Editor’s note: The International Association for the Study of Pain’s 16th World Congress on Pain took place from September 26-30, 2016, in Yokohama, Japan. Nearly 4,500 pain researchers and clinicians from around the world attended a plethora of plenary lectures, workshops, and posters. Below is a summary of a plenary lecture delivered by John Cryan, University College Cork, Ireland, on the role of the microbiome in visceral pain.
Visceral pain is a hallmark symptom of irritable bowel syndrome (IBS) and is severely debilitating, affecting up to 25 percent of the population at any one time. In “The Gut Microbiota―A Key Regulator of Visceral Pain,” a plenary lecture delivered at the 2016 IASP World Congress on Pain, John Cryan of University College Cork, Ireland, addressed how early life disturbances in gut microbiota can have enduring effects on pain responses.
Cryan highlighted that the human gut harbors a dynamic and complex microbial ecosystem, consisting of approximately three pounds of bacteria in the average adult, equivalent to the weight of the human brain. Genes within the human gut microbiota, termed the microbiome, significantly outnumber human genes in the body and are capable of producing a myriad of neuroactive compounds.
The microbiome-gut-brain axis is a complex system including the central nervous system (CNS), the neuroendocrine and neuroimmune systems, both the sympathetic and parasympathetic limbs of the autonomic nervous system, the enteric nervous system (ENS), and, of course, the gut microbiome. Signaling along the axis is facilitated by a complex reflex network of afferent fibers projecting to integrative cortical CNS structures and efferent projections to the smooth muscle in the intestinal wall. These pathways allow the brain to influence the motor, sensory, autonomic, and secretory functions of the gastrointestinal tract. These same connections also allow the gastrointestinal tract to modulate brain function reciprocally.
The role of stress
According to Cryan, the proposed role of the gut microbiota in this two-way communication remains ill defined. Our gut microbiome has a hand in virtually all aspects of normal physiological processes including those immunological features that impact the gut-brain axis. Interestingly, in the context of IBS as a stress-related disorder, the composition of the gut microbiota can be influenced by stressors, and the gut microbiome can itself regulate the host endocrine repertoire.
Stress impacts greatly on virtually all aspects of gut physiology relevant to IBS including motility, visceral perception, gastrointestinal secretion, and intestinal permeability while also having negative effects on the intestinal microbiota. A maladaptive stress response may thus be fundamental to the initiation, persistence, and severity of symptoms in IBS as well as stress-related psychiatric comorbidities (Kennedy et al., 2014).
Cryan said that adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to IBS. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. Early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS. The microbiome is also an epigenetic modifier. Microbial metabolites can influence epigenetics by altering the pool of compounds used for modification or by direct inhibition of enzymes involved in epigenetic pathways.
The microbiome and visceral pain: All roads lead to Vagus
A complex set of interactions among the microbiome, gut, and brain modulate visceral pain responses. These interactions occur at the level of the gastrointestinal mucosa, and via local neural, endocrine, or immune activity, as well as by the production of factors transported through the circulatory system, such as bacterial metabolites or hormones. Various psychological, infectious, and other stressors can disrupt this harmonious relationship and alter both the microbiome and visceral pain responses.
There are critical sensitive periods that can impact visceral pain responses in adulthood. The absence of gastrointestinal (GI) bacteria, such as that which occurs in germ-free mice, is associated with reduced perception of pain following different inflammatory stimuli. Furthermore, modulation of the intestinal microbiome by administration of various probiotics also has been shown to alter pain responses (Mayer et al., 2014). Early-life antibiotic administration increases visceral pain in adulthood. Hence, germ-free animals have increased visceral hypersensitivity.
The vagus nerve is possibly the major modulatory nervous pathway between the brain and the probiotic bacteria in the gut. Studies have shown that anxiety-related behavior was reduced after probiotic treatment, as long as vagus nerve integrity was maintained (Bravo et al., 2011). Hence, Cryan concluded that “What happens in Vagus does not stay in Vagus,” and that the future may bring “crapsules” to “crapulate” sterile guts to treat visceral hyperalgesia.
In the 20th century, the motto was to kill microbiomes with antibiotics. In the 21st century, we may be looking at using microbiomes to treat visceral pain, stress disorders, and mood symptoms. Cryan left the audience with the thought that the state of gut will affect the state of mind.
Genevieve D’souza, MD, is a pediatric pain specialist and an assistant professor in the Department of Anesthesiology, Critical Care and Pain Medicine at Stanford University, US.
Image: International Association for the Study of Pain