Transcript from my updated October 2022 presentation about endometriosis, LPS, and immune dysfunction. Click here to view the presentation slides with references.
Thanks so much for joining me for a discussion of endometriosis. We’re here to look at endometriosis as a disease of immune dysfunction. A discussion that, unfortunately, has been somewhat controversial and got me into hot water in the past.
Let’s start with a non-controversial definition, which is that endometriosis is an inflammatory disease in which endometrial-like tissue grows in places other than inside the uterus. And here is a visual of an endometriosis lesion showing key features such as angiogenesis and localized hypoxia, which also occur in normal endometrial tissue. But also neurogenesis, which does not occur in normal endometrial tissue, and most importantly, macrophages in purple, which will be our focus today. This situation can cause pain and other symptoms. That much is clear.
Beyond that, to say that endo is a complex disease would be an understatement. There are a lot of moving parts. And depending on which convincing part you’re looking at you might be tempted to dismiss immune dysfunction as a primary mechanism of the disease.
It brings to mind the fable about the blind men and the elephant. Each person describes the elephant from their observations, and because their descriptions differ, each person thinks all the other descriptions are crazy.
So, in the interest of acknowledging all the parts of the elephant that is endometriosis, let’s quickly survey many of the aspects of this disease, and then I’ll present the case for a primary mechanism of immune dysfunction that is very similar to autoimmune disease. As well as something called the bacterial contamination hypothesis of endometriosis.
So, here we go. A survey of aspects of this disease.
Starting with the presence of the lesions and the debate about how the lesions got there in the first place. The most widely accepted theory is via retrograde menstruation, Which, incidentally, does routinely happen in most women, but in most women, the immune system just quietly cleans it up. Other theories about “how the lesions got there” include transformation from stem cells and/or tissue laid down before birth. All are likely to be true in different types of endometriosis. Because yes, researchers now think there are different types of lesions based on their origin. In some cases, superficial lesions may be physiological and an incidental finding and not a full explanation for pelvic pain. Other possible causes of pelvic pain include pelvic floor dysfunction, chronic activation of the sympathetic nervous system, history of trauma, bladder issues, and IBS.
And just a comment, that yes, surgical removal of the lesions can help the disease—immensely in some cases. And excision surgery can even dial down the immune dysfunction. But that doesn’t mean that surgery is the only way to improve the disease.
The next huge player in endometriosis is estrogen, a hormone that strongly stimulates endometriosis lesions and is even made by endometriosis lesions. Which is why switching off estrogen has been the standard conventional medical treatment, but unfortunately, that approach has trade-offs because estrogen is important for general health. On the hormonal side of things, there’s also the fact that endometriosis lesions are resistant to progesterone because they have far fewer progesterone receptors than normal endometrial tissue. One of several ways in which endometriosis lesions are not the same as normal endometrial tissue. Progesterone resistance is obviously bad because progesterone is the hormone that normally slows down the growth of endometrial tissue.
As an aside, both estrogen and progesterone also affect the immune system. For example, estrogen generally promotes autoimmune-type inflammation while progesterone generally reduces that type of inflammation. So, giving progesterone or some types of progestins, especially the androgenic progestins, can still be helpful.
Next, there’s the role of the nervous system and the fact that endometriosis lesions are heavily innervated in a way that normal endometrial tissue is not. Another way that endometriosis lesions are different from normal endometrial tissue. And all those nerves are certainly part of why endometriosis can cause such terrible pain. And there’s a lot of cross-talk between nerves, especially the vagus nerve and the immune system. By cross-talk, I mean the immune system affects nerves, Including the fact that macrophages stimulate the growth of new nerves or neurogenesis. Plus, at the same time, activated nerves and pain signals stimulate and modulate immune cells and inflammation.
Next, there are research findings about localised concentrations of iron at the site of the lesions, probably from retrograde menstruation and/or damaged cells. High iron, in turn, stimulates macrophages.
Next, hypoxia or low oxygen at the site of the lesions. Which is also a common feature of inflammatory diseases and of course, hypoxia also stimulates macrophages.
Next, there’s strong evidence linking endometriosis to low androgen exposure in utero probably due to environmental toxins. And how that can cause epigenetic changes to hormone production, hormone-sensitive tissue, and, of course, the immune system, our topic of today. Androgens generally downregulate or improve the autoimmune type of inflammation. Which is why androgenic medication (such as testosterone and androgenic progestins) are more helpful for endometriosis than anti-androgenic progestins.
On the topic of epigenetic changes, there are many papers broadly about that topic. Again, usually from environmental toxins. And some of those epigenetic changes can be transgenerational, which means a patient’s endometriosis of today could be the result of an environmental toxin, such as a dioxin, that her grandmother was exposed to.
There are tons of research findings about genetics, including interesting links with ovarian cancer but ALSO, and relevant to our topic today, women with endometriosis tend to have the HLA polymorphisms that also increase the risk of autoimmune diseases such as lupus, rheumatoid arthritis, celiac disease, autoimmune thyroid disease, and inflammatory bowel disease. In other words, women with that type of immune system are the ones who develop this disease.
Next, there’s a rather intriguing finding that women with endo are also likely to have a nickel allergy, which suggests a common underlying mechanism or immune type. It’s not nickel toxicity but an immune response to nickel. When I shared this on social media, I received a huge response from my endo followers saying how many of them do have an allergy to nickel or cheap jewellery. So, a low-nickel diet can be a strategy.
Next, there are research findings about the role of the microbiome and all the different ways our resident bacteria affect hormones, immune function, and endometriosis. And finally, of course, immune dysfunction, our topic of today. The current number of Pubmed papers on immune and endometriosis is 1231 and counting.
And then there’s this December 2021 textbook, which looks at every aspect and nuance of the immune situation up till that date. That book contains several interesting chapters including:
- Macrophages in endometriosis
- Autoimmunity and endometriosis, and the
- Role of Th1, Th2, Th17, and regulatory T cells.
That particular chapter is written by the Japanese research team who, in 2018, proposed the bacterial contamination hypothesis of endometriosis, which states that “LPS regulates the pro-inflammatory response in the pelvis and growth of endometriosis via the LPS/TLR4 cascade.”
Today, we’ll talk about both LPS, which is lipopolysaccharide from gram-negative bacteria, and TLR4, which is a toll-like receptor on immune cells. This paper, if true, gives a remarkable insight into the disease and if true, is an absolute game-changer. Although it’s definitely not yet the consensus. Which brings me to this quote from Michael Crichton from a lecture he gave at the California Institute of Technology. He says:
“The work of science has nothing whatsoever to do with consensus. Consensus is the business of politics. Science, on the contrary, requires only one investigator who happens to be right, which means that he or she has results that are verifiable by reference to the real world.”
One investigator who happens to be right. Through my lens, I’m looking at the bacterial contamination hypothesis of endometriosis and thinking “what if this is it?”. The presence of LPS at the lesions ties together so many aspects of a complex disease, particularly the observations about hypoxia, macrophage polarisation, and neurogenesis. In other words, is the “bacterial-immune” observation exactly the key insight we’ve been waiting for? The insight that makes all those parts of the elephant make sense.
Before we get too far into what is arguably a paradigm shift for endometriosis,
Let’s do a quick review of the immune system, including the innate immune system, which is the more primitive built-in fast-acting part of the immune system versus the adaptive immune system, which is the part that learns. Here, you can see the cell types, including the mast cells, which are strongly activated in endometriosis, and the cells that communicate between innate and adaptive immunity and should be gobbling up unwanted endometriosis lesions—except they’re not.
Those are the natural killer cells and the macrophages. Macrophages are such big players in endometriosis that one paper calls endometriosis “a disease of the macrophage.” When activated by various stimuli especially bacteria, macrophages activate and transform into different phenotypes that then take a designated role of either promoting acute inflammation or promoting growth. Both phenotypes are present with endometriosis and not in a good way. For example, young endometriosis lesions are associated with the inflammatory M1 macrophages, while older lesions are associated with the M2 macrophages, which promote both angiogenesis (the growth of new blood vessels) and neurogenesis (the growth of nerves). Thus creating complex, mature inflammatory endometriosis lesions. Plus, importantly, macrophages have the all-important role of instructing the adaptive immune system, which is why you then start to see a myriad of abnormalities including potential autoimmunity.
Classically, autoimmune diseases have reduced natural killer cell activity, increased number and cytotoxicity of macrophages, abnormalities in the functions and concentrations of B- and T-lymphocytes, including T-reg cells, plus an increase in the activity of B lymphocytes and the production of autoantibodies. These changes are all present with endometriosis. And in the case of endometriosis, the autoantibodies present are primarily antiendometrial and antiovary antibodies. Which is not to say that endometriosis is definitively an autoimmune disease. It has not yet been officially classified as such. And experts are still very divided. Hence the controversy.
For our purposes, it is not necessary to definitively say that endometriosis is an autoimmune disease. Which got me in trouble previously. Instead, I think we can agree that endometriosis is very similar to autoimmune diseases and go from there. Starting with trying to understand “what is driving the macrophage activation?”
According to the danger model of autoimmunity, the immune system does not distinguish between self and non-self but rather between things that might cause damage and things that will not. In this image, we can see the macrophage (in purple) activation by either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) leading to downstream inflammatory cytokines, immune cell recruitment and engagement of adaptive immunity. Here, you can also see the toll-like receptors which are found on T-cells, B-cells, and most importantly, macrophages. Let’s zoom in on a toll-like receptor.
Toll-like receptors are membrane-bound pattern recognition receptors that respond to cell damage or pathogens. And knowing all that terminology sets us up to look more closely at the bacterial contamination hypothesis.
This is a diagram from the textbook chapter I showed you earlier. The one by the Japanese research team who propose the bacterial contamination hypothesis. Here we see the macrophage in blue engulfing a pathogen, then presenting pathogen-derived peptide antigens to naïve T cells. Plus, at the same time, the toll-like receptors in red recognizing the pathogen-derived components and consequently induce the expression of genes and inflammatory signals, including NF-kB and inflammatory cytokines. Those signals then instruct the T-cells to develop antigen-specific adaptive immunity.
Okay, let’s now put that in perspective with my conceptual summary of key elements of endometriosis or what I call the road to endometriosis. Starting with a background vulnerability to the disease, which is partly genetic and partly epigenetic. In other words, that vulnerability has to be there. Women without a certain immune type will never develop endometriosis no matter how much estrogen or LPS they’re exposed to. Next, there’s the presence of the lesions or endometrial-like tissue. Which as I mentioned, could have arrived there via several mechanisms. Next, there’s the normal level of estrogen that kicks in with puberty. Estrogen stimulates endometrial tissue and can be highly stimulating to macrophages, especially n the presence of LPS. Which, as we’ve seen with the “bacterial contamination hypothesis” of endometriosis, could be an initiating factor in the immune dysfunction of endometriosis. Specifically, LPS upsets macrophages, which then interact with all the other parts of the immune system.
But where does the LPS come from? According to a couple of recent papers, the LPS could be coming from either dysbiosis of the vaginal and uterine microbiome moving upwards out via retrograde menstruation and/or from the gut via intestinal permeability and something called gut microbiota-derived extracellular vesicles. Wow. That means that in women who are vulnerable due to genetics and epigenetics, exposure to LPS from the gut can flare or drive endometriosis. And certainly, there’s a strong link between endometriosis and gut problems. Specifically, women with endo are many times more likely to have irritable bowel syndrome or SIBO, which is small intestinal bacterial overgrowth. And that link had been assumed to be the result of endometriosis affecting the gut. But it could be in the other direction with intestinal permeability and LPS from SIBO driving endometriosis. Indeed, one study found that women with endometriosis are more likely to have intestinal permeability.
Continuing on in our roadmap, downstream from macrophage activation is the profound immune dysfunction of endometriosis including changes to adaptive immunity, autoantibodies, neurogenesis and angiogenesis.
Okay. That’s a zoomed-out view of a complicated disease. But it does provide a few targets for natural treatment: Namely, autoimmune genotype, LPS toxin, and immune dysfunction.
So, let’s target treatment.
The first target is the autoimmune genotype. Well, we can’t change genotype obviously. But the existence of the autoimmune genotype suggests that endometriosis could (and indeed does) respond to many of the same dietary interventions that help with autoimmune disease. Specifically, I’m talking about the strict avoidance of gluten, drawing on the work of Dr Alessio Fasano, who was the first researcher to provide scientific evidence about the role of zonulin, intestinal permeability and gluten in autoimmune disease. The other antigenic proteins that can drive or worsen endometriosis are A1 casein from normal dairy and sometimes eggs, but only in about 1 in 3 women with endo. Mainly it’s about gluten.
And of the women whose pain is from endometriosis — and again, sometimes the lesions may not be the cause. But of those women with active lesions, I guess I believe there are some who don’t need to strictly avoid gluten, but I’ve never met them. As you know, it’s not easy to assess for non-celiac gluten sensitivity, but the tests I use include coeliac serology, coeliac genotype, and thyroid antibodies. I sometimes use positive thyroid antibodies as a surrogate marker of gluten sensitivity. But thyroid antibodies will not be present in all endometriosis patients. And the only time I would not recommend strict gluten avoidance to an endometriosis patient is if she is negative for coeliac genotype.
Moving on, the next target for natural treatment is the LPS toxin, which can be knocked back with an antimicrobial approach. For example, antibiotics have been found to reduce the size of endometriosis lesions in animal studies and recently, a human study. Courses of antimicrobial supplements can also be helpful, especially berberine, which (although it has not been studied for endometriosis) has undergone a lab study for adenomyosis, which concluded that “berberine ameliorates the LPS-induced progression of adenomyosis.” That’s the paper there. Beyond berberine, other treatment ideas include oregano, lactoferrin, resistant starch, Lactobacillus GG and basically, all the treatment protocols for SIBO, which are beyond the scope of today’s presentation.
Let’s look at the final target of supporting immune function, which you can do in part by providing beneficial immune-modulating nutrients. Everything on this list — apart from iodine — has been researched for endometriosis.
The first is zinc. Which is essential for the healthy functioning of immune cells, especially cell-mediated or innate immunity and the normal functioning or downregulation of macrophage matrix metalloproteinases, which are remodelling enzymes involved in angiogenesis and the formation of endometriosis lesions. So, zinc helps to prevent that pathogenic remodelling of tissue. Zinc also helps to downregulate NF-kB, the part of the immune signalling cascade from macrophages that we saw earlier. Incidentally, a lot of nutrients and herbal medicines work by downregulating NF-kB, including n-acetyl cysteine and curcumin, which we’ll come to in a minute.
Next is retinol or preformed vitamin A, which has been found to induce apoptosis (healthy cell death) in endometriosis lesions. Which is a good thing. Retinol is also very important for immune function. But of course, do be careful with the dose of preformed vitamin A. And just as an aside, both zinc and retinol are deficient in an exclusively plant-based diet. So, any vegan patients are absolutely going to require zinc and retinol supplements.
Next is selenium, which has undergone several animal studies. Specifically, it can alleviate LPS-induced TLR4 activation and its downstream signalling pathways.
Next is N-acetyl cysteine or NAC, which underwent a clinical trial in 2013. It was only 95 women, but they got amazing results. Of the 47 women in the NAC treatment group, 24 cancelled their laparoscopy due to a disappearance of endometriomas, reduction of pain, or pregnancy. NAC works by downregulating NF-kB plus converting to glutathione which, in turn, regulates immune function. Specifically, glutathione both upregulates natural killer cells, the cells that are supposed to be gobbling up the endometriosis lesions and normalizes the behaviour of Treg cells. NAC also promotes apoptosis (healthy cell death) and prevents angiogenesis which is the unhealthy growth of blood supply to the endometriosis lesions.
Next is turmeric or curcumin, which has undergone a couple of studies for endometriosis. Curcumin works by several mechanisms including, again, dialling down NF-kB and at the same time supporting the beneficial antiinflammatory NRF2 signalling pathway. Curcumin also promotes apoptosis and suppresses the local production of estrogen, similar to how aromatase inhibitors work for endometriosis. Curcumin inhibits angiogenesis and supports the differentiation of naive immune cells into Treg cells—which then suppress the autoimmune type of inflammation.
Like curcumin, resveratrol is another immune-modulating, NF-KB-reducing phytonutrient that has undergone at least one study for endometriosis.
Medicinal cannabis. Which is anti-inflammatory via several mechanisms including by supporting the endocannabinoid system. And THC relieves pain.
Finally, I also regularly prescribe iodine at the dose of 1-3 milligrams for endometriosis both for its anti-estrogen effects and its antimicrobial, immune-modulating effects. But I use that dose only if the patient is negative for thyroid or TPO antibodies. Because higher dose iodine can trigger autoimmune thyroid disease.
To my knowledge, there are no clinical trials of iodine for endometriosis, but there is a mention of iodine as an immune modulator in this very interesting paper: Immunotherapy of endometriosis. Specifically, they review the unexpected effectiveness of intrauterine iodised poppy seed oil, called Lipiodol, which was initially used only as a contrast medium for imaging studies but was incidentally found to improve pelvic pain and fertility. In this paper, they explain how iodine is immune-modulating and can modulate the peritoneal immune environment. Specifically, iodised poppy seed oil can inhibit peritoneal lymphocyte and macrophage activity and upregulate NK, dendritic, and Treg cells. I would point out that iodine is also anti-microbial which is potentially relevant for the bacterial contamination hypothesis. And of course, giving iodine orally is different from injecting it into the uterus and out of the tubes. But still. I have found oral iodine to be very helpful.
Okay, those were some of the key recommendations. But with such a complex disease, there are, of course, many other considerations including:
- Assessing for other gut pathogens and treating accordingly.
- Assessing for mast cell activation and treating accordingly.
- Considering the role of mold-related illness or Chronic Inflammatory Response Syndrome (CIRS). I’ve definitely seen a few cases of endo that were downstream from mould exposure.
- Considering oral micronised progesterone or Prometrium. Like progestins, Prometrium seems to give relief — possibly both from inhibiting the lesions and from modulating immune function.
- Perhaps referring for neuromuscular therapies or other physical therapies that work on the pelvis including acupuncture, osteopathy and others.
- Looking at supporting the vagus nerve and supporting parasympathetic tone. In fact, there’s a new animal study about vagus nerve stimulation improving endometriosis lesions.
- Downregulating NF-kB with zinc, NAC, curcumin, or many of the other natural treatments that can do that.
- Considering a low nickel diet, which usually involves reducing exposure to canned foods, especially canned acidic foods like tomatoes. Wheat and dairy are also high-nickel foods.
- Finally, considering melatonin, which is immune-modulating and likely deserves more research for endometriosis.
Okay, so what are the takeaways for endometriosis treatments? First, the presence of superficial endometriosis lesions may be physiological and not the explanation for the pain. Consider all the other factors like pelvic floor dysfunction, chronic activation of the sympathetic nervous system, trauma history, bladder issues, and IBS. When the lesions are the source of pelvic pain, immune dysfunction plays a major role in the pathogenesis of the disease. And so look to the gut and LPS endotoxin. By addressing intestinal permeability and reducing LPS exposure, you can get a lot of traction with this disease. Identify and address any and all immune disruptors, especially gluten. But we also touched on mould and mast cell activation. Lots of potential immune disruptors to correct. And finally, nourish and support a healthy immune and nervous system with all the tools you have.
Thanks so much for your attention. You can reach me at larabriden.com and on my social media @larabriden.