2.1 Homesteading (1)

We discussed in the previous chapter that the gut has a cellular wall around it composed of human epithelial cells as well as the fluid mucus layer. Both act as a physical barrier; however, our mucus provides a sort of no-man’s-land where phages wait for prey and microbes establish their niche. The mucus that lines our GI tract is secreted by goblet cells which are part of the gut-associated lymphoid tissue (GALT) system.

The GALT facilitates host-microbe interaction.  In addition to goblet cells, there is also a vast array of human immune cells collectively called lymphocytes. Serving primarily as a defense squad just in case an intrepid microbe decides—Ocean’s 11 style—that it is more lucrative to leave the gut and grab nutrients directly from our bloodstream, GALT cells are busy doing background checks on our microbial inhabitants to make sure that they have the proper permit (usually by sampling the lipopolysaccharide (LPS) chains that microbes wear on their surface like so many pieces of flair) to homestead in our guts. Lymphocytes patrol the host side of the epithelial barrier to prevent leakage of fecal microbes into the body; some, like dendrites, even snake their long arms through the junctions of the epithelial cells to feel if there are any microbes that don’t belong in the upper mucus layer.

As microbes move into our virgin guts for the first time, they have to be able to communicate with the human cells that already live there. This interaction with the locals ensures that they will get the proper permits to settle and build in their niche. The permits come from the gut chapter of our immune system: the GALT. The GALT defenses against interlopers consist of organized Peyer’s patches. These are essentially mini lymph nodes[1].  Peyer’s patches act as sites that regulate the activity going on in the gut by monitoring the microbes that live there. They do so by communicating back and forth with gut epithelial cells as well as with the microbial population thriving in the lumen. This conversation is extremely nuanced and has many diverse components that we are still trying to understand. Roughly, what happens is that immune cells in the GALT learn which microbes are residents and which are invaders. This education happens both through microbial signaling (negotiations with the local law) as well as what human epithelial, dendritic, and antigen presenting cells signal to the human biont. The GALT learns which microbes have legitimate niches and which are potentially pathogenic invaders. The human cells in the Peyer’s patches have PRR’s that recognize a wide range of different microbes. Through communication with colonizing microbes, the puzzle-piece pockets of TLR’s and PRR’s can be cultivated to only recognize LPS chains or other surface features of unfriendly bacteria or viruses. Scientists call this process becoming tolerized[2]. Over time, PRR’s that recognize commensal microbes and sound false alarms to our immune system are removed (i.e. negative selection) as our immune system becomes tolerized to our gut inhabitants. Any invading microbe that doesn’t look like the others will be recognized by immune cells as non-self and dangerous, causing the GALT to set in motion reactions that will try to kill the invader. In a nice evolutionary dance, our GI ecosystem has processes with checks and balances that not only allow massive amounts of foreign material to pass through it but also beneficial strangers to cultivate it, yet it still can mount an effective defensive response to any threat.

[1] Regions of high lymphocyte concentrations. We like to think of them as the fire stations where all the cops, paramedics, and firefighters of a city hang out, waiting for an emergency call.
[2] Tolerized is the act of acquiring immunotolerance to a particular antigen (a microbe) that could be seen as pathogenic under other circumstances. Tolerization begins at birth and is a lifelong process as our immune system is exposed to various non-self elements and must determine which are potentially harmful and which are if not beneficial at least benign. Becoming tolerized to non-threatening elements is very important because rampant immune response can be quite damaging to the body as anyone with allergies or an auto-immune disease can attest. Tolerization give our holobiont adaptive flexibility as we constantly shift environmental pressures.

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