Stop in the name of my gut flora

 

In this post, I want to talk about how your gut flora is an integral player in the development and health of your immune system. Up until now, I’ve talked about how a compromised gut-wall barrier can cause endotoxemia and other immune reactions via translocation of antigens into systemic circulation. However, maintaining gut wall integrity is not the only way commensal gut bacteria affect our immunity.

Diseases like asthma, skin/respiratory/food allergies, rheumatoid arthritis, heart disease, colitis, autoimmune disorders—all of these are mediated by different arms of our immune system, and these arms are in turn influenced by our gut flora.

Many of you reading this have heard of the hygiene hypothesis to explain the increasing prevalence of asthma and allergies in Western populations. The hypothesis is this: because children in industrialized countries are less exposed to a diverse set of microbes and parasites in their environment, and are lacking in certain types of beneficial gut flora, their immune systems are ill-trained to recognize the difference between real and innocuous threats.

A growing number of epidemiological studies seem to confirm the truth of this hypothesis. The following factors have been found to reduce the incidence of asthma and other allergic disorders:

  • breast-feeding
  • vaginal birth
  • having more siblings
  • reduced exposure to antibiotics
  • being raised on a farm
  • drinking raw milk
  • having a pet in the house
  • playing outdoors
  • being born in the developing world
  • exposure to pathogens like H. pylori, parasites or Mycoplasma tuberculosis

Because of this research, more and more parents are getting the message that while cleanliness may be next to Godliness, it certainly doesn’t help your child develop a robust and appropriately tuned immune system.

Now I don’t want to discount some of the things parents are allowing their children to do to build up proper immunity like getting a dog or letting them wallow in the dirt at the local playground. These things should be encouraged. However, for many children already afflicted with asthma and allergies, the solution lies much deeper.

Speaking from experience, I now realize that the repeated episodes of strep throat and ear infections as a child, recurring sinus infections, bronchitis, allergic reactions to dust mites, cat dander and smoke, as well as rosacea were all caused by a long-standing case of disordered gut flora. Once I took care of that, my respiratory and skin allergies went away.

Many of you reading this may have also cleared up your gut dysbiosis to pleasantly discover that not only did your gastrointestinal symptoms resolve, but so too nagging allergies and skin outbreaks.

So how does our commensal gut flora affect our immune system?

As you recall from my earlier posts, as far as your body is concerned the digestive tract from the mouth to the rectum is outside of your body, although located entirely within it. Its contents, and not your skin, is your body’s largest exposure to the outside world. Because of this, there are more immune cells in the gut than in the spleen, lymph nodes and blood combined.

This intestinal system is called the gut-associated lymphoid tissue or GALT.

GALT is rich in immune cells of both the innate and adaptive arms of your immune system. The innate system responds to novel pathogens that your immune system has never seen before. The adaptive system remembers past antigens and responds to them quickly when they are encountered again.

The GALT system has a variety of organized lymphoid tissues called mesenteric lymph nodes and Peyer patches. Also diffused throughout the cells lining the digestive tract, as well as the connective tissue lying below these cells, are other immune vigilant cells or effector sites: intraepithelial lymphocytes, dendritic cells, microfold cells, CD4+ T cells, CD8+ T cells, B cells and plasma cells.

These various immune cells recognize a threat through the use of Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs). All pathogens express a distinct molecular configuration collectively called pathogen-associated molecular pattens or PAMPs. But so too beneficial gut flora. Therefore, our immune system must be properly trained to mount an immune response to the former but not the latter. It must also be primed to distinguish between truly harmful threats and innocuous substances that the body may encounter in the digestive and respiratory tracts.

How this is done is being revealed by studies in germ-free rodents. As I wrote in my post on anxiety:

“A germ-free rodent is just that, an animal whose gut is free of bacteria, both good and bad. This is accomplished by surgically removing baby rodents from their pregnant mothers and keeping them in a sterile environment after birth. It may also be accomplished by giving animals broad-spectrum antibiotics that kill off any microbes in their digestive tract.”

Because germ-free rodents lack beneficial bacteria, they have altered immune structures. The size of their lymphoid tissue, like Peyer patches and mesenteric lymph nodes, are smaller and these tissues contain fewer B and T cells than found in normal rodents.

They also have fewer numbers of dendritic cells, B cells and lower T cell counts within the cells or enterocytes lining the intestine.

They produce less immunoglobulin A (IgA). IgA binds to antigens in the gut lumen and neutralizes them before they reach the gut wall thereby preventing an inflammatory cascade.

Recall from my small intestinal bacterial overgrowth (SIBO) series that anything that promotes inflammation will compromise healthy gut bacteria and cause a “leaky gut”. Therefore, being able to produce necessary quantities of IgA is vital to preventing compromised intestinal permeability. Salmonella, for example, causes intestinal inflammation that directly disrupts beneficial gut flora populations thus allowing it to displace them for attachment sites on the gut wall.

Germ-free animals also have smaller spleens with fewer quantities of both T and B immune cells.

Another set of important immune cells that are reduced in germ-free rodents are regulatory T cells or treg cells. CD4+, CD25+ and FoxP3+ cells are some of the most well-studied treg cells. These cells are responsible for shutting down immune responses after the invading pathogen or antigen has been successfully dealt with. If these cells are greatly reduced, inflammatory responses continue longer than necessary.

Treg cells are also important for maintaining appropriate immune responses and preventing responses to both self-tissue and harmless antigens like pollen, food, dust, etc. This is called immune tolerance. Dysregulated treg cell responses are therefore always a component of autoimmune diseases and allergic reactions.

Germ-free rodents also exhibit a skewed helper T cell type two (Th2) immune response. This is of paramount importance in the development of allergic reactions.

T lymphocytes are a major source of immune signaling proteins or cytokines. There are two main types of these immune cells that express different molecules on their surface: CD4 and CD8 cells. Helper T cells are CD4 cells. Helper T cells are very prolific producers of cytokines.

Helper T cells can be further subdivided into helper T cells type one (Th1) and the aforementioned Th2.

Th1 cytokines mostly produce inflammatory responses necessary for killing parasites that may have taken up residence within cells as well as perpetuating autoimmune responses. The main cytokine produced by these cell types are interferon gamma. If you suffer from an autoimmune disease, it is these immune cells you can blame for the response.

Most systems in the body have mechanisms to balance their opposites. Helper T cells are no different. Th2 cells are the counterbalance to Th1 cells. Cytokines produced by Th2 cells include interleukin 4, 5, 9 and 13 as well as interleukin 10, which is an anti-inflammatory cytokine.

As mentioned, an excess Th1 response is common in autoimmune disorders and someone so afflicted is known as being Th1 dominant. Tipping the balance in the opposite direction towards Th2 responses, however, brings its own set of problems not least of them asthma and allergies affecting the skin, airways and gastrointestinal tract. This is known as being Th2 dominant. Maintaining a proper balance between these two arms of the immune system is what is needed to prevent these extremes.

Another set of immune cells reduced in germ-free rodents that are involved in maintaining Th1 and Th2 balance are Th17 cells. These cells are abundantly found in the gut, especially in the connective tissue below the epithelial layer lining our digestive tract or lamina propia. Germ-free rodents express fewer Th17 cells than normal controls.

 

Courtesy: Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma.

 

This illustration captures the complexity of the interaction between gut flora, the immune system and cytokines responsible for asthma and allergic reactions.

In the upper-left corner of this graphic, commensal or beneficial gut flora directly influences the development of all components of the gut and its immune cells: intestinal epithelial cells (IECs), intraepithelial lymphocytes (IELs), microfold cells (M), Peyer patches (PP) and mesenteric lympth nodes (MLN).

Dendritic cells (DC) are represented in the lower-left corner by their pointed projections. These projections, or dendrites, extend into the gut lumen through the tight junctions between enterocytes and continually sample intestinal content for dangerous pathogens via their toll-like receptors (TLRs).

Our gut microbiota directly influences how these dendritic cells will steer the immune response via their influence on naïve T cells. Naïve T cells are basically blank-slate T cells ready to become immune cells expressing either inflammatory or anti-inflammatory characteristics.

Here we see how dendritic cells, under the influence of gut flora, produce both anti-inflammatory treg cells (T-reg) and Th1 cells. These Th1 cells, as seen at the very bottom of the graphic, tip the Th1/Th2 scale away from Th2 allergic dominance towards Th1/Th2 balance. Therefore, the mediation of both pro-inflammatory and anti-inflammatory immune signals is under the control of our gut flora.

To the right, we see how what occurs in the gut impacts tolerance via effects on various immune cells and cytokine production. Deregulate this system and tissue damage caused by inflammation is the result. This modulation of the GALT extends far beyond the intestines to regulate immune responses in the lungs, the sinuses, the skin, the cardiovascular system and everywhere else in the body.

How exactly beneficial gut flora do this is still under intense investigation. What is known is that different strains have different effects on immune signaling.

Also of interest is that vitamins A and D play a role in the development of GALT cells. Vitamin A, or to be more precise a metabolite of vitamin A, retinoic acid (RA), is capable of converting naïve T cells within dendritic cells into anti-inflammatory treg cells. The vitamin D metabolite 1,25-dihydroxyvitamin D3 can also increase the production of anti-inflammatory treg cells. It appears that these two important vitamins work synergistically with gut flora to regulate immune responses.

Vitamin A and D are fat-soluble vitamins found in foods that we have been told by “health” authorities to stay away from because of their fat and cholesterol content like egg yolks, cod-liver oil, full-fat milk, liver, organ meats, shrimp, etc. It doesn’t surprise me, therefore, that the explosion of asthma and allergies in modern populations coincides not only with the indiscriminate use of antibiotics, but also with a population scared out of their minds from eating foods containing the richest sources of these immune-enhancing vitamins.

Just as germ-free rodents experience disruption of their immune responses, so too infants and children who have experienced prolonged antibiotic treatment. However, no one remains germ-free for long even after drawn-out antibiotic use. While beneficial colonies do reestablish themselves to a point, so too a proliferation of pathogenic bacteria like Clostridium difficile, Klebsiella and E coli.

However, if we could count on bacterial pathogens being the only organisms causing gut dysbiosis, life would be much simpler. Unfortunately, friendly gut flora that have been devastated can no longer keep yeast that resides naturally in each of us at bay. Candida albicans, for example, is not killed by antibiotics but flourishes with their use because they no longer have those “pesky” beneficial gut bacteria to keep them under control.

For this reason, many trying to clear up SIBO or colon-based dysbiosis and the immune disorders that flow from them with antibiotics alone soon find themselves battling other issues: tongues and throats covered in white gunk or thrush, sinuses that are clogged and prone to infection, bronchial inflammation, strange skin rashes or outbreaks, a new set of GI issues, multiplying food intolerances, low energy, brain fog, disturbed sleep, cold extremities, nail infections, vaginal yeast infections, jock and anal itch and more.

There is no pharmaceutical pill in the world today, nor will there ever be, that can restore proper microbial balance in your intestines. And without this balance all hope for a robust and properly tuned immune response is just that, hope.

The reality is that this internal microbial, viral and fungal community is an extremely rich and diverse ecosystem influenced by many factors as seen in the following illustration:

 

Courtesy: Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma.

 

Disrupt any of these influences and dysbiosis results. We, our children and even our pets, are paying a huge and unnecessary price by ignoring this.

 

References:

Hormannsperger G, Clavel T., Haller D. (2011) Gut matters: Microbe-host interactions in allergic diseases. Journal of Allergy and Clinical Immunology, 129: 1452-1459.

McLoughlin R. and Mills K. H. G. (2011) Influence of gastrointestinal commensal bacteria on the immune response that mediate allergy and asthma. Journal of Allergy and Clinical Immunology, 127: 1097-1107.

 

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