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Background: Cough is a common troublesome symptom in asthma which is neuronally mediated. Limosilactobacillus reuteri DSM‐17938 (L. reuteri DSM‐17938) is a probiotic shown to be effective in pre‐clinical models at suppressing neuronal responses to capsaicin, a transient receptor potential vanilloid agonist (TRPV1). Objective: Investigate the effects of DSM‐17938 versus matched placebo on capsaicin‐evoked coughs in mild allergic asthmatics. Methods: We performed a 4‐visit, randomized, double‐blind, placebo‐controlled, two‐way cross‐over study comparing full dose cough responses with inhaled capsaicin in mild allergic asthmatics after 1 month of treatment with DSM‐17938 compared with matched placebo. Randomization and allocation to trial group were carried out by a central computer system. Histamine skin prick testing, airway hyper‐responsiveness and inflammatory cells in induced sputum were measured at every visit. Blood was collected to extract PBMCs and stimulated with CD3/CD28 to ascertain the effects of DSM‐17938 /placebo on T‐cell cytokine responses. Results: Seventeen subjects were recruited and 15 completed the study (8 females, mean age 27.3 years). There was no difference in the change in maximum capsaicin‐evoked coughs (Emax) after treatment with L. reuteri DSM‐17938 compared with placebo [mean difference 2.07 coughs (95% CI −2.77 to 6.91, p =.38) or relative changes in geometric mean ratios for the dose evoking at least half the Emax (ED50) [1.05 (95% CI 0.31–3.58, p =.94)], concentration evoking 2 coughs (C2) [0.63 (0.26–1.53), p =.28] and 5 coughs (C5) [0.79 (0.25–2.50), p =.67]. There was no effect on histamine skin prick wheal size, intensity of itch sensation, methacholine PC20, airway inflammation or T‐cell responses after stimulation with CD3/CD28. There were no serious adverse events. One subject developed a mild upper respiratory tract infection and another mild transient nausea whilst on DSM‐17938. Conclusion: In this small study in adults with mild allergic asthma, we found no evidence that L. reuteri DSM‐17938 has any systemic effects on airway nerves, smooth muscle, sputum inflammatory cells, skin responses or T‐cell responses after oral consumption. Trial Registration: Clinicaltrials.gov Identifier: NCT03603522. [ABSTRACT FROM AUTHOR]

Background: Sex‐dependent discrepancies in prevalence and autoimmune markers are characteristics of Alzheimer's disease (AD). Using the 3xTg‐AD mouse model, we previously reported that adult males show early systemic autoimmunity along with behavioural dysfunction, altered epigenetic factors, and lack of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain AD‐like pathology and behaviour. The present study examines whether gonadal hormones play a role in the etiology of these traits in current cohorts of 3xTg‐AD mice. Method: 3xTg‐AD and wild‐type mice were gonadectomized or sham‐operated at 3 months of age. After behavioural phenotyping at 6 months of age, the animals were assessed for serologic markers of autoimmunity, T splenocyte distribution, molecular markers of AD pathology, and expression of genes and histone variants associated with neurodegeneration. Result: In female transgenic (AD) mice, gonadectomy resulted in reduced levels of circulating antinuclear/nucleosome autoantibodies and poorer spatial learning performance, but did not affect the T cell population. In contrast, in transgenic male animals, gonadectomy improved spatial memory and cognitive flexibility, diminished splenic CD8+ T cells, yet had no impact on anti‐nuclear/nucleosome autoantibodies. Sex hormone‐related effects on anti‐nucleosome autoantibodies led us to focus on histones. Gonadectomized AD females exhibited enhanced expression of mouse (m) and transgenic Mapt genes, consistent with reduced binding activity of the repressive histone variant macroH2A1 at the mMapt gene body, compared to their sham counterparts. In contrast, gonadectomized AD males showed reduced expression of App and H2afy genes, reduced cortical soluble Aβ42 levels, and increased macroH2A1 binding at the mPsen1 promoter, compared to sham‐operated AD males. Conclusion: Female sex hormones enhance autoimmunity and spatial learning, whereas male sex hormones may be detrimental to spatial memory, cognitive flexibility, and autoimmunity in young adulthood. Furthermore, female sex hormones increase expression of the Mapt gene, but have no effect on App expression or Aβ42 levels. Conversely, male sex hormones increase App expression and Aβ42 levels, but have no effect on tau expression. Our work suggests that gonadal hormones contribute to sex differences in autoimmunity, AD‐like pathology, and "cognitive" function in this model. Moreover, histone variants may contribute to sex‐specific differences in AD pathology. [ABSTRACT FROM AUTHOR]

ABSTRACT: This review covers the field of olfaction and chemosensation of odorants and puts this information into the context of interactions between microbes and behaviour; the microbiome–gut–brain axis (MGBA). Recent emphasis has also been placed on the concept of the holobiome which states that no single aspect of an organism should be viewed separately and thus must include examination of their associated microbial populations and their influence. While it is known that the microbiome may be involved in the modulation of animal behaviour, there has been little systematized effort to incorporate into such studies the rapidly developing knowledge of the wide range of olfactory systems. The classical olfactory system is evolutionarily conserved in multiple taxa from insects through to fish, reptiles and mammals, and is represented by the largest gene families in vertebrates. Mice have over 1000 different olfactory receptors and humans about 400. They are distributed throughout the body and are even found in spermatozoa where they function in chemotaxis. Each olfactory receptor has the unique functional capability of high‐affinity binding to several different molecular ligands. These and other properties render the cataloguing of odorants (odorome) with specific actions a difficult task. Some ectopic olfactory receptors have been shown to have functional effects in the gut and kidney, highlighting the complexity of the systems engaged by odorants. However, there are, in addition to classical olfactory receptors, at least two other families of receptors involved in olfaction that are also widely found expressed on tissues in many different organs in addition to the nervous system and brain: the trace‐amine associated and formyl peptide receptors. Bacteria can make many if not most odorants and are responsible for recognition of species and relative relatedness, as well as predator presence, among many other examples. Activation of different combinations of olfactory receptors by bacterial products such as β‐phenylethylamine have been shown even to control expression of emotions such as fear and aggression. The number of examples of bacterial products and volatile odorants influencing brain function and behaviour is expanding rapidly. Since it is recognized that many different bacterial products and metabolites also function as social cues, and may themselves be directly or indirectly causative of behavioural change, it becomes ever more important to include olfaction into studies of the MGBA. Clearly there are broader implications for the involvement of olfaction in this rapidly evolving field. These include improvement in our understanding of the pathways engaged in various behaviours, and the identification of novel approaches and new targets in efforts to modulate behavioural changes. [ABSTRACT FROM AUTHOR]

Ingestion of a commensal bacteria, Lactobacillus rhamnosus JB-1, has potent immunoregulatory effects, and changes nerve-dependent colon migrating motor complexes (MMCs), enteric nerve function, and behavior. How these alterations occur is unknown. JB-1 microvesicles (MVs) are enriched for heat shock protein components such as chaperonin 60 heat-shock protein isolated from Escherichia coli (GroEL) and reproduce regulatory and neuronal effects in vitro and in vivo. Ingested labeled MVs were detected in murine Peyer's patch (PP) dendritic cells (DCs) within 18 h. After 3 d, PP and mesenteric lymph node DCs assumed a regulatory phenotype and increased functional regulatory CD4+25+Foxp3+ T cells. JB-1, MVs, and GroEL similarly induced phenotypic change in cocultured DCs via multiple pathways including C-type lectin receptors specific intercellular adhesion molecule-3 grabbing non-integrin-related 1 and Dectin-1, as well as TLR-2 and -9. JB-1 and MVs also decreased the amplitude of neuronally dependent MMCs in an ex vivo model of peristalsis. Gut epithelial, but not direct neuronal application of, MVs, replicated functional effects of JB-1 on in situ patch-clamped enteric neurons. GroEL and anti-TLR-2 were without effect in this system, suggesting the importance of epithelium neuron signaling and discrimination between pathways for bacteria-neuron and -immune communication. Together these results offer a mechanistic explanation of how Gram-positive commensals and probiotics may influence the host's immune and nervous systems. [ABSTRACT FROM AUTHOR]

Probiotics are live non-pathogenic commensal organisms that exert therapeutic effects in travellers’ diarrhea, irritable bowel syndrome and inflammatory bowel disease. Little is known about mechanisms of action of commensal bacteria on intestinal motility and motility-induced pain. It has been proposed that probiotics affect intestinal nerve function, but direct evidence for this has thus far been lacking. We hypothesized that probiotic effects might be mediated by actions on colonic intrinsic sensory neurons. We first determined whether sensory neurons were present in rat colon by their responses to chemical mucosal stimulation and identified them in terms of physiological phenotype and soma morphotype. Enteric neuron excitability and ion channel activity were measured using patch clamp recordings. We fed 109 Lactobacillus reuteri (LR) or vehicle control to rats for 9 days. LR ingestion increased excitability (threshold for evoking action potentials) and number of action potentials per depolarizing pulse, decreased calcium-dependent potassium channel (IKCa) opening and decreased the slow afterhyperpolarization (sAHP) in sensory AH neurons, similar to the IKCa antagonists Tram-34 and clotrimazole. LR did not affect threshold for action potential generation in S neurons. Our results demonstrate that LR targets an ion channel in enteric sensory nerves through which LR may affect gut motility and pain perception. [ABSTRACT FROM AUTHOR]

Asthma, a chronic inflammatory disease of the airways, is greatly influenced by psychosocial factors and stress. This review looks at clinical studies that have shown strong associations between psychological stress and asthma to identify potential mechanisms for these interactions. Furthermore, we review animal studies involving stress and airway inflammation or airway hyperresponsiveness, and discuss possible mechanisms of stress action in asthma. In conclusion, further research, both in humans and in animal models, into the mechanisms of stress-induced changes in asthma exacerbation are required to help better understand the complex makeup of asthma and assist in the development of therapies directed at the interplay between the nervous system and airway inflammation. [ABSTRACT FROM AUTHOR]