Machines: The Microbiome Part II
by John Atiken
There are at least two ways that bacteria may play a role in inflammatory bowel disease. The top of the Hit Parade at present is the gut microbiome.
Researchers, by using complex new technologies, can take a virtual snapshot of the bacterial DNA in the gut of the IBD patient (and in the normal patient, of course). Successful snapshots end up as publications if they demonstrate a difference in the gut microbiome between these two groups. If the IBD patient shows an abundance of a particular organism when it is not apparent in the control group, then this may indicate the presence of an organism capable of triggering an inflammatory reaction in the gut of the patient.
Over the last two years there have been a number of papers nominating suspected bacterial triggers:
And more specifically, Serratia marcescens, Candida tropicalis, various shades and colours of E. coli, Bacteriodes fragilis, Helicobacter hepaticus, Salmonella species, Campylobacter species, Clostridium difficile, and Mycobacterium avium ssp paratuberculosis to name but a few. Every month, it seems, a new suspect is identified on the basis of analysis of the gut bacteria.
All of this is well and good, and confirms an important milestone in research on Crohn’s disease; that researchers are prepared to think about the role of bacteria in inflammatory bowel disease, and have the equipment to tackle the question: Is Crohn’s disease associated with bacterial infection?
This imbalance of gut flora is thought by some to be the key to understanding how IBD starts, and it is a good theory. Alteration of the gut microflora can clearly be a factor in disease formation. Clostridium difficile is a good example. Salmonella infection is another.
The gut is a huge collection of nutrients, and they are available to any organism lucky enough to join the buffet table. There is enough for all. Removal of some of the gut bacteria, by antibiotics for example, will alter the balance and make room for new organisms.
There is a phenomenon known by microbiologists as competitive inhibition. It is similar to how a sports team works. Each team member occupies a key position and the whole team works together to defend the goal. If one member of the team is removed, then the team is weakened. Competitive inhibition simply explains how the mix of bacteria in the human body perfectly conforms to the requirement of the parts of the body needing protection from alien bacteria.
We know this because we see the results of removal of some bacteria with antibiotics or illness. The most common example is a yeast infection. Clostridium difficile is another. In both cases, the infecting organisms exploit an opening and expand their numbers to occupy vacant space.
Let’s look at all of this in terms of the human being. Bacteria produce specific metabolic products in the gut. These form part of the digestive process and can be absorbed by the gut and taken into the bloodstream. The host cannot control this, unless dietary changes are made or there is a change in the bacterial population. The gut microbiome is a machine, operating in response to the requirements of the body for internal harmony and provision of metabolic products. A change in this balance can be brought about by a number of different interventions, from gastrointestinal infection, to ongoing probiotic use, to faecal transplantation. The analysis of the organism makeup of the gut microbiome detects these changes.
But there is another effect lurking in the background. These organisms will produce metabolic products. We know little about this process in relation to IBD. Once you start thinking about this, however, questions bubble up.
- Does IBD affect the ability of the gut to fill the shopping order sent in by the body? (Yes)
- Are patients who use diet as an aid to achieving remission helping to make up the shortage of compounds required by the body? (Probably)
- Does FMT provide more workers for the overworked gut microbiome?
Whether or not Crohn’s disease is a consequence of an imbalance, there are worrying signs that the gut organisms are somehow involved. This does not exclude MAP as a cause, but raises the possibility that there complexities in the chain of events that lead to a flare-up, or onset of Crohn’s disease, that have so far escaped the attention of researchers.
There are other indirect indications that onset of disease is accompanied by multi-system variations, and these are often reported by patients. In simple terms, the factory in the gut goes onto overtime. This, in turn, may result in an oversupply. There is some debate, for example, as to whether mood swings may accompany and/or precede onset of a flare-up. Some authors suggest that an episode of depression may precede illness.
DNA profiling of the gut microbiome also highlights differences in the gut organisms of CD patients when compared to non-CD patients. I should note that the underlying problem with this approach to Crohn’s research results in the “finding” of a new proposed bacterial trigger every month or so. To put it another way, do the hotel tenants influence the state of the hotel? There is plenty of evidence to support this suggestion. However there is an old saying that “there are 13 ways to look at a blackbird, but the blackbird still doesn’t look back.” Researchers can come up with these observations, but where is the plan of attack? Can remission be achieved with dietary means?
It seems so. Apart from numerous accounts on the internet posted by Crohn’s patients, a recent report in the Journal of Clinical Gastroenterology outlined the response of 10 affected children to the specific carbohydrate diet therapy. All else aside, and pending confirmation in other studies, diet may play a role in naive Crohn’s disease patients. If repeated, then it is powerful evidence that manipulating the gut microbiome may exercise some influence over the inflammatory process. Therefore, changing the availability of specific nutrients may be a clinically indicated intervention.
To borrow from Lieutenant Columbo, (formerly of the LAPD), there is just one thing that bothers me. If the gut microbiome is triggering Crohn’s disease, then why has this not happened before now? We have been friends with our tummy bacteria for millennia, whereas the emergence of Crohn’s disease globally is a recent event. An epidemic, in fact. Seems a bit extreme to suddenly have a global shift in bowel flora of such magnitude that it is killing people. That seems odd to the Lieutenant and me. Not so much a strike in the factory but a world-wide revolution
I wrote above that there were at least two ways to trigger IBD. The second way is very simple, and involves the introduction of a causative organism. Crohn’s disease is characterised by specific changes in the gut (the pathological features) that indicate a diagnosis of Crohn’s disease. These changes can be triggered by known infecting bacteria and parasites. Examples include Yersinia pseudotuberculosis, Entamoeaba histolytica and Mycobacterium tuberculosis (TB). TB is known as the great mimic, and can cause a variety of different infective presentations.
Before the discovery of the TB bacillus, (Mycobacterium tuberculosis, MTB) there were many explanations as to what caused TB: lack of sunlight, “the consumptive personality”, overcrowding, excitability, poor diet, army service, ethnic origin, interfamily marriages, and low “index of vitality.” Understanding consumption was also complicated by the fact that not all people who contract TB will develop active disease. This is not a true carrier state, but represents the ability of the immune system to detect and control the primary infection.
Thanks to the sustained flashes of brilliance and the hard work of Robert Koch, the tubercle bacillus was discovered and described. His findings were confirmed throughout the world, and the suspect organism was inoculated into animals to reproduce the disease. In the light of Koch’s discovery, all of the diverse presentations and epidemiology of the disease of consumption could be explained and understood.
If all of this is hard to understand, then think of a splinter in the hand. The splinter becomes infected, and the wound is dressed. Despite the use of antiseptics at home, the infection gets worse. The white cell count rises; tissue is damaged, there is pus production, a fever develops, antibiotics are administered to fight the infection, sepsis develops and the clinical outcome for the patient becomes uncertain. Or the splinter could just be removed and the problem solved.
I believe that it is important to be able to hold two diametrically opposed propositions in the mind at the same time, and critically compare and contrast them. The resulting theory should be revisited in the light of new evidence. That approach works for crosswords, and other difficult problems.
Medicine, before the discovery of M. tuberculosis, saw TB as a multi-factorial disease with many causes. Retrospectively this view was revised.So the second explanation for Crohn’s disease could be a single organism. A single organism that the body is doing its best to try and control, by manipulation of the biochemical pathways of the body, and of the gut microbiome. An organism that has evolved to be difficult to detect and is able to utilize new ways to trigger inflammation.
Is that far too obvious?