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Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn’s disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.

Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a potential protective action of apamin in animal models of PD is available to date. The specific goals of the present study were to (i) establish that the protective effect of bee venom for dopaminergic neurons is not restricted to acupoint stimulation, but can also be observed using a more conventional mode of administration and to (ii) demonstrate that apamin can mimic the protective effects of a bee venom treatment on dopaminergic neurons. Using the chronic mouse model of MPTP/probenecid, we show that bee venom provides sustained protection in an animal model that mimics the chronic degenerative process of PD. Apamin, however, reproduced these protective effects only partially, suggesting that other components of bee venom enhance the protective action of the peptide.

In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3-10 mg/kg s.c.) and tapentadol (10-20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain.

ABSTRACT Adherent-invasive Escherichia coli (AIEC) were investigated for their involvement in the induction/chronicity of intestinal inflammation in Crohn's disease (CD). AIEC gut establishment is favoured by overexpression of the glycoprotein CEACAM6 in the ileal epithelium. We generated a transgenic mouse model, named ‘Vill-hCC6’, in which the human CEACAM6 gene was under the control of the villin promoter, conditioning expression in the small intestine. We demonstrated that CEACAM6 is strongly expressed in the small intestine mucosa and is correlated with numerous glycosylations displayed at the brush border of enterocytes. Ex vivo, the AIEC–enterocyte interaction was enhanced by CEACAM6 expression and necessitated the presence of the bacterial adhesive factor FimH. Finally, AIEC bacteria preferentially persisted in a FimH-dependent manner in the ileal mucosa of Vill-hCC6 mice compared to wild-type mice. This preclinical model opens new perspectives in the mechanistic study of the AIEC pathobiont and represents a valuable tool to evaluate the efficacy of new strategies to eliminate AIEC implanted in the ileal mucosa, such as phages, inhibitory and/or anti-virulence molecules, or CRISPR-based strategies targeting virulence or fitness factors of AIEC bacteria.

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A) receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A) receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

Altered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR trafficking may also be involved. We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice. Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive disorder and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys. We found sex differences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions. These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy.

Background:Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas.Methods:Mice lacking the 5-HT reuptake carrier (5-HTT-/-) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR–induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos–induced expression) levels.Results:Although 5-HTT-/- mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR–mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR–mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT-/- mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT-/- mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR–like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT-/- mutants.Conclusions:Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT-/- mice.

High-affinity transporters for norepinephrine (NE) and serotonin (5-HT), which ensure neurotransmitter clearance at the synapse, are the principal targets of widely used antidepressant drugs. Antidepressants targeting these high-affinity transporters, however, do not provide positive treatment outcomes for all patients. Other monoamine transport systems, with lower affinity, have been detected in the brain, but their role is largely unknown. Here we report that OCT2, a member of the polyspecific organic cation transporter (OCT) family, is expressed notably in the limbic system and implicated in anxiety and depression-related behaviors in the mouse. Genetic deletion of OCT2 in mice produced a significant reduction in brain tissue concentrations of NE and 5-HT and in ex vivo uptake of both these neurotransmitters in the presence of the dual 5-HT–NE transport blocker, venlafaxine. In vivo clearance of NE and 5-HT evaluated using microiontophoretic electrophysiology was diminished in the hippocampus of OCT2 −/− mice in the presence of venlafaxine, thereby affecting postsynaptic neuronal activity. OCT2 −/− mice displayed an altered sensitivity to acute treatments with NE- and/or 5-HT-selective transport blockers in the forced-swim test. Moreover, the mutant mice were insensitive to long-term venlafaxine treatment in a more realistic, corticosterone-induced, chronic depression model. Our findings identify OCT2 as an important postsynaptic determinant of aminergic tonus and mood-related behaviors and a potential pharmacological target for mood disorders therapy.

BackgroundThe incidence of Crohn’s disease (CD) has increased drastically in newly industrialised countries with rapid urbanization. The colonisation of adherent-invasive Escherichia coli (AIEC) was associated with CD pathogenesis and the presence of AIEC closely correlated with mucosal E.coli load. In this study, we aimed to identify risk factors for AIEC colonization in CD patients and determine the effect of urbanization on AIEC prevalence.MethodsA total of 137 CD patients were recruited from Yunnan (rural China) and Hong Kong (urban China). Clinical questionnaires and ileal biopsy samples were collected during colonoscopies. Patient were categorised as high E.coli load (colony-forming units (CFU) > 300), low E.coli load (CFU ≤ 300) and E.coli negative (CFU = 0). Statistical significance for continuous and categorical variables was calculated by the Kruskal-Wallis test and Pearson’s chi-squared test in univariate analysis. The association between individual-level factors and log-transformed E.coli CFU was assessed using multivariate regression. Mucosal E.coli prevalence was compared in rural and urban regions and Ordinal Logistic Regression was used to evaluate the risk of urbanization on mucosal E.coli prevalence.ResultsAmong individual-level factors, a surgery history (P = 0.019) was significantly associated with different E.coli prevalence (IDDF2022-ABS-0230 Table 1). Multivariate analysis showed that a past surgical history (Beta = -3.12, P = 0.01) was negatively correlated with mucosal E.coli while age was positively associated with mucosal E.coli (Beta = 0.09, P = 0.04) in CD patients. The prevalence of mucosal E.coli was significantly higher in the urban region than rural region in overall CD populations and in patients with and without surgery history (IDDF2022-ABS-0230 Table 2). The odds ratio (OR) of mucosal E.coli in patients living in urban areas was 6.69 (95% of confidence interval 3.04 -16.10).Abstract IDDF2022-ABS-0230 Table 1Characteristics of CD patients with different mucosal E.coli prevalence in Yunnan cohort Characteristics E.coli negative(CFU = 0) Low E.coli load (0 < CFU ≤ 300) High E.coli load (CFU > 300) P-value Age (median, IQR) a 32(16.1) 43(13.1) 48.5(19.1) 0.601 BMI (median, IQR) a 21.1(6.12) 20.7(3.38) 20.2(4.73) 0.983 Inflammation b Inflamed n(%) 13(72.2%) 36(78.3%) 8(100%) non-inflamed n(%) 1(0.06%) 3(6.5%) 0(0%) 0.581 Unknown n(%) 4(22.2%) 7(15.2%) 0(0%) Surgery history n(%) b 13(72.2%) 24(52.2%) 1(12.5%) 0.019 Treatment compliance(ordinary) n(%) b 9(50.0%) 30(65.2%) 4(50%) 0.113 Smoker status b ex-smoker n(%) 2(11.1%) 5(10.9%) 1(12.5%) non-smoker n(%) 14(77.8%) 33(71.7%) 6(75.0%) 0.977 smoker n(%) 2(11.1%) 8(17.4%) 1(12.5%) Alcohol consumption b current drinker n(%) 0(0%) 4(8.7%) 0(0%) former drinker n(%) 2(11.1%) 4(8.7%) 2(25%) 0.5931 lifetime abstainer n(%) 16(88.9%) 37(80.4%) 6(75.0%) unknown n(%) 0(0%) 1(2.2%) 0(0%) a significance was assessed by Kruskal-Wallis test b significance was assessed by Pearson’s chi-squared testAbbreviations: IQR, interquartile rangeAbstract IDDF2022-ABS-0230 Table 2The difference of mucosal E.coli prevalence in rural and urban areas E.coli prevalence Rural Urban P-value With surgery history a E.coli negative(CFU = 0) n(%) 13(34.2%) 0(0%) Low E.coli load(0 < CFU ≤ 300) n(%) 24(63.2%) 8(80%) 0.022 High E.coli load (CFU > 300) n(%) 1(2.6%) 2(20%) Without surgery history a E.coli negative(CFU = 0) n(%) 5(14.7%) 1(2.6%) Low E.coli load(0 < CFU ≤ 300) n(%) 22(64.7%) 20(52.6%) 0.034 High E.coli load (CFU > 300) n(%) 7(20.6%) 17(44.7%) Unstratified a E.coli negative(CFU = 0) n(%) 18(25%) 1(1.5%) Low E.coli load(0 < CFU ≤ 300) n(%) 46(63.9%) 40(61.5%) <0.001 High E.coli load (CFU > 300) n(%) 8(11.1%) 24(36.9%) Total CD patients 72 65 a significance was assessed by Pearson’s chi-squared testConclusionsWe identified for the first-time surgery history as an independent risk factor for the presence of AIEC in CD patients. CD patients living in urban areas had a six-fold higher prevalence of mucosal E.coli than those in rural areas. These findings provide novel insights into the potential effect of urbanization and the associated individual-level factors in driving AIEC prevalence and epidemiology of CD.

In 1998, Arlette Darfeuille-Michaud, Christel Neut and Jean-Frederic Colombel discovered a novel pathovar of Escherichia coli, adherent and invasive Escherichia coli (AIEC), in the ileum of patients with Crohn’s disease (CD), that was genetically distinct from diarrheagenic E. coli, could adhere to and invade intestinal epithelial cells and survive in macrophages. The consistent association between AIEC and CD (approximately 30% across the world), their ability to exploit CD-associated genetic traits, and virulence in preclinical colitis models but not healthy hosts spurred global research to elucidate their pathogenicity. Research focused on integrating AIEC with the microbiome, metabolome, metagenome, host response and the impact of diet and antimicrobials has linked the luminal microenvironment and AIEC metabolism to health and disease. This deeper understanding has led to therapeutic trials and precision medicine targeting AIEC-colonised patients. In November 2023, prominent members of the AIEC research community met to present and discuss the many facets of basic, translational and clinical AIEC fields at ‘AIEC: past, present and future’ in NYC. This review is a summary of this international meeting highlighting the history of AIEC, knowledge accumulated over the past 25 years about its pathogenic properties and proposes a standardised approach for screening patients for AIEC.