Stress and inflammation: the missing link for IBS?

Is IBS  all in the mind or all in the gut?  Is it mainly the effect of stress or might infection, inflammation or disturbances in the colonic micro-biome be major factors.  Each have their supporters, but it seems that most reviewers acknowledge that all of the above are involved;  central factors such as the effect of life events and life situation interact with peripheral influences, such as the inflammatory responses to changes in the bacterial content of the colon to cause the typical symptoms of IBS.  The difficulty is: it is not clear what the mechanism might be.  The type of IBS that occurs after an attack of gastroenteritis provides a specific model to study this.

Post infectious IBS

One of the first documented reports of what might now be called post infectious IBS (then termed ‘post dysenteric colitis’) was documented in soldiers returning home from South-east Asia after the second world war.   Dr G.T. Stewart reported a group of patients, who continued to be ill with diarrhoea and abdominal pain often for years even though  there was no evidence of residual infection.   Since then the same illness has been observed after outbreaks of food poisoning, but only about 8 to 20% of people who have an attack of gastroenteritis, develop persistent symptoms resembling IBS.

I was intrigued to know why.  So in 1995, Dr Kok-Ann Gwee, recently arrived as a research fellow from Singapore, and I collaborated with Dr Michael McKendrick, Consultant in Infectious Diseases at The Royal Hallamshire Hospital in Sheffield to try to find out. Together we carried out a range of clinical, bacteriological, physiological and psychological tests on 104 consecutive patients admitted to the infectious disease ward with severe gastroenteritis. We followed these patients up for six months and found that 22 of them had persistent symptoms of diarrhoea and pain that resembled IBS, but without any evidence of active infection. We compared the results with patients, whose symptoms had recovered, in order to determine what factors might predict the development of IBS.

The data showed that there were more women than men with persistent symptoms and they had had a more severe attack of gastroenteritis, but the most striking difference between the two groups was that scores for anxiety, depression and traumatic life events at the outset of the infection were all greater in the group with persistent symptoms. It was as if the social and personal context of the attack of gastroenteritis had established a link between the mind and the gut. Or to put it another way:  like the symptoms of gastroenteritis had been recruited to express the unresolved stress.

A few years later, we published a follow up paper with Professor Steven Collins from McMaster University, Canada. This showed that the combination of psychological disturbance and gastroenteritis not only led to persistent symptoms of IBS, but was accompanied by low grade inflammation of the bowel and increases in pro-inflammatory ‘cytokines’ or cell to cell signalling molecules.

Our observations were confirmed in a much larger natural experiment. In May 2000, the highly dangerous 0157:H7 strain of E.coli seeped from an adjacent farm into the reservoir supplying water to the small town of Walkerton in Ontario. The deadly bacteria slipped through the maze of pipes into peoples’ homes. Unsuspecting residents drank the polluted water and bathed in tubs, ridden with bacteria. Over the next few weeks, 1,286 people suffered severe gastroenteritis with bloody diarrhoea. Over a third of these continued with persistent gut upset for several years. Analysis confirmed that, as in our study, these were more likely to be women who had a more severe infection and more anxiety and depression during the outbreak.

What happened in Walkerton constituted a major trauma in that quiet, rural community. Seven people died during the outbreak. Residents were not only fearful of their lives and the lives of their families but they were angry at the water engineers who allowed it to happen. Thus, it seems likely that the circumstances of the outbreak etched the experience on the brain as a traumatic memory that left them with a gut that was unusually sensitive and reactive.

Using post infectious IBS as a model to study the pathogenesis of IBS, several groups have demonstrated revealed that the combination of gastroenteritis and emotional stress instigates a cascade of events, making the gut more permeable, activating the gut immune system, accelerating the rate at which food travels through the gut, depleting populations of beneficial bacteria and acting on the gut brain axis to influence how we and our gut feels and reacts.

Immune modulation by the Autonomic Nervous System.

The missing link is the physiological mechanism by which psychological distress could lead to a persistence of the gastroenteritis-like symptoms?  I asked my friend and colleague, Professor Yan Yiannakou from the University of Durham, who alerted me to a paper that explained how the autonomic nervous system could modulate immune reactions.  The answer, according to this review lay in ‘the cytokine theory of illness’

Cytokines are a loosely defined group of signalling molecules that are predomantly released from immuno-reactive cells but also from cells lining the gut and other cell types. They modulate local inflammatory reactions to combat and isolate the infection, but they also act on the brain to more general signs of illness: fever, anorexia, lassitude and nausea. Cytokines are what cause a person to feel ill and rest while energy is diverted to the immune system to deal with the infection.

We all know it. If we are over-tired, stressed out, upset by what’s happened, not only are we more likely to get any infection that is going around, but any illness we get is likely to be more serious and last longer.

Gastroenteritis, like many other acute infections, only tends to last a few days. Then the inflammatory responses are damped down and the patient feels a lot better. For many years it was assumed that this suppression of immune reactivity was due to a combination of a reduction in cytokine release, the refractory nature of the immune response, the anti-inflammatory action of the release of steroid hormones and the production of anti-inflammatory cytokines, but now scientists have discovered an important pathway involving the autonomic nervous system. Nerve endings in the gut detect inflammatory stimuli (cytokines, bacterial endotoxins and bacterial cell wall lipopolysaccharides) and alert the brain stem via the afferent nerves from the gut. This then triggers signals that go down the efferent sympathetic and parasympathetic nerves to the gut, modulating the release of pro-inflammatory and anti-inflammatory cytokines. Similar reactions are likely to apply to anything that causes inflammation in the bowels and symptoms of IBS: instability of the microbiome,  small intestinal bacterial overgrowth, allergy, irritant effects of alcohol or bile acids.

This autonomic reflex is not only affected by the activity of the infection and the degree of cell damage, it is also likely to be modulated by influences from cerebral cortex.  In his Polyvagal Theory,  Professor Stephen Porges has proposed that our feelings are encoded in our body and mediated through activity in the different branches of the autonomic nervous system.  These are the sympathetic nerves which mediate an active (fight and flight) response to change and stress, the ventral division of the vagus nerve which facilitates confidence, calmness and social interaction and the dorsal division that mediates collapse and dissociation as a last ditch response to inescapable stress.  This would suggest that it is the activation of the ventral vagus that damps down the immune response, while continued stress activates the sympathetic nervous system and reduces activity in the ventral vagus nerve fibres to peripheral organs and tissues, maintaining the release of pro-inflammatory cytokines.  Symptoms of sepsis are said to be much worse if patients are stressed.  The same lack of suppression is observed if the vagus nerve has been cut.

Thus, activity in the autonomic nervous system modulates the inflammatory response, damping it down under restful conditions when it is no longer needed, and maintaining release of cytokines under conditions of stress and emotional upset.  So anything that impairs vagal function, such as emotional upset or cervical instability caused by Ehlers Danlos Syndrome or whiplash injury, would prevent the immune system from settling down after infection. Persistent immune activation might then lead to prolonged changes in permeability, pain perception, microbial composition, consolidating the signs and symptoms of chronic illness, such as IBS.

This would explain why patients with IBS as well as those with autoimmune disease (diabetes and rheumatoid arthritis) often show evidence of suppression of vagal activity and increase in sympathetic nervous activity.  It would also explain why meditation, mindfulness and hypnotherapy as well as vagal stimulation in the neck may calm down symptoms of IBS and other poorly explained disorders, such as migraine, epilepsy and fibromyalgia.