Autoimmunity Originates in the Gut

intestineThe global prevalence of autoimmune conditions such as type-1 diabetes, rheumatoid arthritis, and celiac disease has increased rapidly over the most recent decades. These types of diseases are no longer extremely rare; they are starting to become quite common. Chances are you know at least one person who’s got an immune system that has spun out of control and has for some reason started attacking some of the tissues that make up the eukaryotic organism it is a part of; a process or condition referred to as autoimmunity.

What’s going on? Why do more and more people develop autoimmune diseases?

What is it about our modern environment that’s causing our immune systems to go into a tailspin?

Some people seem to be under the belief that autoimmune conditions such as type-1 diabetes develop as a result of “bad genes”. This idea has little evolutionary support

There’s no doubt that genetics do play a role in the etiology of autoimmunity; however, in most cases, it’s unlikely to be the primary factor involved. This statement is supported by the fact that the prevalence of autoimmune disease has increased markedly over the past centuries, despite the fact that our genes have changed very little over the same time period. Moreover, it’s supported by the finding that autoimmune diseases are very rare among hunter-gatherers and other traditional groups of people who live in environments that bear resemblance to the Paleolithic environments in which more than 99% of the evolutionary history of our genus Homo took place (1, 2, 3).

When we think about it, it isn’t surprising that foragers rarely develop autoimmunity, given that a person’s ability to survive and reproduce in a natural environment would be significantly impaired by an autoimmune disorder such as type-1 diabetes or Inflammatory Bowel Disease (IBD). These types of conditions can have a devastating impact on health, physical fitness, and well-being, particularly if there are no drugs available for managing the problems they cause.

All of this clearly suggests that there has to be something about our modern environment that’s causing the human immune system to malfunction. We can’t simply blame it all on “bad genes”. It’s not our genes that are bad, it’s our environment. The genes that reside inside the tiny little compartment of our cells called the nucleus did just fine inside the bodies of our ancestors; they didn’t trigger the development of autoimmunity back in ancestral times. It’s only when they are exposed to the conditions of modern life that they seem to express themselves in such a way that our immune systems spins out of control and start attacking us.

The question then becomes: What’s causing our genes to express themselves in this fashion? Over the past several years it has become increasingly clear to me that the answer to this question lies within the world of the microbiome. I believe, based on my own experience and everything I’ve read, that dysbiosis is the fundamental cause of autoimmunity. It’s not the only cause, but it’s definitely an important one.

It makes complete sense to me that more and more people are developing conditions such as type-1 diabetes and psoriasis. It’s what one would expect to see, given the changes that have occurred to our environment lately. Over the most recent centuries, a wide range of microbiota-disrupting agents, such as antibiotics and other pharmaceutical drugs and highly processed foods, have made their way into our world.

Combine that with the fact that we’ve become increasingly disconnected from the natural world and that it’s become very common to deliver babies via c-section and feed them formula, as opposed to breast milk, and you can quickly understand why the microbiome of the modern man is in such a sorry state.

Gut microbes prime and regulate the immune system of the host

The human immune system is magnificent. It’s very complex and adaptable. It’s not self-sufficient though. It doesn’t do a very good job if it’s left to its own devices. In order to function correctly, it depends on signals from microbes.

Most of the immune cells in the human body are located in and around the gastrointestinal tract. The large intestine, which is where most of the microbes associated with the human body reside, is essentially on big immune organ and plays an absolutely critical role in the immune orchestra of the body.

If the microbiome is in a sorry state, the immune system of the host will also be in a sorry state. The various immune cells that line the intestine won’t receive the signals they require to do what they are evolutionarily designed to do, and the immune system may become “confused” and think that benign, healthy cells pose harm and should be destroyed.  This may then lead to destruction of the pancreatic beta cells, which is what happens in type-1 diabetes, or other immune attacks against benign, useful tissues.

If these types of immune responses occur early in life, the impact on health may be particularly destructive, due to the fact that much epigenetic programming occurs during the first months and years of life. I suspect that many cases of autoimmune disease (e.g., IBD) develop partly as a result of incorrect prenatal and postnatal development and priming of the immune system, as a consequence of abnormal microbial stimuli. When this happens, it can be difficult and perhaps even impossible, to fully reverse the damage later in life.

The fact that only a minority of people in our society has been diagnosed with an autoimmune disease doesn’t mean that most people have a well-functioning immune system. There is little doubt in my mind that a significant part of the population in western societies have a compromised immune system, due in large part to the many microbiota-disrupting agents that are present in the modern environment. Some, or perhaps a lot of, people may be “halfway” on the road to autoimmunity.

The science

Over the most recent years, a long range of studies investigating the link between autoimmunity and the microbiome has been published. These studies have made it abundantly clear that the microbiome plays a key role in the pathogenesis of autoimmune disease.

In today’s article, I’m not going to take an in-depth look at the science pertaining to the link between gut microbes and host immunoregulation. That would quickly turn the post into a book. What I thought I would do instead is to summarize some of the most recent research in this area, so as to bring you on board with the idea that the microbiome plays a critical role in the development of autoimmune disease.

Some of the many autoimmune diseases that have been linked with gut dysbiosis:

  • Sjögren syndrome
    “SS is marked by a dysbiotic intestinal microbiome driven by low relative abundance of commensal bacteria and high relative abundance of potentially pathogenic genera that is associated with worse ocular mucosal disease in a mouse model of SS and in SS patients.” (4)
  • Rheumatoid arthritis
    “Emerging data implicates the microbiome in RA pathogenesis. Mucosal sites exposed to a high load of bacterial antigens – such as the periodontium, lung, and gut – may represent the initial site of autoimmune generation.” (5)
  • Psoriasis
    “Intestinal Microbiota Promotes Psoriasis-Like Skin Inflammation by Enhancing Th17 Response” (6).
  • Type-1 diabetes
    “A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites.” (7)
  • Inflammatory bowel disease
    “… profiling studies of the intestinal microbiome have associated pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system.” (8)
  • Hashimoto’s thyroiditis
    “A growing body of evidence has demonstrated that environmental factors including infection are critical in triggering Hashimoto’s thyroiditis in genetically predisposed individuals. Not only pathogens but also intestinal symbiotic microorganisms can influence extra-intestinal immune responses, and thus dysbiosis in the gut might lead to the loss of tolerance to self-antigens including thyroglobulin and the autoimmunity that underlies Hashimoto’s thyroiditis.” (9)
  • Celiac disease
    “Recent evidence regarding celiac disease has increasingly shown the role of innate immunity in triggering the immune response by stimulating the adaptive immune response and by mucosal damage. The interaction between the gut microbiota and the mucosal wall is mediated by the same receptors which can activate innate immunity. Thus, changes in gut microbiota may lead to activation of this inflammatory pathway.” (10)

The science on the microbiome-autoimmunity link is still in its infancy. The research clearly suggests that the microbiome plays a key role in autoimmunity; however, more studies are needed to elucidate the full role of the microbiome in host immunoregulation.

My statement that autoimmunity originates in the gut is not just based on the aforementioned studies, but also on observations I’ve made, my personal experience, and the knowledge I’ve gathered over the years with regards to the role microbes play in regulating the human immune system. When I combine and examine all of the information I’ve assimilated, I’m left with no other possible conclusion than that dysbiosis is at the root of autoimmunity. Again, it’s not the only factor at play. Other things also play a role. However, I strongly believe that microbial imbalances are the major component of the foundation upon which immune-related diseases develop.

Establishing cause and effect and putting it all together

I would argue that it’s not that important to know the exact details regarding what types of microbes that have been shown to be lost, diminished, or amplified in different autoimmune states. The important thing is to understand the general mechanisms and how everything hangs together.

There is a general set of principles that apply across the board and that help us make sense of the results of all the different studies in this area. The most important thing to understand is that loss of biota diversity and dysbiosis are at the center of the microbiome-dysfunctions that characterize autoimmunity. These conditions can develop both as a cause and consequence of disease.

It’s well established that many diseases and health problems can cause a drop in microbiome diversity and proliferation of proinflammatory bacteria. However, it’s also well established that it can happen the other way around. Numerous studies have shown that a loss of microbiota diversity and dysbiosis compromise a wide variety of immune functions and set the stage for autoimmunity (11, 12, 13).

Here’s what a recent review paper had to say about this matter:

Humans are superorganisms. The human body harbors an extensive microbiome, which has been shown to differ in patients with autoimmune diagnoses. Intracellular microbes slow innate immune defenses by dysregulating the vitamin D nuclear receptor, allowing pathogens to accumulate in tissue and blood. Molecular mimicry between pathogen and host causes further dysfunction by interfering with human protein interactions. Autoantibodies may well be created in response to pathogens.

The catastrophic failure of human metabolism observed in autoimmune disease results from a common underlying pathogenesis – the successive accumulation of pathogens into the microbiome over time, and the ability of such pathogens to dysregulate gene transcription, translation, and human metabolic processes. Autoimmune diseases are more likely passed in families because of the inheritance of a familial microbiome, rather than Mendelian inheritance of genetic abnormalities. We can stimulate innate immune defenses and allow patients to target pathogens, but cell death results in immunopathology. (11)

Autoimmunity likely develops as part of a vicious cycle, in which a loss of biota diversity and/or dysbiosis lead to autoimmunity, which may then further exacerbate the microbiome-related issues. For example, in IBD, a combination of genetic susceptibility with faulty stimulation of the immune system (both early and late in life) as a result of exposure to a species-inappropriate microbial environment, sets the stage for chronic inflammation of gut tissues. It’s not surprising that a person who develops one autoimmune disease is likely to develop one or more autoimmune diseases as well, given that most, if not all, autoimmune diseases seem to have a similar set of root causes.

Rebooting the immune system

It’s often assumed that autoimmune diseases such as type-1 diabetes are incurable. I’m skeptical of this notion. In some cases of autoimmunity, the damage that has been inflicted may be so severe that it is indeed difficult or impossible to completely remedy the situation. However, these cases are probably in a minority; a statement supported by studies showing that microbiome manipulation is useful in the treatment of autoimmune disease. For example, recent studies have found that many patients with IBD respond favorably to Fecal Microbiota Transplantation (FMT) (14, 15).

I strongly suspect that the results of these studies would have been even more impressive if FMT had been combined with other treatments aimed at manipulating the microbiota. Moreover, I think that these types of interventions would likely be even more effective in the treatment of certain other autoimmune disease. For example, I strongly suspect that a lot of people with type-1 diabetes could recover much of their pancreatic beta-cell function if they were to repair their microbiota.

The bottom line: Microbiome restoration should become a routine part of the prevention and treatment of autoimmunity.

Comments

  1. is it possible that f we thought of us living AROUND the micro biome, as opposed to it ling INSIDE of us, this might explain the issues current to today – as if that idea holds true, we have to rethink evolution and then it makes more sense that gene changes occurring at this level is a species change that was inevitable

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  3. […] diseases and health problems, including acne vulgaris, colon cancer, chronic depression, and autoimmune conditions such as type-1 diabetes (1, 2, 3, 4, 5, 6, 7, 8). Dysbiosis and inflammation can develop secondary […]

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