The Microbiome Visceral pain: role of the microbiome-gut-brain axis Kieran Rea, Siobhain M. A growing body of preclinical and clinical evidence supports a relationship between the complexity O’ Mahony, Timothy G. and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiome) Dinan and John F. Cryan and health status. These microbes can influence centrally regulated emotional behaviour Downloaded from http://portlandpress.com/biochemist/article-pdf/39/2/6/852131/bio039020006.pdf by guest on 01 October 2021 (University College Cork, through mechanisms including microbially derived bioactive molecules, mucosal immune and Ireland) 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. Pain is an unpleasant experience combining a sensory central nervous system (CNS). Of interest, there is component with a complex emotional response. substantial overlap in the brain areas underlying This physiological survival mechanism is conserved visceral pain and those that are involved in the throughout evolution to protect against potential or processing of psychological stress, a key predisposing existing tissue damage. While the anatomical pathways factor for visceral hypersensitivity. and signalling mechanisms involved in pain signalling from skin and deep tissue are relatively well defined, Visceral pain pathways the mechanisms underlying pain from internal organs (visceral pain) and its treatment are proving a difficult After an event such as injury, stress or infection, the target for therapeutic intervention. Visceral pain is sensory information coding for visceral pain is sent believed to affect up to 40% of the population at some from the site of origin to the spinal cord, and then stage in their lifetime and is commonly associated with through ascending spinal and vagus nerve pathways an aching or throbbing sensation with varying degrees to the brain. Pain receptors in the viscera respond of discomfort, and is often difficult to localize to a to mechanical stimulation such as distension or precise anatomical region. pressure, tissue damage and chemical stimulation as a Although visceral pain disorders include consequence of inflammation, infection or ischaemia. myocardial infarction (heart attack), dysmenorrhoea, These receptors are localized on bare nerve endings appendicitis, bladder pain and pelvic pain it is the containing transient receptor potential (TRP) functional gastrointestinal disorders (FGIDs) including channels that detect tissue damage or injury. Agents irritable bowel syndrome (IBS) that represent the more that activate TRP channels include globulin, protein common forms of visceral pain. IBS alone affects an kinases, arachidonic acid, prostaglandins, histamine, estimated 10–15% of the population in developed nerve growth factor, substance P, calcitonin gene- countries with an estimated economic burden to related peptide, serotonin, acetylcholine, ATP and healthcare systems in the billions. changes in pH. The perception of visceral pain and discomfort At the dorsal horn of the spinal cord, biochemically from the gastrointestinal tract involves complex active agents including substance P, glutamate, mechanisms. These include sensitization of sensory aspartate, vasoactive intestinal peptide (VIP), nerves in the periphery, and dysregulation of thalamic cholecystokinin (CCK), somatostatin, calcitonin and corticolimbic signalling pathways within the gene-related peptide (CGRP) and galanin are released 6 April 2017 © Biochemical Society The Microbiome from the nerve terminals of the visceral primary Brain Cortex Central Processing afferents to send the nociceptive signal to second order Hippocampus Thalamus Ascending aerent Brain neurons. Under normal physiological conditions, these Amygdala nociceptive signalling Hypothalamus neurons are under ‘gated’ control. However, once a Corticolimbic-mediated certain threshold of stimulation is exceeded, these Midbrain top-down regulation of PAG descending pain pathway neurons are no longer suppressed and the nociceptive information coding for general location and intensity Medulla !! ! !! projects to supraspinal sites. The two major ascending !!! !! RVM pain pathways in mammals are the spinothalamic ! and the spinoparabrachial tracts, which encode the Amines (histamine, sensory-discriminatory and affective aspects of pain 5-hydroxytryptamine), bradykinin, ions, respectively. Once the nociceptive information has Vagus inammatory cytokines, nerve Downloaded from http://portlandpress.com/biochemist/article-pdf/39/2/6/852131/bio039020006.pdf by guest on 01 October 2021 been processed in the CNS, the descending pathways substance P (from brain to spinal cord) can exert an inhibitory or Spinal cord facilitatory effect on the sensation of pain. Sensitization Gastro- NPs Cytokines of pain receptors, as a consequence of repeated or SCFAs + intestinal Microbial NTs prolonged activation, can lead to chronic, and often by-products Tract unpredictable bouts of visceral pain. Thus, by targeting / T Cell T Cell EEC Cell DC B Cell DC key bioactive chemicals or receptor systems on these B Cell sensory afferent neurons, the sensation of visceral pain Epithelium could be significantly ameliorated. More recently, a Lumen new player has emerged in the regulation of visceral Microbiome pain signals – the gut microbiome. The microbiome Microbiome regulation of visceral pain The human gut harbours a complex and dynamic microbial ecosystem. We each harbour a unique microbiome signature of bacteria, archaea, yeasts, Microbiome and visceral pain single-celled eukaryotes, as well as helminth parasites and viruses, including bacteriophage. Under normal Sensitization of primary afferent nociceptors (pain homeostatic conditions, this microbial population receptors) may lead to visceral hypersensitivity in helps maintain intestinal peristalsis, mucosal integrity, FGIDs. A number of different receptor types are pH balance, immune priming and protection against involved in the process of peripheral sensitization invading pathogens. Numbering approximately 100 including the TRPV family, proteinase activated trillion, these microorganisms have an estimated receptors, cholecystokinin receptors, serotonin collective mass of 1–2 kg, approximately the same receptors, cannabinoid receptors, as well as an array weight as the human brain. Genes within the human of ion channels including ATP-gated ion channels, gut microbiome significantly outnumber host human voltage-gated sodium and calcium channels, and acid- genes and are capable of producing a plethora of sensing ion channels. The gastrointestinal microbiome centrally acting compounds, influencing virtually all can activate these receptors directly or indirectly aspects of human physiology and biology. through immune responses at the mucosal surface The microbiome-gut-brain axis is a complex during infection, inflammation and autoimmunity, bi-directional system including the CNS, the formyl peptides and protease release, polyunsatturated neuroendocrine and neuroimmune systems, the fatty acid (PUFA) release, short chain fatty acid autonomic nervous system, the enteric nervous (SCFA) production, neurotransmitter production and system (ENS), and, of course, the gut microbiome. hormone secretion. The gastrointestinal microbiome Through endocrine, immune and neuropeptide/ can also stimulate the release of the body’s natural neurotransmitter systems, the microbiome can pain-suppressing biomolecules including opioids from relay information about the health status of the gut. innate neutrophils and monocytes, endocannabinoids This in turn can profoundly impact upon neuronal from colonic tissue, as well as other pain modulators signalling in the brain and, as a result, impact including monoamines. Microbial metabolites can also emotional systems and behavioural response; thus, influence epigenetic mechanisms, by altering substrate visceral pain pathways are poised to be regulated by concentrations or by direct inhibiton of enzymatic the microbiome. machinery in epigenetic pathways. However, the extent April 2017 © Biochemical Society 7 The Microbiome to which these mechanisms either individually or collectively affect the aetiology of influence the gastrointestinal microbiome, in the FGIDs remains unaddressed. treatment of visceral sensitivity – provided vagus nerve From a physiological perspective relevant to IBS visceral sensitivity, stress can integrity is maintained. influence gut motility, alter gastroinestinal secretions and exacerbate