F, Berry SH, et al. Microbiota of de-novo pediatric IBD: increased Faecalibacterium prausnitzii and reduced bacterial diversity in Crohn’s but not in ulcerative colitis. Am J Gastroenterol 2012;107:1913–22.
Khan MT, Duncan SH, Stams AJM, van Dijl JM, Flint HJ, Harmsen HJM. The gut anaerobe Faecalibacterium prausnitzii uses an extracellular electron shuttle to grow at oxic-anoxic interphases. ISME J 2012;6:1578–85.
Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux J-J, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008;105:16731–6.
Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2014;63:1275–83.
Cao Y, Shen J, Ran ZH. Association between Faecalibacterium prausnitzii reduction and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Gastroenterol Res Pract 2014;2014:872725.
Sarrabayrouse G, Alameddine J, Altare F, Jotereau F. Microbiota-specific CD4CD8αα Tregs: role in intestinal immune homeostasis and implications for IBD. Front Immunol 2015;6:522.
Lopetuso LR, Scaldaferri F, Petito V, Gasbarrini A. Commensal Clostridia: leading players in the maintenance of gut homeostasis. Gut Pathog 2013;5:23.
Turroni F, Ventura M, Buttó LF, Duranti S, O’Toole PW, Motherway MO, et al. Molecular dialogue between the human gut microbiota and the host: a Lactobacillus and Bifidobacterium perspective. Cell Mol Life Sci 2014;71:183–203.
Grangette C. Bifidobacteria and subsets of dendritic cells: friendly players in immune regulation! Gut 2012;61:331–2.
Gionchetti P, Rizzello F, Lammers K-M, Morselli C, Sollazzi L, Davies S, et al. Antibiotics and probiotics in treatment of inflammatory bowel disease. World J Gastroenterol 2006;12:3306–13.
Veerappan GR, Betteridge J, Young PE. Probiotics for the treatment of inflammatory bowel disease. Curr Gastroenterol Rep 2012;14:324–33.
Quigley EMM. Therapies aimed at the gut microbiota and inflammation: antibiotics, prebiotics, probiotics, synbiotics, anti-inflammatory therapies. Gastroenterol Clin North Am 2011;40:207–22.
Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol 2004;54:1469–76.
Derrien M, Van Baarlen P, Hooiveld G, Norin E, Müller M, de Vos WM. Modulation of mucosal immune response, tolerance, and proliferation in mice colonized by the Mucin-Degrader Akkermansia muciniphila. Front Microbiol 2011;2:166.
Kang C-S, Ban M, Choi E-J, Moon H-G, Jeon J-S, Kim D-K, et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One 2013;8:e76520.
Png CW, Lindén SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010;105:2420–8.
Clausen MR. Butyrate and colorectal cancer in animals and in humans (mini-symposium: butyrate and colorectal cancer). Eur J Cancer Prev 1995;4:483–90.
Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013;341:569–73.
Takahashi K, Nishida A, Fujimoto T, Fujii M, Shioya M, Imaeda H, et al. Reduced abundance of butyrate-producing bacteria species in the fecal microbial community in Crohn’s disease. Digestion 2016;93:59–65.
Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 2012;487:104–8.
Leone V, Chang EB, Devkota S. Diet, microbes, and host genetics: the perfect storm in inflammatory bowel diseases. J Gastroenterol 2013;48:315–21.
Legaki E, Gazouli M. Influence of environmental factors in the development of inflammatory bowel diseases. World J Gastrointest Pharmacol Ther 2016;7:112–25.
Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, Gobourne A, et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 2014;517:205–8.
Joyce SA, Gahan CGM. Bile acid modifications at the microbe-host interface: potential for nutraceutical and pharmaceutical interventions in host health. Annu Rev Food Sci Technol 2016;7:313-33. doi: 10.1146/annurev-food-041715-033159. Epub 2016 Jan 11. Review.
Chehoud C, Albenberg LG, Judge C, Hoffmann C, Grunberg S, Bittinger K, et al. Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2015;21:1948–56.
Sokol H, Leducq V, Aschard H, Pham H-P, Jegou S, Landman C, et al. Fungal microbiota dysbiosis in IBD. Gut 2016 Feb 3. pii: gutjnl-2015-310746. doi: 10.1136/gutjnl-2015-310746. [Epub ahead of print].
Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 2015;160:447–60.
Aguilera M, Vergara P, Martínez V. Stress and antibiotics alter luminal and wall-adhered microbiota and enhance the local expression of visceral sensory-related systems in mice. Neurogastroenterol Motil 2013;25:e515–29.
Aguilera M, Cerdà-Cuéllar M, Martínez V. Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice. Gut Microbes 2014;6:1–14.
Verdú EF, Bercik P, Verma-Gandhu M, Huang X-X, Blennerhassett P, Jackson W, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 2006;55:182–90.
O’Mahony SM, Felice VD, Nally K, Savignac HM, Claesson MJ, Scully P, et al. Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats. Neuroscience 2014;277C:885–901.
El Aidy S, Dinan TG, Cryan JF. Immune modulation of the brain-gut-microbe axis. Front Microbiol 2014;5:146.
Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology 2014 May;146(6):1500-12. doi: 10.1053/j.gastro.2014.02.037. Epub 2014 Feb 28.
Barbara G, Cremon C, Stanghellini V. Inflammatory bowel disease and irritable bowel syndrome: similarities and differences. Curr Opin Gastroenterol 2014;30:352–8.
Aguilera M, Pla J, Martinez V. Tu1723 stimulation of colonic toll-like receptor 4 (TLR4) with LPS enhances host-bacterial interactions and leads to a local immune activation and an up-regulation of sensory-related systems in rats. Gastroenterology 2013;144:S–831.
Aguilera M, Martínez V. STIMULATION OF COLONIC TOLLLIKE RECEPTORS 4 AND 7 INDUCES A SPECIFIC NEUROIMMUNE ACTIVATION IN RATS. Oral sessions. Acta Physiol 2016;216:34–84.
Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, et al. Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol 2011;186:6417–26.
Brun P, Giron MC, Qesari M, Porzionato A, Caputi V, Zoppellaro C, et al. Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system. Gastroenterology 2013;145:1323–33.
Tramullas M, Finger BC, Moloney RD, Golubeva A V, Moloney G, Dinan TG, et al. Toll-like receptor 4 regulates chronic stress-induced visceral pain in mice. Biol Psychiatry 2014;76:340–8.
Dheer R, Santaolalla R, Davies JM, Lang JK, Phillips MC, Pastorini C, et al. Intestinal epithelial TLR4 signaling affects epithelial function, colonic microbiota and promotes risk for transmissible colitis. Infect Immun 2016 Jan 11;84(3):798-810. doi: 10.1128/IAI.01374-15.
Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 2011;25:397–407.
Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, et al. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem 2011;286:9587–97.
Tada Y, Ishihara S, Kawashima K, Fukuba N, Sonoyama H, Kusunoki R, et al. Down-regulation of serotonin reuptake transporter gene expression in healing colonic mucosa in presence of remaining low grade inflammation in ulcerative colitis. J Gastroenterol Hepatol 2015 Dec 16. doi: 10.1111/jgh.13268. [Epub ahead of print].
Stoyanova II, Gulubova M V. Mast cells and inflammatory mediators in chronic ulcerative colitis. Acta Histochem 2002;104:185–92.
Holzer P, Hassan AM, Jain P, Reichmann F, Farzi A. Neuroimmune pharmacological approaches. Curr Opin Pharmacol 2015;25:13–22.
Lomax AE, Linden DR, Mawe GM, Sharkey KA. Effects of gastrointestinal inflammation on enteroendocrine cells and enteric neural reflex circuits. Auton Neurosci 2006;126–127:250–7.