Microbiota: educating our immune system

The adaptive immune system of a newborn is very naïve. Still, it learns at a fast pace to recognize and differentiate microbial friends from foes. Its primary teachers and educators are the diverse microbial population of bacteria, viruses, and fungi that codevelop with them in their gut. As both immune cells and microbes co-evolve, they continuously interact and learn from each other, just like toddlers attending kindergarten learn to socialize and  pickup their “manners”.

But, how exactly does microbiota teach the immune system?

As microbiota grows and differentiates in a baby’s gut, it actively engages with a repertoire of immune cells. Through constant interaction with the microbiota these cells learn these basic simple rules:

  1. Become acquainted with and tolerate beneficial bacteria
  2. Seek, attack and destroy the intruder

The immune cells achieve these objectives, effectively sensing and sampling not only the gut microbiota but also some small molecular motifs that the microbiota constantly sheds as debris called microbe-associated molecular patterns or MAMPS. Immune cells start to differentiate between the familiar patterns that normal residents shed and those from aliens or pathogens. The immune system learns to intervene only when the situation changes and new unknown and possible harmful bacteria is sensed.

The young gut immune system is like fuzzy teenage recruits in boot camp, trained by the microbiota. These newbie trainees “learn” to cooperate and respond to different “threats”. They are divided into sub-groups which specialize in various tasks. Each group uses alien weaponry; some carry “rifles”, other “machines guns” and others man the “artillery”. They learn to work together and call upon other groups as need be.

Similarly, the gut microbiota actively trains the immune soldiers (cells) to mount a defence against “threats” and learn when to “sound-off “ the alarm when just friendly bacteria are going about their day. The microbes achieve these tasks either by interacting directly with immune soldiers or indirectly by releasing substances which activate immune cells that only tackle the pathogens.

For instance, the microbiota influences and coordinates the production of antibodies by special immune cells located in the gut. This antibody is an immune-protective molecule known as immunoglobulin Ig(A). Ig(A) is secreted in linked pairs in the gut where microbes reside. These antibodies specifically attach and neutralize pathogens, and the toxins these pathogens are constantly shedding that irritates the gut lining[1]

The friendly beneficial or commensal microbiota assist the host in preventing pathogen infection stimulating the production of anti-microbial factors, gaining space and resources to thrive. Thus, intestinal microbiota contributes to the establish a long-term balance of gut immunity: resisting pathogenic infections, whereas not mounting a response to friendly bacteria. While all of this is occurring in the gut, the protection is systemic. That is, immune cells that are “primed” (trained) in the gut, will eventually migrate to sites as distant as the brain where they form a new immune colony, ready to counteract any local threat.

Intestinal microbiota contributes to the establish a long-term balance of gut immunity: resisting pathogenic infections, whereas not mounting a response to friendly bacteria

What happens when immune cells go rogue?

Several types of experiments have been designed to learn how gut microbiota helps mature our early immune system. Experiments with germ-free (GF) animals (animals bred in sterile, microbe-free environment) or experiments that manipulated the microbiota (either by antibiotic treatment or microbial reconstitution), showed that an altered gut microbiota results in an impaired or inadequately developed immune system.

Researchers noticed two critical aspects of this immune chaos

  1. Reduced number of immune cells: There was a decrease of varied immune cells, and they exhibited reduced protective activity.
  2. Reduced concentrations of messenger molecules: These animals also showed a decrease in the production of “cytokines”- chemical messengers used for communication between host and immune cells. Communication links between cells were either missing or not at all coherent with the microbial reality.

In fact, the absence of a friendly microbiota, or an altered microbiota is like having no teacher at all or a bad teacher that sends mixed signals to the immune system. If there’s no microbiota, the immune system is never exposed to any bacteria to learn from. Why train or create strong communication links if there’s no one at the gates? GF Mice, for example, show a “leaky” unstructured gut wall, with loosely linked cells at the border. It makes sense, why bother maintaining a wall if there is no need to defend it?

On the other hand, a disruptive, unhealthy microbiota is like having a mean teacher that instead of teaching the kids, stirs unrest, provokes chaos and joins the party-throwing chairs out the window. This sustained situation sends contradictory signals to the immune cells that enter an internalized state of hyperactivity, in which they fail to differentiate between friendly bacteria, rogue pathogens and normal gut functioning; the situation becomes so chaotic that even immune cells end up turning against normal cells. This abnormal microbiome to immune cells relationship is correlated with a higher occurrence of autoimmune diseases (AID). Such IAD can be local as inflammatory bowel disease, or even systemic like rheumatoid arthritis, multiple sclerosis, and type 1 diabetes.

Conclusions

While perinatal and early postnatal events are critical periods for the establishment of gut microbiota, as individuals, we may have little control over them. However, as with genes, one may feel that the microbiota developed during our early years is final. If gene therapy seem to finally be able to edit our genes effectively, we certainly can also take positive actions during adult life to help reconstitute the balance in our gut. Diet, intermitted fasting, exercise, along with the use of pre-, pro- and post-biotics may help your immune system to rekindle with a more beneficial microbiota resulting from a more positive environment.

[1] Mantis, N. J., & Forbes, S. J. (2010). Secretory IgA: arresting microbial pathogens at epithelial borders. Immunological investigations, 39(4-5), 383–406.

[2] Katja Maria Bangsgaard Bendtsen: How our gut influences our health, Science Nordic, 2018

[3] Sara Adaes: How the gut microbiota influences our immune system, Neurohacker collective, 2019

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