Effect of prebiotic fiber on physical function and gut microbiota in adults, mostly women, with knee osteoarthritis and obesity: a randomized controlled trial.

PURPOSE: Obesity is a primary risk factor for knee osteoarthritis (OA). Prebiotics enhance beneficial gut microbes and can reduce body fat and inflammation. Our objective was to examine if a 6-month prebiotic intervention improved physical function in adults with knee osteoarthritis and obesity. We also measured knee pain, body composition, quality of life, gut microbiota, inflammatory markers, and serum metabolomics. METHODS: Adults (n = 54, mostly women) with co-morbid obesity (BMI > 30 kg/m2) and unilateral/bilateral knee OA were randomly assigned to prebiotic (oligofructose-enriched inulin; 16 g/day; n = 31) or isocaloric placebo (maltodextrin; n = 21) for 6 months. Performance based-tests, knee pain, quality of life, serum metabolomics and inflammatory markers, and fecal microbiota and short-chain fatty acids were assessed. RESULTS: Significant between group differences were detected for the change in timed-up-and-go test, 40 m fast paced walk test, and hand grip strength test from baseline that favored prebiotic over placebo. Prebiotic also reduced trunk fat mass (kg) at 6 months and trunk fat (%) at 3 months compared to placebo. There was a trend (p = 0.059) for reduced knee pain at 6 months with prebiotic versus placebo. In gut microbiota analysis, a total of 37 amplicon sequence variants differed between groups. Bifidobacterium abundance was positively correlated with distance walked in the 6-min walk test and hand grip strength. At 6 months, there was a significant separation of serum metabolites between groups with upregulation of phenylalanine and tyrosine metabolism with prebiotic. CONCLUSION: Prebiotics may hold promise for conservative management of knee osteoarthritis in adults with obesity and larger trials are warranted. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov/study/NCT04172688.

Neuroimmunophysiology of the Gastrointestinal Tract.

Gut physiology is the epicentre of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labelled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on inter-cellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies, and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation and 'external' influences such as the central nervous system and the gut microbiota.

Non-Intoxicating Cannabinoids in Visceral Pain.

Cannabis and cannabis products are becoming increasingly popular options for symptom management of inflammatory bowel diseases, particularly abdominal pain. While anecdotal and patient reports suggest efficacy of these compounds for these conditions, clinical research has shown mixed results. To date, clinical research has focused primarily on delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is a ligand of classical cannabinoid receptors (CBRs). CBD is one of a large group of nonintoxicating cannabinoids (niCBs) that mediate their effects on both CBRs and through non-CBR mechanisms of action. Because they are not psychotropic, there is increasing interest and availability of niCBs. The numerous niCBs show potential to rectify abnormal intestinal motility as well as have anti-inflammatory and analgesic effects. The effects of niCBs are frequently not mediated by CBRs, but rather through actions on other targets, including transient receptor potential channels and voltage-gated ion channels. Additionally, evidence suggests that niCBs can be combined to increase their potency through what is termed the entourage effect. This review examines the pre-clinical data available surrounding these niCBs in treatment of abdominal pain with a focus on non-CBR mechanisms.

Impact of depression and antidepressant use on clinical outcomes of hepatitis B and C: a population-based study.

BACKGROUND: Depression is common in patients with chronic viral hepatitis. We evaluated the impact of major depressive disorder (MDD) and antidepressant use on survival among patients with HBV and HCV. METHODS: We used The Health Improvement Network database, the largest medical database in the UK, to identify incident HBV (n=1401) and HCV (n=1635) in patients between 1986 and 2017. Our primary composite outcome was the development of decompensated cirrhosis or death. MDD and each class of antidepressants were assessed in multivariate Cox proportional hazards models. Models were adjusted for age, sex, and clinical comorbidities. RESULTS: The prevalence of MDD among HCV patients was higher compared with HBV patients (23.5% vs. 9.0%, p<0.001, respectively). Similarly, HCV patients were more likely to use antidepressants (59.6%) compared with HBV patients (27.1%), p>0.001. MDD was not an independent predictor for decompensated cirrhosis-free survival or mortality. However, the use of tricyclic and tetracyclic antidepressants (TCAs) was associated with poor decompensated cirrhosis-free survival in HBV and HCV cohorts (adjusted HR: 1.80, 95% CI, 1.00-3.26 and 1.56, 95% CI, 1.13-2.14, respectively). Both TCAs in the HBV cohort and selective serotonin reuptake inhibitors among the HCV cohort were associated with poor overall survival (adjusted HR: 2.18, 95% CI, 1.16-4.10; 1.48, 95% CI, 1.02-2.16, respectively). CONCLUSIONS: Although prevalent among viral hepatitis patients, MDD did not affect disease progression or survival in either HBV or HCV cohorts. TCA use was associated with poor decompensated cirrhosis-free survival. Therefore, its use should be further studied among viral hepatitis patients.

Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice.

The enteric nervous system (ENS) regulates the motor, secretory and defensive functions of the gastrointestinal tract. Enteric neurons integrate mechanical and chemical inputs from the gut lumen to generate complex motor outputs. How intact enteric neural circuits respond to changes in the gut lumen is not well understood. We recorded intracellular calcium in live-cell confocal recordings in neurons from intact segments of mouse intestine in order to investigate neuronal response to luminal mechanical and chemical stimuli. Wnt1-, ChAT- and Calb1-GCaMP6 mice were used to record neurons from the jejunum and colon. We measured neuronal calcium response to KCl (75 mM), veratridine (10 µM), 1,1-dimethyl-4-phenylpiperazinium (DMPP; 100 µM) or luminal nutrients (Ensure®), in the presence or absence of intraluminal distension. In the jejunum and colon, distension generated by the presence of luminal content (chyme and faecal pellets, respectively) renders the underlying enteric circuit unresponsive to depolarizing stimuli. In the distal colon, high levels of distension inhibit neuronal response to KCl, while intermediate levels of distension reorganize Ca2+ response in circumferentially propagating slow waves. Mechanosensitive channel inhibition suppresses distension-induced Ca2+ elevations, and calcium-activated potassium channel inhibition restores neuronal response to KCl, but not DMPP in the distended colon. In the jejunum, distension prevents a previously unknown tetrodotoxin-resistant neuronal response to luminal nutrient stimulation. Our results demonstrate that intestinal distension regulates the excitability of ENS circuits via mechanosensitive channels. Physiological levels of distension locally silence or synchronize neurons, dynamically regulating the excitability of enteric neural circuits based on the content of the intestinal lumen. KEY POINTS: How the enteric nervous system of the gastrointestinal tract responds to luminal distension remains to be fully elucidated. Here it is shown that intestinal distension modifies intracellular calcium levels in the underlying enteric neuronal network, locally and reversibly silencing neurons in the distended regions. In the distal colon, luminal distension is integrated by specific mechanosensitive channels and coordinates the dynamics of neuronal activation within the enteric network. In the jejunum, distension suppresses the neuronal calcium responses induced by luminal nutrients. Physiological levels of distension dynamically regulate the excitability of enteric neuronal circuits.

Proteolipid protein 1 is involved in the regulation of intestinal motility and barrier function in the mouse.

Proteolipid protein 1 (Plp1) is highly expressed in enteric glia, labeling cells throughout the mucosa, muscularis, and the extrinsic innervation. Plp1 is a major constituent of myelin in the central and peripheral nervous systems, but the absence of myelin in the enteric nervous system (ENS) suggests another role for Plp1 in the gut. Although the functions of enteric glia are still being established, there is strong evidence that they regulate intestinal motility and permeability. To interrogate the role of Plp1 in enteric glia, we investigated gut motility, secretomotor function and permeability, and evaluated the ENS in mice lacking Plp1. We studied two time points: ∼3 mo (young) and >1 yr (old). Old Plp1 null mice exhibited increased fecal output, decreased fecal water content, faster whole gut transit times, reduced intestinal permeability, and faster colonic migrating motor complexes. Interestingly, in both young and old mice, the ENS exhibited normal glial and neuronal numbers as well as glial arborization density in the absence of Plp1. As Plp1-associated functions involve mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Mapk/Erk1/2) signaling and Mapk/Erk1/2 are reported to have a regulatory role in intestinal motility, we measured protein expression of Erk1/2 and its active form in the small intestine. Old Plp1 null mice had reduced levels of phosphorylated-Erk1/2. Although Plp1 is not required for the normal appearance of enteric glial cells, it has a regulatory role in intestinal motility and barrier function. Our results suggest that functional changes mediated by Plp1-expressing enteric glia may involve Erk1/2 activation.NEW & NOTEWORTHY Here, we describe that Plp1 regulates gut motility and barrier function. The functional effects of Plp1 eradication are only seen in old mice, not young. The effects of Plp1 appear to be mediated through the Erk1/2 pathway.

The enteric nervous system.

Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.

Cannabidiol Impairs Brain Mitochondrial Metabolism and Neuronal Integrity.

Background: The mechanisms underlying the clinical effects of CBD remain poorly understood. Given the increasing evidence for CBD's effects on mitochondria, we sought to examine in more detail whether CBD impacts mitochondrial function and neuronal integrity. Methods: We utilized BE(2)-M17 neuroblastoma cells or acutely isolated brain mitochondria from rodents using a Seahorse extracellular flux analyzer and a fluorescent spectrofluorophotometer assay. Mitochondrial ion channel activity and hippocampal long-term potentiation were measured using standard cellular electrophysiological methods. Spatial learning/memory function was evaluated using the Morris water maze task. Plasma concentrations of CBD were assessed with liquid chromatography-mass spectrometry, and cellular viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction neuronal injury assay. Results: At low micromolar concentrations, CBD reduced mitochondrial respiration, the threshold for mitochondrial permeability transition, and calcium uptake, blocked a novel mitochondrial chloride channel, and reduced the viability of hippocampal cells. These effects were paralleled by in vitro and in vivo learning/memory deficits. We further found that these effects were independent of cannabinoid receptor 1 and mitochondrial G-protein-coupled receptor 55. Conclusion: Our results provide evidence for concentration- and dose-dependent toxicological effects of CBD, findings that may bear potential relevance to clinical populations.

Multimodal Brain MRI of Deep Gray Matter Changes Associated With Inflammatory Bowel Disease.

BACKGROUND: Behavioral symptoms, including mood disorders, substantially impact the quality of life of patients with inflammatory bowel disease (IBD), even when clinical remission is achieved. Here, we used multimodal magnetic resonance imaging (MRI) to determine if IBD is associated with changes in the structure and function of deep gray matter brain regions that regulate and integrate emotional, cognitive, and stress responses. METHODS: Thirty-five patients with ulcerative colitis (UC) or Crohn's disease (CD) and 32 healthy controls underwent 3 Tesla MRIs to assess volume, neural activity, functional connection strength (connectivity), inflammation, and neurodegeneration of key deep gray matter brain regions (thalamus, caudate, pallidum, putamen, amygdala, hippocampus, and hypothalamus) involved in emotional, cognitive and stress processing. Associations with sex, presence of pain, disease activity, and C-reactive protein (CRP) concentration were examined. RESULTS: Significantly increased activity and functional connectivity were observed in cognitive and emotional processing brain regions, including parts of the limbic system, basal ganglia, and hypothalamus of IBD patients compared with healthy controls. Inflammatory bowel disease patients exhibited significantly increased volumes of the amygdala and hypothalamus, as well as evidence of neurodegeneration in the putamen and pallidum. Hippocampal neural activity was increased in IBD patients with active disease. The volume of the thalamus was positively correlated with CRP concentration and was increased in females experiencing pain. CONCLUSIONS: Patients with IBD exhibit functional and structural changes in the limbic and striatal systems. These changes may be targets for assessing or predicting the response to therapeutic interventions aimed at improving comorbid emotional and cognitive symptoms.

Magnetic resonance imaging revealed structural and functional changes within the brains of inflammatory bowel disease patients, in regions known to be involved in processing brain signals associated with behavioral symptoms, anxiety, pain, stress, and cognitive deficits.

Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome.

The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.

New Concepts of the Interplay Between the Gut Microbiota and the Enteric Nervous System in the Control of Motility.

Propulsive gastrointestinal (GI) motility is critical for digestive physiology and host defense. GI motility is finely regulated by the intramural reflex pathways of the enteric nervous system (ENS). The ENS is in turn regulated by luminal factors: diet and the gut microbiota. The gut microbiota is a vast ecosystem of commensal bacteria, fungi, viruses, and other microbes. The gut microbiota not only regulates the motor programs of the ENS but also is critical for the normal structure and function of the ENS. In this chapter, we highlight recent research that has shed light on the microbial mechanisms of interaction with the ENS involved in the control of motility. Toll-like receptor signaling mechanisms have been shown to maintain the structural integrity of the ENS and the neurochemical phenotypes of enteric neurons, in part through the production of trophic factors including glia-derived neurotrophic factor. Microbiota-derived short-chain fatty acids and/or single-stranded RNA regulates the synthesis of serotonin in enterochromaffin cells, which are involved in the initiation of enteric reflexes, among other functions. Further evidence suggests a crucial role for microbial modulation of serotonin in maintaining the integrity of the ENS through enteric neurogenesis. Understanding the microbial pathways of enteric neural control sheds new light on digestive health and provides novel treatment strategies for GI motility disorders.

Acute gut inflammation reduces neural activity and spine maturity in hippocampus but not basolateral amygdala.

Gastrointestinal tract (gut) inflammation increases stress and threat-coping behaviors, which are associated with altered activity in fear-related neural circuits, such as the basolateral amygdala and hippocampus. It remains to be determined whether inflammation from the gut affects neural activity by altering dendritic spines. We hypothesized that acute inflammation alters dendritic spines in a brain region-specific manner. Here we show that acute gut inflammation (colitis) evoked by dextran sodium sulfate (DSS) did not affect the overall spine density in the CA1 region of hippocampus, but increased the relative proportion of immature spines to mature spines on basal dendrites of pyramidal neurons. In contrast, in animals with colitis, no changes in spine density or composition on dendrites of pyramidal cells was observed in the basolateral amygdala. Rather, we observed decreased spine density on dendrites of stellate neurons, but not the relative proportions of mature vs immature spines. We used cFos expression evoked by the forced swim task as a measure of neural activity during stress and found no effect of DSS on the density of cFos immunoreactive neurons in basolateral amygdala. In contrast, fewer CA1 neurons expressed cFos in mice with colitis, relative to controls. Furthermore, CA1 cFos expression negatively correlated with active stress-coping in the swim task and was negatively correlated with gut inflammation. These data reveal that the effects of acute gut inflammation on synaptic remodeling depend on brain region, neuronal phenotype, and dendrite location. In the hippocampus, a shift to immature spines and hypoactivity are more strongly related to colitis-evoked behavioral changes than is remodeling in basolateral amygdala.

Cannabinoid hyperemesis syndrome in North America: evaluation of health burden and treatment prevalence.

BACKGROUND: Cannabinoid hyperemesis syndrome (CHS) is a poorly understood vomiting disorder associated with chronic cannabis use. AIMS: To characterise patients experiencing CHS in North America and to obtain a population-based estimate of CHS treatment prevalence in Canada before and during the Covid-19 pandemic METHODS: Internet survey of 157 CHS sufferers in Canada and the United States. Administrative health databases for the province of Alberta (population 5 million) were accessed to measure emergency department (ED) visits for vomiting, with a concurrent diagnostic code for cannabis use. Three time periods of 1 year were assessed: prior to recreational cannabis legalisation (2017-2018), after recreational legalisation (2018-2019) and during the first year of the Covid-19 pandemic (2020-2021). RESULTS: Problematic cannabis use (defined as a CUDIT-R score ≥8) was universal among the survey cohort, and 59% and 68% screening for moderate or worse anxiety or depression, respectively. The overall treatment prevalence of CHS across all ages increased from 15 ED visits per 100,000 population (95% CI, 14-17) prior to legalisation, to 21 (95% CI, 20-23) after legalisation, to 32 (95% CI, 31-35) during the beginning of the Covid-19 pandemic (p < 0.001). Treatment prevalence among chronic cannabis users was as high as 6 per 1000 in the 16-24 age group. CONCLUSION: Survey data suggest patients with CHS almost universally suffer from a cannabis use disorder, which has significant treatment implications. Treatment prevalence in the ED has increased substantially over a very short time period, with the highest rates seen during the Covid-19 pandemic.

A monocyte-leptin-angiogenesis pathway critical for repair post-infection.

During infection, inflammatory monocytes are thought to be key for bacterial eradication, but this is hard to reconcile with the large numbers of neutrophils that are recruited for each monocyte that migrates to the afflicted tissue, and the much more robust microbicidal functions of the neutrophils. However, unlike neutrophils, monocytes have the capacity to convert to situationally specific macrophages that may have critical functions beyond infection control1,2. Here, using a foreign body coated with Staphylococcus aureus and imaging over time from cutaneous infection to wound resolution, we show that monocytes and neutrophils are recruited in similar numbers with low-dose infection but not with high-dose infection, and form a localization pattern in which monocytes surround the infection site, whereas neutrophils infiltrate it. Monocytes did not contribute to bacterial clearance but converted to macrophages that persisted for weeks after infection, regulating hypodermal adipocyte expansion and production of the adipokine hormone leptin. In infected monocyte-deficient mice there was increased persistent hypodermis thickening and an elevated leptin level, which drove overgrowth of dysfunctional blood vasculature and delayed healing, with a thickened scar. Ghrelin, which opposes leptin function3, was produced locally by monocytes, and reduced vascular overgrowth and improved healing post-infection. In sum, we find that monocytes function as a cellular rheostat by regulating leptin levels and revascularization during wound repair.

Role of CB1 receptors in the acute regulation of small intestinal permeability: effects of high-fat diet.

The endocannabinoid system of the gastrointestinal tract is involved in the control of intestinal barrier function. Whether the cannabinoid 1 (CB1) receptor is expressed on the intestinal epithelium and acutely regulates barrier function has not been determined. Here, we tested the hypothesis that ligands of the CB1 receptor acutely modulate small intestinal permeability and that this is associated with altered distribution of tight junction proteins. We examined the acute effects of CB1 receptor ligands on small intestinal permeability both in chow-fed and 2-wk high-fat diet (HFD)-fed mice using Ussing chambers. We assessed the distribution of CB1 receptor and tight junction proteins using immunofluorescence and the expression of CB1 receptor using PCR. A low level of CB1 expression was found on the intestinal epithelium. CB1 receptor was highly expressed on enteric nerves in the lamina propria. Neither the CB1/CB2 agonist CP55,940 nor the CB1 neutral antagonist AM6545 altered the flux of 4kDa FITC dextran (FD4) across the jejunum or ileum of chow-fed mice. Remarkably, both CP55,940 and AM6545 reduced FD4 flux across the jejunum and ileum in HFD-fed mice that have elevated baseline intestinal permeability. These effects were absent in CB1 knockout mice. CP55,940 reduced the expression of claudin-2, whereas AM6545 had little effect on claudin-2 expression. Neither ligand altered the expression of ZO-1. Our data suggest that CB1 receptor on the intestinal epithelium regulates tight junction protein expression and restores barrier function when it is increased following exposure to a HFD for 2 wk.NEW & NOTEWORTHY The endocannabinoid system of the gastrointestinal tract regulates homeostasis by acting as brake on motility and secretion. Here we show that when exposed to a high fat diet, intestinal permeability is increased and activation of the CB1 receptor on the intestinal epithelium restores barrier function. This work further highlights the role of the endocannabinoid system in regulating intestinal homeostasis when it is perturbed.

Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis.

The maintenance of intestinal homeostasis is fundamentally important to health. Intestinal barrier function and immune regulation are key determinants of intestinal homeostasis and are therefore tightly regulated by a variety of signaling mechanisms. The endocannabinoid system is a lipid mediator signaling system widely expressed in the gastrointestinal tract. Accumulating evidence suggests the endocannabinoid system is a critical nexus involved in the physiological processes that underlie the control of intestinal homeostasis. In this review we will illustrate how the endocannabinoid system is involved in regulation of intestinal permeability, fluid secretion, and immune regulation. We will also demonstrate a reciprocal regulation between the endocannabinoid system and the gut microbiome. The role of the endocannabinoid system is complex and multifaceted, responding to both internal and external factors while also serving as an effector system for the maintenance of intestinal homeostasis.

Recruitment of α4ß7 monocytes and neutrophils to the brain in experimental colitis is associated with elevated cytokines and anxiety-like behavior.

BACKGROUND: Behavioral comorbidities, such as anxiety and depression, are a prominent feature of IBD. The signals from the inflamed gut that cause changes in the brain leading to these behavioral comorbidities remain to be fully elucidated. We tested the hypothesis that enhanced leukocyte-cerebral endothelial cell interactions occur in the brain in experimental colitis, mediated by α4ß7 integrin, to initiate neuroimmune activation and anxiety-like behavior. METHODS: Female mice treated with dextran sodium sulfate were studied at the peak of acute colitis. Circulating leukocyte populations were determined using flow cytometry. Leukocyte-cerebral endothelial cell interactions were examined using intravital microscopy in mice treated with anti-integrin antibodies. Brain cytokine and chemokines were assessed using a multiplex assay in animals treated with anti-α4ß7 integrin. Anxiety-like behavior was assessed using an elevated plus maze in animals after treatment with an intracerebroventricular injection of interleukin 1 receptor antagonist. RESULTS: The proportion of classical monocytes expressing α4ß7 integrin was increased in peripheral blood of mice with colitis. An increase in the number of rolling and adherent leukocytes on cerebral endothelial cells was observed, the majority of which were neutrophils. Treatment with anti-α4ß7 integrin significantly reduced the number of rolling leukocytes. After anti-Ly6C treatment to deplete monocytes, the number of rolling and adhering neutrophils was significantly reduced in mice with colitis. Interleukin-1ß and CCL2 levels were elevated in the brain and treatment with anti-α4ß7 significantly reduced them. Enhanced anxiety-like behavior in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist. CONCLUSIONS: In experimental colitis, α4ß7 integrin-expressing monocytes direct the recruitment of neutrophils to the cerebral vasculature, leading to elevated cytokine levels. Increased interleukin-1ß mediates anxiety-like behavior.