Endometriosis Awareness Month - Part III

Endometriosis is a puzzling disease, there are still many unanswered question surrounding its origin, who gets it and why. In this way it makes studying endometriosis like exploring the world in the 17^th century, there is a sense of undiscovered territory to explore, but rather than large wooden ships and subjugating natives, we have theories and hypotheses to test with science. Some of those theories prove worth exploring, some have a little, a lot, or no evidence to support them. Creating new theories sometimes seems like muddying the water and complicated an already complicated subject, but it is only by coming up with and testing new ideas, we get closer to the truth (however, all ideas must be testable and all tests must be fair, objective and subject to scrutiny by peer review, something pseudoscience always fails at).

With that in mind I’m going to be doing a bit of theorising myself in this week’s blog post. A big part of my research is examining the role that inflammation plays in endometriosis, specifically what controls inflammation in endometriotic and normal endometrial tissue. Part of this research involves looking into the initial causes of inflammation, and one thing in particular has caught my attention recently and that is bacteria.

Some types of bacteria are essential for our health, without them we would become very ill indeed and several of our organs have their own population of micro-organisms that help them function correctly. The gut and the vagina are two good examples, the gut in particular contains between 500 and 1000 different species of bacteria, numbering in the trillions of individual micro-organisms. Interestingly, the harmless bacteria that naturally populate the vagina actually help prevent infections by more harmful bacterial types. But sometimes disruption of the natural order of our internal microflora can lead to harmful effects.

Now I’m not falling into the trap of confusing endometriosis with endometritis and I’m certainly not suggesting that endometriosis is an infection or caused by an infection. Rather bacteria may play a hitherto under-recognised role in inflammation and the generation of painful symptoms in endometriosis.

How might bacteria contribute to endometriosis? To clarify I’m talking about a specific type of bacteria, called Gram-negative bacteria, which is a group of bacteria including E.coli, one of the better known species of bacteria. Why these organisms are important is because of something they secrete, namely lipopolysaccharides (LPS). LPS are essentially toxins the bacteria produce that are responsible for making you ill, but they are also powerful stimulants for inflammation and this is the key point of interest.

To start with we need to know which bacteria are normally present in the uterus and how this differs in women with endometriosis. A study published in 2014 investigated this very phenomena and found that several bacteria types, especially E.coli, were increased in the endometrium of women with endometriosis (see the figure below)

The solid white boxes represent the levels of micro-organisms found in the endometrium of women without endo, the dashed boxes represent the levels in women with endo.Figure source: http://humrep.oxfordjournals.org/content/29/11/2446.long

The solid white boxes represent the levels of micro-organisms found in the endometrium of women without endo, the dashed boxes represent the levels in women with endo.

What we can see from this is that there are several types of micro-organism found at increased levels in the endometrium of women with endometriosis, in particular a large increase in E.coli. Following on from this further studies found that LPS was found at a much higher concentration in the menstrual fluid and peritoneal fluid of women with endo as you can see if you click this link and look at figures C and D (the white bars represent the levels of LPS in women without endo, the black bars are women with endo). 

The increase in LPS in the menstrual fluid can be attributed to the increase in E.coli in the endometrium, but what about the peritoneal fluid? This can be explained by retrograde menstruation, where menstrual fluid is passed upwards through the fallopian tubes and out into the peritoneal cavity. Retrograde menstruation is a natural event in the female body during menstruation, occurring in as much as 90% of women and it was long thought that this was the root cause of endo, with endometrial cells shed during a period being passed into the peritoneal cavity where they implant and grow. This theory has since fell from favour somewhat as more evidence accumulates against it being the cause of endo, but there may be a role for retrograde menstruation in endometriosis, just perhaps not what was previously thought.

It seems plausible then that increased levels of E.coli in the endometrium lead to higher concentrations of LPS in the menstrual blood, which can get refluxed into the peritoneal cavity by retrograde menstruation, increasing the concentration of LPS in the peritoneal fluid, which can be in close/direct contact with endometriotic lesions. The next step is to assess what can happen when

LPS interacts with endometriosis.

Some studies have looked into this and found that LPS can stimulate endometriotic cells to release factors, like prostaglandin E2 (PGE2) and tumour necrosis factor (TNFα)  which promote inflammation and stimulate pain signals (PGE2 has been implicated in a number of important facets for endometriosis survival including cell growth, inhibition cell destruction and hormone production). This would lead to a heightened inflammatory state around endometriotic lesions and in the normal endometrium, possibly contributing to symptoms frequently associated with endometriosis, such as chronic pelvic pain and excessively painful periods. The whole process can be summed up on the diagram below.

Original image from https://edc2.healthtap.com/ht-staging/user_answer/reference_image/7081/large/Uterus.jpeg?1386669522

The final question, which we don’t have an answer to yet, is why E.coli and other micro-organisms are increased in the endometrium of women with endo.  It may be due to alterations of vaginal acidity leading to easier colonisation of the uterus by bacteria, or dysfunction of the immune cells in the uterus of women with endo resulting in them not being able to keep micro-organisms in check? Also, what effect would restoring the normal balance of uterine micro-organisms have and how can this be achieved? There are a lot of issues that need to be addressed here, but hopefully this will be an area of investigation that yields positive results in terms of relief from painful symptoms.