Influence d'un traitement probiotique (Lactobacillus farciminis) sur les altérations de la sensibilité viscérale liées au stress : rôle de la barrière épithéliale colique

De nombreuses études précliniques et cliniques plaident en faveur de potentialités thérapeutiques des probiotiques en particulier vis-à-vis des pathologies digestives. Parmi ces pathologies le syndrome de l'intestin irritable (SII) souvent associé à des événements de vie stressants est caractérisé par une hypersensibilité viscérale associé à la distension de la paroi intestinale et une augmentation de la perméabilité intestinale. Bien que quelques études cliniques ont montré une efficacité des traitements probiotiques dans le SII, les effets ainsi que les mécanismes d'action des ces agents microbiens dans les anomalies sensitives viscérales restent très peu étudiés. Ainsi, l'objectif de ce travail était d'évaluer les effets, et les mécanismes d'action impliqués dans un traitement par une souche probiotique Lactobacillus farciminis sur l'hyperalgésie viscérale en réponse à une distension colorectale, induite par un stress aigu (stress de contrainte) chez le rat. Le choix de la souche a été basé sur des études précédentes ayant montré une efficacité d'un traitement par L. farciminis vis-à-vis d'une colite expérimentale et la douleur viscérale associée par un mécanisme d'action impliquant le monoxyde d'azote (NO) libéré par cette souche dans la lumière intestinale. Dans un premier temps nous avons montré que le stress de contrainte induit une augmentation de la perméabilité paracellulaire colique, par contraction du cytosquelette des cellules épithéliales via l'activation de la kinase de chaînes légères de myosine (MLCK) et que cette augmentation est responsable de l'hyperalgésie viscérale induite par le stress. Le traitement par L. farciminis diminue l'hyperalgésie viscérale, l'augmentation de la perméabilité paracellulaire colique et la phosphorylation de la MLC au niveau des colonocytes, induites par le stress. Cet effet antinociceptif implique également une action directe ou indirecte du NO libéré par ce probiotique dans la lumière intestinale. Enfin, nous avons montré que le stress aigu potentialise l'expression de la protéine c-Fos des neurones au niveau spinal et supraspinal induite par une distension colorectale. Le traitement par L. farciminis diminue cette potentialisation. L'ensemble de nos travaux montre que chez le rat, le traitement par L. farciminis diminue l'hyperalgésie viscérale en réponse à une distension colorectale induite par un stress aigu, via une diminution de la contraction du cytosquelette des cellules épithéliales et l'ouverture des jonctions serrées qui en résulte. Cette effet antinociceptif implique également un mécanisme NO dépendant et résulte d'une diminution de l'activation/sensibilisation des neurones sensitifs au niveau spinal et supraspinal induite par le stress. ABSTRACT : A large body of literature underlines potential beneficial effect of various probiotic strains in gastrointestinal diseases. Among these diseases, irritable bowel syndrome (IBS) frequently associated with psychological distress is characterized by hypersensitivity to intestinal wall distension and increased intestinal permeability. Despite some clinical evidence on positive effects of probiotics in IBS the role and mechanisms of action of these micro-organisms in visceral pain remains poorly investigated. The goal of this study was to determine the effect and mechanisms of action involved in a probiotic (Lactobacillus farciminis) treatment on visceral hypersensitivity in response to colorectal distension induced by an acute stress (restraint stress) in rats. The use of L. farciminis was based on previous studies showing that this strain improves an experimental colitis and reduces visceral hyperalgesia in colitis rats through the delivery of nitric oxide (NO) by this strain in the gut lumen. In a first part of this study, we have shown that restraint stress increases colonic paracellular permeability resulting from epithelial cell cytoskeleton contraction through myosin light chain kinase (MLCK) activation and this increase is responsible for stress-induced rectal hypersensitivity. L. farciminis treatment prevents stress-induced hypersensitivity, increase of colonic paracellular permeability and colonocyte MLC phosphorylation. This antinociceptive effect involves also a direct or indirect action of NO delivered intraluminally by this probiotic. Moreover we have shown that the restraint stress enhances c-Fos protein expression induced by colorectal distension in a spinal and supraspinal level, and L. farciminis treatment reduces this enhancement. Finally this work shows that L. farciminis treatment in rats, suppresses stressinduced visceral hypersensitivity in response to colorectal distension through an inhibition of the epithelial cell cytoskeleton contraction and the subsequent tight junction opening. This antinociceptive effect involves also a direct or indirect Nodependent action and results from a decrease in the stress-induced activation/sensitization of sensory neurons at the spinal or supraspinal level

Microbiota regulates visceral pain in the mouse

The perception of visceral pain is a complex process involving the spinal cord and higher order brain structures. Increasing evidence implicates the gut microbiota as a key regulator of brain and behavior, yet it remains to be determined if gut bacteria play a role in visceral sensitivity. We used germ-free mice (GF) to assess visceral sensitivity, spinal cord gene expression and pain-related brain structures. GF mice displayed visceral hypersensitivity accompanied by increases in Toll-like receptor and cytokine gene expression in the spinal cord, which were normalized by postnatal colonization with microbiota from conventionally colonized (CC). In GF mice, the volumes of the anterior cingulate cortex (ACC) and periaqueductal grey, areas involved in pain processing, were decreased and enlarged, respectively, and dendritic changes in the ACC were evident. These findings indicate that the gut microbiota is required for the normal visceral pain sensation

Basic and Translational Understandings of Microbial Recognition by Toll-Like Receptors in the Intestine

Microbial recognition by multicellular organisms is initially accomplished by a group of pattern recognition receptors which are specialized to recognize microbe-associated molecular patterns (MAMPs) such as lipopolysaccharide, bacterial lipoprotein, CpG DNA motif, double strand RNA and flagellin. Toll-like receptors (TLRs) are the representative pattern recognition receptors, and microbial recognition by TLRs elicits innate and inflammatory responses. Ten TLR family members have been presently identified in human genome, and numerous studies discovered that intracellular responses from MAMPs-TLR engagements are mediated by a participation of at least 4 immediate adaptor molecules such as myeloid differentiation primary response gene-88 (MyD88), MyD88 adaptor-like (Mal) (also known as Toll/IL-1 receptor domain-containing adaptor protein [TIRAP]), Toll/IL-1 receptor domain-containing adaptor-inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM) leading to activate transcription factors including nuclear factor κB, activator protein-1 and interferon-regulatory factors. Given that large amounts of commensal microbiota constantly reside in the intestinal lumen, enteric microbial recognition by TLRs at the intestinal epithelium provides a critical impact on regulating intestinal homeostasis. Indeed, aberrant TLR4 and TLR5 activations are etiologically associated with the development and progress of intestinal inflammatory diseases including inflammatory bowel disease and necrotizing enterocolitis. In this review article, we present the molecular mechanism by which TLRs elicit intracellular signal transduction, and summarize the physiological relevance of TLRs related to the gastrointestinal tract

Plasma Hormones Facilitated the Hypermotility of the Colon in a Chronic Stress Rat Model

Objective: To study the relationship between brain-gut peptides, gastrointestinal hormones and altered motility in a rat model of repetitive water avoidance stress (WAS), which mimics the irritable bowel syndrome (IBS). Methods: Male Wistar rats were submitted daily to 1-h of water avoidance stress (WAS) or sham WAS (SWAS) for 10 consecutive days. Plasma hormones were determined using Enzyme Immunoassay Kits. Proximal colonic smooth muscle (PCSM) contractions were studied in an organ bath system. PCSM cells were isolated by enzymatic digestion and IKv and IBKca were recorded by the patch-clamp technique. Results: The number of fecal pellets during 1 h of acute restraint stress and the plasma hormones levels of substance P (SP), thyrotropin-releasing hormone (TRH), motilin (MTL), and cholecystokinin (CCK) in WAS rats were significantly increased compared with SWAS rats, whereas vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and corticotropin releasing hormone (CRH) in WAS rats were not significantly changed and peptide YY (PYY) in WAS rats was significantly decreased. Likewise, the amplitudes of spontaneous contractions of PCSM in WAS rats were significantly increased comparing with SWAS rats. The plasma of WAS rats (100 ml) decreased the amplitude of spontaneous contractions of controls. The IKv and IBKCa of PCSMs were significantly decreased in WAS rats compared with SWAS rats and the plasma of WAS rats (100 ml) increased the amplitude of IKv and IBKCa in normal rats

'Gut health': a new objective in medicine?

'Gut health' is a term increasingly used in the medical literature and by the food industry. It covers multiple positive aspects of the gastrointestinal (GI) tract, such as the effective digestion and absorption of food, the absence of GI illness, normal and stable intestinal microbiota, effective immune status and a state of well-being. From a scientific point of view, however, it is still extremely unclear exactly what gut health is, how it can be defined and how it can be measured. The GI barrier adjacent to the GI microbiota appears to be the key to understanding the complex mechanisms that maintain gut health. Any impairment of the GI barrier can increase the risk of developing infectious, inflammatory and functional GI diseases, as well as extraintestinal diseases such as immune-mediated and metabolic disorders. Less clear, however, is whether GI discomfort in general can also be related to GI barrier functions. In any case, methods of assessing, improving and maintaining gut health-related GI functions are of major interest in preventive medicine

Using fish models to investigate the links between microbiome and social behaviour: the next step for translational microbiome research?

Recent research has revealed surprisingly important connections between animals’ microbiome and social behaviour. Social interactions can affect the composition and function of the microbiome; conversely, the microbiome affects social communication by influencing the hosts’ central nervous system and peripheral chemical communication. These discoveries set the stage for novel research focusing on the evolution and physiology of animal social behaviour in relation to microbial transmission strategies. Here, we discuss the emerging roles of teleost fish models and their potential for advancing research fields, linked to sociality and microbial regulation. We argue that fish models, such as the zebrafish (Danio rerio, Cyprinidae), sticklebacks (‎Gasterosteidae), guppies (Poeciliidae) and cleaner–client dyads (e.g., obligate cleaner fish from the Labridae and Gobiidae families and their visiting clientele), will provide valuable insights into the roles of microbiome in shaping social behaviour and vice versa, while also being of direct relevance to the food and ornamental fish trades. The diversity of fish behaviour warrants more interdisciplinary research, including microbiome studies, which should have a strong ecological (field‐derived) approach, together with laboratory‐based cognitive and neurobiological experimentation. The implications of such integrated approaches may be of translational relevance, opening new avenues for future investigation using fish models

International Society of Sports Nutrition Position Stand: Probiotics.

Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.GB Rogers, DJ Keating, RL Young, M-L Wong, J Licinio, and S Wesseling

Microbiome to Brain:Unravelling the Multidirectional Axes of Communication

The gut microbiome plays a crucial role in host physiology. Disruption of its community structure and function can have wide-ranging effects making it critical to understand exactly how the interactive dialogue between the host and its microbiota is regulated to maintain homeostasis. An array of multidirectional signalling molecules is clearly involved in the host-microbiome communication. This interactive signalling not only impacts the gastrointestinal tract, where the majority of microbiota resides, but also extends to affect other host systems including the brain and liver as well as the microbiome itself. Understanding the mechanistic principles of this inter-kingdom signalling is fundamental to unravelling how our supraorganism function to maintain wellbeing, subsequently opening up new avenues for microbiome manipulation to favour desirable mental health outcome