In the previous two posts we have established how the microbiome is established and then the pressures the host puts on it to maintain a balance between the required functions and the commensal bacteria providing them. In this post I want to look a little deeper at what happens if this balance is disturbed or never properly forms at all.
There are two scenarios where the balance is disturbed that we need to consider either way the person gets sick but how they et sick is important. Sickness can be caused by either a new pathogenic organism or an environmental change that results in the commensal bacteria becoming accidental or opportunistic pathogens. In both cases balance is lost at the epithelial layer, generally resulting in inflammation and disease. This loss of balance is commonly referred to as dysbiosis. It is also important to point out here that despite a previously romantic view of the association between the microflora and the gut the interaction is better described as a tense stand-off always on the precipice of collapsing.
Introduction of an invasive pathogen results in a global decrease in microbial numbers as well as a loss of microbial diversity with a marked relative increase in the populations of proteobateria. These same changes can be observed when inflammation of the gut is induced by the addition of T-cells targeting the gut epithelium suggesting it's not the pathogen but the inflammation that drives this microbiome change. This tells us pretty clearly that, as I said in the last post, while the bacteria indicates to the host whether it should be considered ‘good’ or ‘bad’ any inflammation will result in a purge by the host.
This purge will often remove the offending pathogens along with the majority of everything else but some pathogens require and even promote the purge as a survival and invasion mechanism. The E. coli strain LF82 is an opportunistic pathogen that would normally pass through the body without incident as it can only bind to inflamed epithelia. Without the inflammation the pathogen is of minimal concern so tempting of the immune system is all part of its life-cycle. Salmonella enterica serovar Typhimurium (SET) on the other hand will directly promote this purging response as it disrupts the commensal populations enough for it to generate a niche for itself to proliferate and bind at the disrupted and inflamed surface.
This inflammation is responsible for a huge number of diseases mainly because the inflammation is self perpetuating. The microbiome disruption allows for pathogens to establish themselves resulting in inflammation and more microbiome disruption. This cycle leads to chronic inflammation and inflammatory bowel disease (IBD). This can be corrected over time by re-population by commensal bacteria but if left long enough may induce very serious gastro-intestinal problems.
IBD and chronic inflammation can only occur if the host can’t turn off this inflammation and restore balance. This dysbiosis sometimes does not even resolve when the initial pathogen is removed, probably as a new ‘normal’ has been established which lacks the same proportion of non-inflammatory species.
A major complication of IBD is Crohn’s Disease (CD), a patchy yet chronic inflammation along the length of the gut that can result in ulceration and then even more complications. CD is actually quite common and increasing in prevalence worldwide, which is always good for researchers looking for funding, and a few studies have begun to look at the species shifts that occur in these patients. Interestingly CD patients see an increase in E. coli species and a decrease across the board in Firmicutes. Alongside this we see that the particular Firmicutes are reduced more than other including species that produce products such as butyrate, methylamine and trimethylamine all of which are known to have an anti-inflammatory effect.
The disruption of of the microbiomes balance is one thing but what happens if it never forms properly in the first place.? This was the basis of the original ‘Hygiene Hypothesis’ proposed by Strachan in ’89. Most people recognise it as ‘we are too clean for our own good’ but this is incorrect. Strachan’s original hypothesis suggested a decrease in exposure to infectious agents might result in the incomplete development of the immune system, which under certain conditions, may develop into various chronic conditions. This hypothesis was developed as a possible explanation for the disparity in allergic and autoimmune disease development in the developed world.
It appears that Strachan was close but not entirely correct as its become a question of quality and specific type of agents one is exposed too, not simply the quantity. This revised Hygiene Hypothesis, commonly called the ‘Old Friends Hypothesis’ suggests that there are micro-organisms that we have co-evolved with for a very long time and they train our immune system for tolerance and establish the all important balance. As I’ve pointed out a number of times in this series the reliance on the microbes to train our immune system is fundamental to our ability to develop a normal and healthy immune system.
Furthermore the ‘Old Friends Hypothesis’ seems to picking up some pretty interesting support. Many studies have observed a diference in the composition of fecal microbiota between infants who do or do not develop allergies. Further work has even identified Lactobacilli and Bifidobacterium species as particularly important to prevent the onset of allergies.
Even more interesting are some probitic trials wher mothers and infants have been provided with probiotics for 1 month pre-natal and 6 months post-natal and a drop in the incidence of eczema and some food allergies is observed. It is important to note that this result was observed in caesarean infants only and vaginally delivered children saw no lasting benefit after the age of two.
Despite these interesting results there is still not enough data to make a call either way on the validity of the ‘Old Friends Hypothesis’ but beyond doubt is the importance of the microbiome in the upkeep and training of the immune system.
Cerf-Bensussan N, & Gaboriau-Routhiau V (2010). The immune system and the gut microbiota: friends or foes? Nature reviews. Immunology, 10 (10), 735-44 PMID: 20865020
Fujimura, K., Slusher, N., Cabana, M., & Lynch, S. (2010). Role of the gut microbiota in defining human health Expert Review of Anti-infective Therapy, 8 (4), 435-454 DOI: 10.1586/eri.10.14
Strachan, D. (1989). Hay fever, hygiene, and household size. BMJ, 299 (6710), 1259-1260 DOI: 10.1136/bmj.299.6710.1259
Rook GA, & Brunet LR (2005). Old friends for breakfast. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 35 (7), 841-2 PMID: 16008666