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Gut Feeling

Credit: BrianAJackson/iStockphoto

Credit: BrianAJackson/iStockphoto

By Nicholas Talley

Does indigestion lead to anxiety and other mood disorders, and could a cure be in sight for both?

Eating is one of the most fundamental experiences we share, but it’s not without risk. Every time we eat we put several foreign substances into our body that may or may not hurt us, including bacteria and substances that may cause an allergic reaction. The stomach kills harmful bacteria – one of the reasons it produces acid that could scald our skin if applied – relaxes after we eat so we feel pleasantly full and stop eating, and moves the food into the upper intestine without us having to think about it at all.

The gastrointestinal nerves and muscles are silently controlled by a very complex system located in the wall of the stomach and bowel. Sometimes called the “second brain”, it connects to the big brain in the head via large nerve fibres.

We don’t usually feel the movement of food through our intestine, although sometimes we do hear noises or pass gas. Nor is digestion typically felt or sensed; often the only clue our system is working normally is that we feel comfortable but then gradually start to look forward to our next meal.

Enzymes and bacteria quietly break down the food, and we absorb the nutrients and vitamins until just the waste products remain. These move through the bowel and are expelled.

From time to time, however, this system becomes dysfunctional. For some people, eating turns from a pleasure into a pain – or worse.

Everyone occasionally suffers with indigestion, but people of any age can develop a stomach disease that makes them feel really full and uncomfortable or bloated after eating. These people can’t eat normally anymore, and this can happen after every meal. Sometimes pain also then develops in the pit of the stomach (just below the breast bone), and nausea may be felt too. A burning sensation can also be experienced in the belly, sometimes travelling up into the chest.

These common abdominal symptoms signal the presence of indigestion, or what doctors often call dyspepsia. Up to 10% of Australians suffer with symptoms after they eat, and quality of life can be severely impaired, which is why you see so many over-the-counter remedies in the pharmacy. But the cause of more than 70% of cases of severe indigestion has until recently remained a mystery. Doctors rather confusingly call this mysterious disorder “functional” dyspepsia (“functional” meaning that the stomach and upper intestine are thought to be no longer functioning normally.) Other conditions like a stomach ulcer can cause similar symptoms, but ulcers are much less common than functional dyspepsia.

We can all develop “stomach butterflies” or “nervous indigestion” when under acute stress or become very anxious, and people with chronic stomach troubles diagnosed as functional dyspepsia often feel very anxious or depressed too, and they may sleep poorly and feel fatigued. Doctors have therefore surmised that the mood problems must be a direct cause of the stomach symptoms they experience after eating.

But what if it’s the other way around? What if, in some cases, there is an underlying problem that leads to symptoms we call functional dyspepsia, and this stomach problem causes alterations in the brain that manifest as anxiety, depression or fatigue? There is now such evidence emerging, leading to the exciting possibility we may be able to fix not only indigestion but also mood disorders in some people.

When you look down into the stomach and upper intestine with an endoscope in a patient with functional dyspepsia it looks normal. But is it? We asked ourselves if we could be missing subtle microscopic changes overlooked by pathologists in the small tissue biopsies taken through the endoscope.

Think about even a really small skin boil, and remember how red, painful and unpleasant this can be because of the inflammation from the cells and chemicals marshalled into the small area. Could similar inflammation have been missed in the intestine?

This has happened before. Pathologists routinely failed to see the bacteria that cause stomach ulcers and stomach cancer and the inflammation all around the bacteria was ignored, even though the findings were all plain to see in the biopsy tissue – you tend to see what you expect and are trained to see, and no more! Only after Robin Warren and Barry Marshall in Perth published their discovery of the bacterium Helicobacter pylori did other pathologists start noticing them. Marshall and Warren won the Nobel prize for their discovery.

So we undertook a unique study in northern Sweden, inviting people from a local community during the winter when there was not much to do to visit a local clinic and have a free look down into the stomach, including taking tissue biopsies (which is painless). All we offered was a free T-shirt, yet 80% of those approached agreed to take part in the study. We enrolled 1000 volunteers, whether they had bad stomach symptoms or none at all. And we looked very carefully at the biopsies, in particular the samples from the upper intestine because we suspected we would find increased cells that would signal the presence of a specific type of allergic inflammation.

We were right: we found that pathologists had been missing subtle changes in the upper intestine. When we counted the number of cells in the duodenum there were increased numbers of eosinophils. These special white blood cells are normally recruited to help fight parasites and inflammation but are also seen in allergic conditions.

In studies from around the world, including in Australia, we have confirmed these findings. We had discovered a new disease in adults that appeared to account for a large number of cases of the mysterious disorder functional dyspepsia, which we have renamed duodenal eosinophilia. The pathology we can observe is a bit like the microscopic changes seen in the lung in cases of allergic asthma.

We now have evidence that the eosinophils in people with functional dyspepsia can break down and release toxic products near nerves in the gut. This must alter the functioning of the nerve and muscle, leading to symptoms.

Circulating chemicals called cytokines are released into the bloodstream too. Cytokines make you feel sick and tired, and the circulating cytokines we observed are strongly linked to anxiety in people with abdominal troubles.

In other words, we now have direct evidence that changes in the upper intestine near the stomach are likely to cause brain symptoms such as anxiety and possibly fatigue and sleep disturbances.

In long-term follow up studies of people with and without symptoms, we have observed that some people will develop new stomach symptoms and then, for the first time ever, develop anxiety, providing further evidence that a stomach disturbance can be the cause of brain symptoms.

It goes the other way too. Anxiety can develop initially and then the stomach symptoms can begin after stomach function becomes newly disturbed. Knowing what happens first may help doctors decide whether to treat the stomach or the brain initially.

Having discovered that cells linked to allergy are present in functional dyspepsia, we have found that people with these same indigestion symptoms are also more likely to suffer with asthma or allergic skin rashes. Certain foods people eat, like wheat, may be important in setting off the intestinal inflammation in some cases, although proving that wheat intolerance is a cause has not yet been completed.

We have also observed that people exposed to horses or similar pets are more at risk of developing bad indigestion, implicating parasites or other infections as a cause of allergic inflammation of the intestine.

Those who develop acute bacterial gastroenteritis, which usually starts with sudden severe vomiting and diarrhoea, are also at much higher risk of developing functional dyspepsia long-term.

And finally, if you develop this allergic inflammation in the upper intestine, the stomach fails to relax normally in some cases. This may lead to the muscle around the lower end of the oesophagus relaxing when it should not, allowing stomach acid to move up and cause yet another common problem: acid reflux.

A thrilling area in medical science at the moment is the realisation we are all only part-human: more than 100 trillion bugs live in our mouth, intestines, skin and elsewhere, equating to ten times the number of human cells in our body. These living organisms are not passive passersby; they almost certainly do things with us and to us, including preventing or causing disease depending on the circumstances.

Our latest data indicate that the bacteria in the upper intestine are different in people with functional dyspepsia, and we are working to understand the implications. It may be that disturbances in the bacteria in some cases alter intestinal inflammation, and this leads to brain dysfunction and then anxiety or depression. If so, manipulating these organisms or replacing the bad bacteria with good ones may allow a return to health for those with chronic gut and mental health problems. Animal model experiments support these assumptions, but much more work will be needed to devise the best approaches going forward.

Do you often feel full soon after eating most meals and can’t finish a normal-sized meal? Or do you often feel really bloated and uncomfortable after a meal, or suddenly develop pain or a burning sensation in the pit of your stomach after eating? What should you do if you think you or a loved one might have functional dyspepsia because of these symptoms?

Asking your doctor to evaluate you is the sensible first step as there are other less common causes of these symptoms. And if you do have functional dyspepsia, there is hope that new treatments aimed at allergic inflammation in the upper intestine may help to relieve the symptoms in the gut and perhaps the brain. For example, the allergic gut inflammation may respond to certain anti-asthma drugs that stop eosinophils from causing harm. We are currently conducting a clinical trial of a locally acting drug that dampens inflammation.

The stomach and bowel are easier to reach and manipulate than the brain. Doing so looks likely to open the door to new health possibilities for us all.

Nicholas Talley is Laureate Professor of Medicine at The University of Newcastle.