Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines.

Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis.

Enteric nematodes and the path to up-regulation of type 2 cytokines IL-4 and IL-13.

Protective immunity against enteric parasitic nematodes is dependent on IL-4, IL-13 activation of their exclusive transcription factor STAT6. The precise pathways by which enteric parasitic nematodes are recognized by the host is unclear, but elimination of this important interaction in developed nations is thought to contribute to the dysregulated immune responses that are a characteristic of autoimmune diseases. Nematode-derived products are involved in evading host defenses to promote their life cycle leading to modulation of host immune responses. Host protective immunity has adapted to enteric parasitic nematode infection by elaboration of mucins, increasing intraluminal fluid to control access to the surface epithelium, increasing cell turnover to maintain an effective barrier to their invasion, initiating immune responses through activation of resident immune cells, and recruitment of additional immune cells to release immune mediators that help orchestrate these responses. Both the immune and functional outcomes depend largely on IL-4/IL-13 signaling through STAT6, with a dominant role for IL-13 working through the type 2 IL-4 receptor (IL-4R). The recent observation that enteric nematode infection prevents the onset of a number of experimental models of IBD, diabetes, and several extraintestinal autoimmune diseases including multiple sclerosis has generated considerable interest in the identification of worm/egg products involved in the generation and maintenance of Th2 cytokines that may mediate the beneficial effects of nematode infection in autoimmune and inflammatory pathologies.

IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent.

IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical "type 2" immune response in the gastrointestinal tract, yet the underlying mechanisms remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. The present study investigated IL-33-dependent intestinal immunity and function in mice. Exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88 dependent but STAT6 and IL-13 independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hypercontractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on intestinal epithelial function were STAT6 dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle function, however, were attributable to both STAT6-dependent and -independent mechanisms. In addition, IL-13 induction of insulin-like growth factor-1 was implicated in IL-33-induced smooth muscle hypertrophy. Finally, alternative activation of macrophages induced by IL-33 revealed a novel pathway that is IL-4, IL-13, and STAT6 independent. Thus manipulating IL-33 or related signaling pathways represents a potential therapeutic strategy for treating inflammatory diseases associated with dysregulated intestinal function.

Diabetic ketoacidosis associated with aripiprazole.

Metabolic adverse effects such as hyperglycemia, alterations in insulin sensitivity, and weight gain are known to be potential complications of atypical antipsychotic therapy. In certain cases, hyperglycemia may be so profound that diabetic ketoacidosis (DKA) or hyperosmolar coma may result. Aripiprazole, approved by the United States Food and Drug Administration in 2002, appears to have fewer metabolic adverse effects than other atypical antipsychotics. We describe a 44-year-old man with no personal or family history of diabetes mellitus who was prescribed aripiprazole for schizoaffective disorder. Two weeks after starting this therapy, the patient developed DKA, which was corrected with insulin therapy and aggressive hydration. According to the Naranjo adverse drug reaction probability scale, aripiprazole was the probable trigger of his DKA. An exhaustive search for other causes of DKA was unrevealing. Administration of aripiprazole or any other atypical antipsychotic should be terminated when impaired glucose tolerance is suspected. Vigilance regarding the potential adverse effects of this class of drugs, including new agents such as aripiprazole, is crucial to preventing potentially life-threatening complications of hyperglycemia.

Adverse events in IBD therapy: the 2018 update.

INTRODUCTION: Crohn's disease and ulcerative colitis affect an increasing number of patients, and utilization of immune suppressant and biologic therapies is also increasing. These agents are linked to adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. Areas covered: This review provides an updated discussion on adverse events associated with immunomodulator, anti-TNF-α, anti-integrin, and anti-IL 12/IL-23 antibody therapies. In addition, we review the risk profile of the currently widely available infliximab biosimilar medication. Expert commentary: Providers should engage in risk-benefit discussion with information specific to each medication discussed, and consider individualized risk factors when selecting therapeutic agents. Drug monitoring and shared decision-making results in more personalized medical management of inflammatory bowel disease.

Frequency of Surveillance and Impact of Surveillance Colonoscopies in Patients With Ulcerative Colitis Who Developed Colorectal Cancer.

BACKGROUND: The risk of developing colorectal cancer (CRC) in patients with chronic ulcerative colitis (UC) is increased. The aim of this study was to evaluate if patients who developed CRC in the setting of UC were undergoing guideline-recommended surveillance colonoscopies and to determine the impact of surveillance on the staging of CRC. PATIENTS AND METHODS: Data was obtained from the Veterans Affairs healthcare system to identify patients with UC and CRC. Stage 0 and I were considered early-stage CRC, whereas stage ≥ II were considered advanced-stage CRC. Patients were considered to have adequate surveillance if they had a colonoscopy within 2 years before developing CRC. We conducted a case-case analysis using multivariable logistic regression to estimate the odds ratio for presenting with advanced-stage CRC associated with lack of adequate surveillance. RESULTS: Of the 48 patients, the majority were white (70.8%) and male (100%). Sixty-nine percent of patients had inadequate surveillance. In multivariable analysis, prior adherence to CRC surveillance was associated with a decreased risk of presenting with advanced-stage CRC (vs. early-stage CRC) (adjusted odds ratio, 0.20; 95% confidence interval, 0.05-0.85; P = .029). CONCLUSION: The majority of patients who developed CRC in the setting of UC underwent inadequate surveillance, and they were more likely to present with advanced-stage CRC.

Integrin antagonists as potential therapeutic options for the treatment of Crohn's disease.

INTRODUCTION: Anti-integrin therapy for the treatment of patients with Crohn's disease is rapidly evolving. Two agents, natalizumab and vedolizumab, are approved by the United States Food and Drug Administration for the treatment of Crohn's disease, with vedolizumab the primary anti-integrin used due to a more favorable safety profile. Several other anti-integrins are in various stages of development. AREAS COVERED: This review discusses the current state of anti-integrin therapy as well as suggestions for positioning of these agents in clinical practice. Emerging anti-integrin therapies, their underlying mechanisms of action, and available safety and clinical data are also reviewed. EXPERT OPINION: Anti-integrins are effective for the treatment of Crohn's disease, even in patients refractory to other therapies. Their use should be considered in patients with Crohn's disease who do not respond to, develop non-response to, or have contraindications to anti-TNF therapy. Anti-integrin therapies can be offered as a first biologic therapy, in particular for older patients, patients with concurrent multiple sclerosis (natalizumab only), and in patients with contraindications to anti-TNF therapy. In patients with more severe symptoms, providers should consider co-induction with corticosteroids if possible to hasten remission.

Pharmacodynamic assessment of vedolizumab for the treatment of ulcerative colitis.

INTRODUCTION: Vedolizumab is an anti-integrin approved for the treatment of Crohn's disease and ulcerative colitis. By binding the α4ß7-integrin heterodimer, vedolizumab blocks leukocyte translocation into gastrointestinal tissue. AREAS COVERED: This review discusses the chemistry, pharmacologic properties, clinical efficacy, and safety of vedolizumab in ulcerative colitis. Other medications available for the treatment of ulcerative colitis are also discussed. EXPERT OPINION: Vedolizumab is a promising new agent for the treatment of ulcerative colitis. Its mechanism of action differs from TNF-α inhibitors and immune suppressants, allowing it to be used in cases of TNF-α inhibitor failure or non-response, or as a first-line biologic drug. Available safety data suggests that vedolizumab is not associated with an increased risk of infection or malignancy; however, additional post-marketing data are required to confirm these initial reports. Vedolizumab is likely to be used in growing numbers of patients over the coming years.

M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury.

The role of muscarinic receptor subtypes in modulating acute liver injury is unknown. We detected M1 muscarinic receptor (M1R) expression in human and murine hepatocytes, and investigated the consequences of M1R deficiency on acute liver injury in vivo and inhibiting M1R activation on hepatocyte injury in vitro. Age-matched wild-type (WT) and M1R-deficient (Chrm1(-/-)) male mice were injected intraperitoneally with 200mg/kg acetaminophen (APAP) and euthanized 0, 2, 4, 16, 24, and 36h later. Biochemical and histological parameters indicated that liver injury peaked within 16h after APAP treatment and resolved by 24h. Compared to WT, M1R-deficient mice had reduced intrahepatic hemorrhage and hepatocyte necrosis, reflected by an attenuated rise in serum alanine aminotransferase levels. Livers of M1R-deficient mice showed reduced hepatocyte DNA fragmentation and attenuated expression of injury cytokines (Il-1α, Il-1ß, Il-6, and Fasl). In all mice hepatic glutathione levels decreased after APAP injection, but they recovered more quickly in M1R-deficient mice. During the course of APAP-induced liver injury in M1R-deficient compared to WT mice, hepatic Nrf-2, Gclc, and Nqo1 expressions increased and nitrotyrosine generation decreased. APAP metabolic pathways were not altered by M1R deficiency; expression of hepatic Cyp2e1, Cyp1a2, Cyp3a11, Cyp3a13, Car, and Pxr was similar in Chrm1(-/-) and WT mice. Finally, treatment of murine AML12 hepatocytes with a novel M1R antagonist, VU0255035, attenuated H2O2-induced oxidative stress, prevented GSH depletion, and enhanced viability. We conclude that M1R modify hepatocyte responses to oxidative stress and that targeting M1R has therapeutic potential for toxic liver injury.

Type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium.

BACKGROUND: The role of muscarinic receptors in mucosal homeostasis, response to enteric pathogens, and modulation of immune cell function is undefined. METHODS: The contribution of type 3 muscarinic receptors (M3R) to mucosal homeostasis within the colon and host defense against Citrobacter rodentium was determined in uninfected and C. rodentium-infected WT and M3R-deficient (Chrm3) mice. In addition, WT and Chrm3 bone marrow-derived macrophages were studied to determine the ability of M3R to modulate macrophage phenotype and function. RESULTS: In Chrm3 mice, clearance of C. rodentium was delayed despite an amplified TH1/TH17 response. Delayed clearance of C. rodentium from Chrm3 mice was associated with prolonged adherence of bacteria to colonic mucosa, decreased goblet cell number, and decreased mucin 2 gene expression. Treatment of bone marrow-derived macrophages with bethanechol, a muscarinic-selective agonist, induced a classically activated macrophage phenotype, which was dependent on M3R expression. Chrm3 bone marrow-derived macrophages retained their ability to attain a classically activated macrophage phenotype when treated with the TH1 cytokine IFN-γ. CONCLUSIONS: In Chrm3 mice, mucin production is attenuated and is associated with prolonged adherence of C. rodentium to colonic mucosa. The immune response, as characterized by production of TH1/TH17 cytokines, in C. rodentium-infected Chrm3 mice is intact. In addition, M3R activity promotes the development of classically activated macrophages. Our data establish a role for M3R in host defense against C. rodentium through effects on goblet cell mucus production and in the modulation of macrophage phenotype and function.

Adverse events in IBD: to stop or continue immune suppressant and biologic treatment.

Crohn's disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered.

Role of macrophages in the altered epithelial function during a type 2 immune response induced by enteric nematode infection.

Parasitic enteric nematodes induce a type 2 immune response characterized by increased production of Th2 cytokines, IL-4 and IL-13, and recruitment of alternatively activated macrophages (M2) to the site of infection. Nematode infection is associated with changes in epithelial permeability and inhibition of sodium-linked glucose absorption, but the role of M2 in these effects is unknown. Clodronate-containing liposomes were administered prior to and during nematode infection to deplete macrophages and prevent the development of M2 in response to infection with Nippostrongylus brasiliensis. The inhibition of epithelial glucose absorption that is associated with nematode infection involved a macrophage-dependent reduction in SGLT1 activity, with no change in receptor expression, and a macrophage-independent down-regulation of GLUT2 expression. The reduced transport of glucose into the enterocyte is compensated partially by an up-regulation of the constitutive GLUT1 transporter consistent with stress-induced activation of HIF-1α. Thus, nematode infection results in a "lean" epithelial phenotype that features decreased SGLT1 activity, decreased expression of GLUT2 and an emergent dependence on GLUT1 for glucose uptake into the enterocyte. Macrophages do not play a role in enteric nematode infection-induced changes in epithelial barrier function. There is a greater contribution, however, of paracellular absorption of glucose to supply the energy demands of host resistance. These data provide further evidence of the ability of macrophages to alter glucose metabolism of neighboring cells.

Combined blockade of IL-17A and IL-17F may prevent the development of experimental colitis.

The contribution of Th17 cells to the development of colitis is well described. The effector cytokines IL-17A and IL-17F have been proposed as potential therapeutic targets for the treatment of patients with inflammatory bowel disease. In a proof-of-concept study for the treatment of patients with Crohn's disease, secukinumab, a monoclonal antibody directed against IL-17A, was ineffective and associated with more adverse events than placebo. Wedebye Schmidt et al. propose that blockade of both IL-17A and IL-17F, rather than either cytokine alone, attenuates the development of colitis in a T-cell transfer model of experimental colitis. These findings suggest that combined blockade of IL-17A and IL-17F may be an effective strategy for the treatment of patients with inflammatory bowel disease.

Vedolizumab for the treatment of ulcerative colitis and Crohn's disease.

Crohn's disease and ulcerative colitis are chronic, relapsing inflammatory disorders of the GI tract. In both Crohn's disease and ulcerative colitis, leukocytic infiltration of the mucosa is associated with epithelial damage. Recently, monoclonal antibodies directed against cell adhesion molecules (CAMs) involved in leukocyte extravasation have been developed. Natalizumab, the first drug brought to market targeting CAMs, is clinically effective but is associated with serious adverse effects including the uncommon, but often fatal, neurological disease progressive multifocal leukoencephalopathy. Vedolizumab targets a subset of the CAMs blocked by natalizumab and is currently in Phase III trials to study its efficacy and safety in patients with inflammatory bowel disease. Here, we discuss the current treatment options available for patients with Crohn's disease or ulcerative colitis, the history of CAM inhibitors, the current state of development of vedolizumab and its future role in inflammatory bowel disease, if approved by regulatory agencies.