Visceral pain: role of the microbiome-gut-brain axis

A growing body of preclinical and clinical evidence supports a relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiome) and health status. These microbes can influence centrally regulated emotional behaviour through mechanisms including microbially derived bioactive molecules, mucosal immune and enteroendocrine cell activation, as well as vagal nerve stimulation. Changes to the microbial environment, as a consequence of illness, stress or injury can lead to a broad spectrum of local physiological and behavioural effects including a decrease in gut barrier integrity, altered gut motility, inflammatory mediator release, as well as nociceptive and distension receptor sensitization. Impacts at a central level include alterations in the hypothalamic-pituitary-adrenal axis, neuroinflammatory events and concomitant changes to neurotransmitter systems. Thus, both central and peripheral pathways associated with pain manifestation and perception are altered as a consequence of the microbiome-gut-brain axis imbalance. The dogmatic approach of antibiotic treatment in the latter century, for the treatment of many diseases and conditions, has undergone a radical change. We are 90% microbe, and pragmatism suggests that we manipulate this ecosystem for the treatment of various ailments, stress dysfunction and affective disorders, including the alleviation of visceral pain

High and Mighty? Cannabinoids and the microbiome in pain

Within the human gut, we each harbour a unique ecosystem represented by trillions of microbes that contribute to our health and wellbeing. These gut microbiota form part of a complex network termed the microbiota-gut-brain axis along with the enteric nervous system, sympathetic and parasympathetic divisions of the autonomic nervous system, and neuroendocrine and neuroimmune components of the central nervous system. Through endocrine, immune and neuropeptide/neurotransmitter systems, the microbiota can relay information about health status of the gut. This in turn can profoundly impact neuronal signalling not only in the periphery, but also in the brain itself and thus impact on emotional systems and behavioural responses. This may be true for pain, as the top-down facilitation or inhibition of pain processing occurs at a central level, while ascending afferent nociceptive information from the viscera and systemic areas travel through the periphery and spinal cord to the brain. The endogenous cannabinoid receptors are ubiquitously expressed throughout the gut, periphery and in brain regions associated with pain responding, and represent targets for endogenous and exogenous manipulation. In this review, we will focus on the potential role of the endogenous cannabinoids in modulating microbiota-driven changes in peripheral and central pain processing. We also focus on the overlap in mechanisms whereby commensal gut microbiota and endocannabinoid ligands can regulate inflammation and further aim to exploit our understanding of their role in microbiota-gut-brain axis communication in pain processing

Gut microbiome patterns depending on children's psychosocial stress : reports versus biomarkers

Aim: Chronic stress increases disease vulnerability factors including inflammation, a pathological characteristic potentially regulated by the gut microbiota. We checked the association between the gut microbiome and psychosocial stress in children/adolescents and investigated which stress parameter (negative versus positive emotion, self-report versus parental report, events versus emotions, biomarker cortisol versus parasympathetic activity) is the most relevant indicator herein. Methods: Gut microbiome sequencing was completed in fecal samples from 93 Belgian 8-16y olds. Stress measures included negative events, negative emotions, emotional problems reported by parents, happiness, hair cortisol and heart rate variability (pnn50 parameter reflecting parasympathetic activity). Alpha diversity, beta diversity and linear discriminant analysis were the unadjusted analyses. Age, sex, socio-economic status, diet, physical activity, sleep and weight status were adjusted for via a redundancy analysis and differential abundance via zero-inflated negative binomial regression. Results: High stress as reflected by low pnn50 and more negative events were associated with a lower alpha diversity as indicated by the Simpson index. Happiness and pnn50 showed significant differences between high and low stress groups based on weighted UniFrac distance, and this remained significant after confounder adjustment. Adjusted and unadjusted taxonomic differences were also most pronounced for happiness and pnn50 being associated respectively with 24 OTU (=11.8% of bacterial counts) and 31 OTU (=13.0%). As a general pattern, high stress was associated with lower Firmicutes at the phylum level and higher Bacteroides, Parabacteroides, Rhodococcus, Methanobrevibacter and Roseburia but lower Phascolarctobacterium at genus level. Several genera gave conflicting results between different stress measures e.g. Ruminococcaceae UCG014, Tenericutes, Eubacterium coprostanoligenes, Prevotella 9 and Christensenellaceae R7. Differential results in preadolescents versus adolescents were also evident. Conclusion: Even in this young healthy population, stress parameters were cross-sectionally associated with gut microbial composition but this relationship was instrument specific. Positive emotions and parasympathetic activity appeared the strongest parameters and should be integrated in future microbiota projects amongst other stress measures

The antimicrobial capacity of embalming solutions: a comparative study

Aims: Infectious health risks are associated with handling human cadavers and to decrease such risks, cadavers are embalmed using different chemicals. The aim of this study is to quantify the amount of microorganisms present in different regions of human cadavers before embalming, after embalming and over a period of eight months. Methods and Results: Human cadavers were embalmed using Thiel, formalin, Genelyn and the Imperial College London soft-preservation (ICL-SP) solution with two cadavers per technique. Sterile swabs were used to collect samples from different regions. Samples were collected every two months. All cadavers had a high number of microbial colonies before embalming. While no colonies were detected on formalin and Genelyn embalmed cadavers post embalming, the number of colonies decreased significantly in Thiel embalmed cadavers and nearly stayed the same in ICL-SP embalmed cadavers. Conclusions: Formalin embalmed cadavers showed the strongest disinfecting abilities followed by Thiel embalmed cadavers, then Genelyn embalmed cadavers and finally by ICL-SP cadavers. Significance and Impact of Study: This study highlights how under researched this area is and the evident variation in the antimicrobial abilities of different embalming solutions on the cadaver as a whole and within different regions of the same cadaver

Pain bugs: Gut microbiota and pain disorders

The microbiota-gut–brain axis is a complex and dynamic multi-directional ‘communication superhighway’ within the body including the central nervous system, the autonomic nervous system, the neuroendocrine and neuroimmune systems, the lymphatic system, the enteric nervous system and the gastrointestinal microbiota. The mechanisms of communication are slowly being unravelled and involve the main systems mentioned along with the by-products produced such as neuropeptides, neurotransmitter, hormones and immune modulators. Over the last decade increasing evidence points to an essential role of this axis in many fundamental neural processes and brain disorders. However, the limited clinical and preclinical studies do not clearly delineate a role for gut microbiota in the pathophysiology of pain state. The most researched area is in irritable bowel syndrome and in visceral pain studies in animal models. However, one cannot overlook the involvement of the microbiota in symptoms that are comorbid with chronic pain especially affective disorders. In this review we synthesise the available information highlighting the gut microbiota in visceral, inflammatory, and neuropathic pain states, including fibromyalgia, migraine, cancer and chemotherapy-associated pain. Given its part in many effector systems, there is a clear need for more focused investigations on the mechanism of action of the microbiota in human pain states, as current treatment strategies are often ineffective or provide limited relief

Estrous cycle and ovariectomy-induced changes in visceral pain are microbiota-dependent

Visceral hypersensitivity (VH) is a hallmark of many functional gastrointestinal disorders including irritable bowel syndrome and is categorized by a dull, diffuse sensation of abdominal pain. Recently, the gut microbiota has been implicated in VH in male mice, but the effects in females have yet to be explored fully. To this end, we now show that somewhat surprisingly, female germ-free mice have similar visceral pain responses to colorectal distension (CRD) as their conventional controls. However, we show that although sensitivity to CRD is estrous cycle stage-dependent in conventional mice, it is not in germ-free mice. Further, ovariectomy (OVX) induced VH in conventional but not germ-free mice, and induced weight gain regardless of microbiota status. Finally, we show that estrogen-replacement ameliorated OVX-induced VH. Taken together, this study provides evidence for a major role of female sex hormones and the gut microbiota in sensation of visceral pain in females.Funding: This work was funded by Science Foundation Ireland through the Irish Government’s National Development Plan in the form of a center grant (APC Microbiome Institute Grant Number SFI/12/RC/2273_P2)

Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: Effects of early-life stress

Background: Early-life stress (ELS) is a recognized risk factor for chronic pain disorders, and females appear to be more sensitive to the negative effects of stress. Moreover, estrous cycle-related fluctuations in estrogen levels have been linked with alternating pain sensitivity. Aberrant central circuitry involving both the anterior cingulate cortex (ACC) and the lumbosacral spinal cord has also been implicated in the modulation of visceral pain in clinical and preclinical studies. Here we further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS. Methods: We investigated visceral sensitivity in adult female Sprague-Dawley rats, which had undergone maternal separation (MS) in early life or remained non-separated (NS), by performing colorectal distension (CRD). We also assessed excitatory amino acid uptake through excitatory amino acid transporters (EAATs) in the lumbosacral spinal cord and ACC. Results: NS animals in proestrus and estrus exhibited reduced EAAT uptake and decreased threshold to CRD. Moreover, total pain behaviors were increased in these stages. MS rats exhibited lower pain thresholds and higher total pain behaviors to CRD across all stages of the estrous cycle. Interestingly, cortical EAAT function in MS rats was inhibited in the low estrogen state—an effect completely opposite to that seen in NS rats. Conclusions: This data confirms that estrous cycle and ELS are significant factors in visceral sensitivity and fluctuations in EAAT function may be a perpetuating factor mediating central sensitization

Toll-Like Receptor mRNA Expression Is Selectively Increased in the Colonic Mucosa of Two Animal Models Relevant to Irritable Bowel Syndrome

Background: Irritable bowel syndrome (IBS) is largely viewed as a stress-related disorder caused by aberrant brain-gut– immune communication and altered gastrointestinal (GI) homeostasis. Accumulating evidence demonstrates that stress modulates innate immune responses; however, very little is known on the immunological effects of stress on the GI tract. Toll-like receptors (TLRs) are critical pattern recognition molecules of the innate immune system. Activation of TLRs by bacterial and viral molecules leads to activation of NF-kB and an increase in inflammatory cytokine expression. It was our hypothesis that innate immune receptor expression may be changed in the gastrointestinal tract of animals with stressinduced IBS-like symptoms. Methodology/Principal Findings: In this study, our objective was to evaluate the TLR expression profile in the colonic mucosa of two rat strains that display colonic visceral hypersensivity; the stress-sensitive Wistar-Kyoto (WKY) rat and the maternally separated (MS) rat. Quantitative PCR of TLR2-10 mRNA in both the proximal and distal colonic mucosae was carried out in adulthood. Significant increases are seen in the mRNA levels of TLR3, 4 & 5 in both the distal and proximal colonic mucosa of MS rats compared with controls. No significant differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in both rat strains. The WKY strain have increased levels of mRNA expression of TLR3, 4, 5, 7, 8, 9 & 10 in both the distal and proximal colonic mucosa compared to the control Sprague-Dawley strain. No significant differences in expression were found for TLR2 while as before TLR6 could not be detected in all samples in both strains. Conclusions: These data suggest that both early life stress (MS) and a genetic predisposition (WKY) to stress affect the expression of key sentinels of the innate immune system which may have direct relevance for the molecular pathophysiology of IBS

Microbiota and Neurodevelopmental Trajectories: Role of Maternal and Early-Life Nutrition

peer-reviewedPregnancy and early life are characterized by marked changes in body microbial composition. Intriguingly, these changes take place simultaneously with neurodevelopmental plasticity, suggesting a complex dialogue between the microbes that inhabit the gastrointestinal tract and the brain. The purpose of this chapter is to describe the natural trajectory of microbiota during pregnancy and early life, as well as review the literature available on its interaction with neurodevelopment. Several lines of evidence show that the gut microbiota interacts with diet, drugs and stress both prenatally and postnatally. Clinical and preclinical studies are illuminating how these disruptions result in different developmental outcomes. Understanding the role of the microbiota in neurodevelopment may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders

Relevance of anatomy to medical education and clinical practice: perspectives of medical students, clinicians, and educators

Introduction: Against a backdrop of ever-changing diagnostic and treatment modalities, stakeholder perceptions (medical students, clinicians, anatomy educators) are crucial for the design of an anatomy curriculum which fulfils the criteria required for safe medical practice. This study compared perceptions of students, practising clinicians, and anatomy educators with respect to the relevance of anatomy education to medicine. Methods: A quantitative survey was administered to undergraduate entry (n = 352) and graduate entry students (n = 219) at two Irish medical schools, recently graduated Irish clinicians (n = 146), and anatomy educators based in Irish and British medical schools (n = 30). Areas addressed included the association of anatomy with medical education and clinical practice, mode of instruction, and curriculum duration. Results: Graduate-entry students were less likely to associate anatomy with the development of professionalism, teamwork skills, or improved awareness of ethics in medicine. Clinicians highlighted the challenge of tailoring anatomy education to increase student readiness to function effectively in a clinical role. Anatomy educators indicated dissatisfaction with the time available for anatomy within medical curricula, and were equivocal about whether curriculum content should be responsive to societal feedback. Conclusions: The group differences identified in the current study highlight areas and requirements which medical education curriculum developers should be sensitive to when designing anatomy courses