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Crohn's disease and the role of microbes

Writing some information to make the video more clear.

Intestinal mucus consists of different layers. The outer mucus layer is colonized with bacteria. It is also mobile, it physically moves which prevents bacteria from easily attaching themselves to inner mucus, it is a very thin layer. There are much less bacteria in inner mucus, because for one, the outer mucus keeps them at bay, and secondly because of antibodies (they're secreted by plasma cells in deeper tissue) and antimicrobial proteins.

Below the mucus is a sheet of epithelial cells, they're closely held together with tight junctions, epithelial cells absorb nutrients, water and form a barrier of tissue.

Bacteria are not supposed to interact with epithelial cells nor attach to them. Epithelial cells can sense bacteria with their TLRs, specialised Paneth cells in the small intestine have those TLRs too.

Those TLRs should not ring all the alarm bells if some commensal happened to cross the mucus layer by accident. To prevent the immune system from going haywire every time a harmless bacteria got lost, those TLRs are strategically placed. TLR2 and TLR4 are found on the cell surface and won't make much of a scene.

TLRs that detect pathogenic flagellin like TLR5, on the other hand, are found deeper in tissue, and when they detect bacteria, they are pathogens and they will ring the alarm bells.

Often images have this pictures of a dendritic cell that seems to poke out of the epithelial barrier, you can see it on the top right on the image of the video. They never explain what it is actually doing.

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The dendritic cell is simply sensing for antigen, they have their own TLRs, they are usually creating tolerance, so the immune system doesn't overreact to commensal bacteria. They can also activate the adaptive immune system of course, with antigen presentation, in case they encouter an actual pathogen.

The immune system generally wants to leave commensal bacteria alone, they actively help the immune system on the surface, by lowering pH and can release their own antimicrobial peptides.

When a pathogen actually enters tissue and TLRs spot them, an army of macrophages that have waited in tissue below the epithelial barrier, in the lamina propria, are activated.

In crohn's disease, those macrophages are not competent enough to kill the invading pathogens, so you end up with macrophages that are chronically activating the adaptive immune system, and you get chronic inflammation.

One of those bacteria exploiting this situation, is AIEC, which is very good at evading all the above mechanics.
 
Note when M cells are mentioned in CD studies, this generally refers to the small intestine, specifically peyer's patches. Unlike the rest of the intestine, M Cells are not protected with mucus, they can take up antigen for antigen presenting cells like DCs.

But many bacteria have become very good at invading those M cells, not surprisingly, AIEC favorite way to get into tissue, is by invading M cells, which probably explains why AIEC are associated with ileal disease and less so colonic disease (colon has no peyer's patches).

My theory as to why crohn's disease diagnosis is around the ages 14-20, is the activity of peyer's patches around puberty.
 
Coombes argues in the video that we find AIEC in 45%-70% of crohn's patients, which is true. He argues we will likely find AIEC in 100% of patients. I don't think 100% of patients, since there is always a 10% of patients in infectious diseases where the cause is something completely different, there is also a small group of patients who were diagnosed as having crohn's disease who clearly don't have crohn's disease.

But we're going to discover more AIEC once we have better testing.

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Note when M cells are mentioned in CD studies, this generally refers to the small intestine, specifically peyer's patches. Unlike the rest of the intestine, M Cells are not protected with mucus, they can take up antigen for antigen presenting cells like DCs.

But many bacteria have become very good at invading those M cells, not surprisingly, AIEC favorite way to get into tissue, is by invading M cells, which probably explains why AIEC are associated with ileal disease and less so colonic disease (colon has no peyer's patches).

My theory as to why crohn's disease diagnosis is around the ages 14-20, is the activity of peyer's patches around puberty.
Around this age kids usually gain more independance, and therefore make their own food choices, which are much worse then their parents would allow.
 
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