IBD Flashcards
IBD - Crohn’s and Ulcerative colitis pathology difference in pathology
Crohn’s: everywhere but patchy, can be even outside colon, eye skin.
inflamed patchy ulcers are observed. Some parts are really inflamed, and some parts look OK.
Inflammation can go through all the layers of colon from crypt to mucosa, and epithelial lining is completely destroyed in some areas
In Crohn’s disease, also fat tissue acts weird, it starts to wrap around the colon. Wall gets thickened, there can be fissures/fistulas (cracks inside the thickened walls) and it can even pass the epithelia & go down, and u will have an open wound.
In Crohn’s disease, it reacts the microbiota, and it causes the disease.
Ulcerative colitis: Only colon inflamed
It’s not patchy, you can clearly differentiate between flamed and inflamed parts. More like a continuous inflammation /ulcers.
No healthy tissue at all, ulcers are white. Inflammation is only in the epithelial layer/mucosa! Not deeper. Crypts are completely destroyed, it has random gaps, very weird = no crypt left at all.
Crypt distortions are also seen, where crypts aren’t organized anymore.
There’s massive immune infiltration.
Fat tissue doesn’t act differently.
Even though their sites are different, in endoscopy usually they can’t be distinguished at first sight.
Healthy colon
Pink, smooth, no ulcerations.
There’s a mucus layer on top of the colon. Antimicrobials etc. are being produced to keep the intestine balanced with the bacteria passing. Epithelia under the mucus is always renewed with the stem cells found under the crypts. Cells divide on the bottom of crypt, and become epithelial cells and move upwards to replace the damaged cells. Colon has different layers.
Immune system in gut vs colon - healthy + M cells
Mucus layer in colon is much thicker (compared to where the cells end), and there’s no villi. There’s also much more bacteria in colon. There’s commensal bacteria in small intestine that provides nutrients that body can’t produce itself. Underneath the epithelia, immune cells are found. Stromal cells are really important to keep the stem cell niche intact. Immune cells are instructed not to respond to normal microbiota.
Inside the epithelia, there’s lymphoid follicles with M-cells that transports the bacteria from microbiom inside. DCs are waiting to digest them and present them to immune cells around = it samples what’s inside the microbiome. Then immune cells make IgA against those, and secrete it to lumen. Bacteria are coated with IgA, and controlled in a way, since IgA prevents them from colonizing/attaching to the epithelial lining but still being found in the microbiota! = Great balance. Directed to tolerate them, but prevent them to enter. Innate cells train the adaptive immune cells in such a way that there’s not much immune response to microbiome.
DCs also sample outside by sticking their dendrites out. More likely to happen in small intestine where mucus layer is much thinner compared to the colon.
If the barrier is breached though, there’s so many bacteria that enters and the response will be great and hard to dampen = IBD.
Microbiome role in intestine
It’s also useful to have a healthy gut epithelium, and they can go more forward and become beneficial for allergy responses in distant organs. It’s important to keep the microbiome really diverse to get benefits from it. = healthy and diverse diet can help it.
1) Synthetizes essential metabolites
2) Breaks down plant fibers
Eating fibers are good since it allows certain type of bacteria to live on the intestine, and the short chain fatty acids it creates is very beneficial.
3) Inactivate toxic substances
4) Prevent pathogens to reside
Epithelia defense mechanism - TLR/NODs
NODs, they can sense the bacteria themselves. It leads to activation of NFkB. And epithelia provide proper response to the invading bacteria with production of cytokines, chemokines etc. So it’s a proper balance of tolerating the microbiome inside the gut, but give a strong response once they enter.
M cell placed DC activated T cell pathway -
Bacteria enter through M cell, DCs sample them and present them via MHC, T cells that recognize peptide starts dividing/activated, T cells actually come from the blood stream (endothelial venule). They move inside the Peyer’s Patch, it will go to draining LN and eventually go to blood, they have the right adhesion molecules so they sense where those bacteria are, and pass through the vessels back to the gut, and sit there. And wait for any bacteria to leak inside and mount a proper response for them. B cells also follow the same route, and go back to gut to secrete IgA. Not only they are induced to create a proper response, but they also start secreting the proper adhesion molecules to go to a specific place on the intestine. Those molecules are: Integrin alpha 4 beta 7 – CCR9. Those are induced only when they are activated inside the gut! Ligand for this is MAdCAM-1 expressed on epithelia of intestine.
When there’s way too many response, those molecules are targeted to stop the excessive immune response. Feroluzimab recognizes Integrin alpha 4 beta 7. = block the interaction of MADCAM and Integrin, so immune cells can’t migrate to gut.
Impaired mucus - what happens in gut
If there’s impaired mucus = you get massive influx of bacteria inside colon.
It acts like a wound, activated DCs, macrophages, Interleukins are secreted, more leukocytes are recruited, circulating T-cells via MadCAM are recruited, TH2 cells are activated, NKT cells secrete cytokines that disrupts the epithelia barrier and increases permeability that takes more bacteria in = never ending cycle of inflammation.
You can try dampening the inflammation by cutting down IL secretion, or cutting down T cell entry by interfering with MadCAM and alpha-4 Beta 7.
IBD treatment possibilities:
You can try dampening the inflammation by cutting down IL secretion, or cutting down T cell entry by interfering with MadCAM and alpha-4 Beta 7.
you can try these, but you don’t really know how patient is going to respond. In %30 of patients, Anti TNFalpha works, in 20 percent, Peroluzimab helps = we need better biomarkers to distinguish subgroups of patients, and determine what will work.
Causes of IBD - genetic factors - NOD2
If 1 monozygotic twin has it, the other one has around %40 to get it too. Dizygotic = much less.
So genetic makeup has an impact, but even though you are completely identical with your twin = there’s only %40 chance. = Disease depends on environment a lot.
Key risk allele gene identified in GWAS for developing IBD: NOD2
NOD2 is expressed in intestinal epithelia, it senses PGNs from microbiota which activates it, and it induces NFkB gene expression. It acts on monocytes, and they do immune surveillance in lamina propria. It also leads to TH17 cells, they produce IL17, and need it for Barrier function.
You need IL17/22 for antimicrobial peptides (kills bacteria you don’t want), mucins (forms mucus layer) = generate right diversity in microbiome.
NOD2 -/-: No PGN sensing. Loss of protective response in lamina propria with monocytes / TH17 cells. Much more immune cells come due to bacteria in gut. Much more monocytes, there’s neutrophils, TH1 cells = leading to chronic inflammation. Less mucin, less antimicrobials, more permeability = microbes can come in.
PGN both binds to TLR2 and sensed by NOD2, TLR2 induction normally leads to secretion of IL-12, but NOD2 blocks it. If NOD2 is mutated, NOD2 can’t inhibit IL-12 production, and it leads to Crohn’s.
So that’s why there’s therapy against IL-12 and IL-23 (kind of similarly induced) in market, and that’s unfortunately only effective in some patients.
Prevalence in world -IBD
There’s something wrong with Western lifestyle, but it’s so complex = very hard to identify the components. So they don’t know what exactly causes it.
In Japan for ex, it’s very low, but still going up (marked).
Japanese people migrate to USA = their kids have same prevalence as the people living in USA. Environment effects the development of IBD.
Microbiome in IBD + how to solve the problem
: Altered microbiome observed in IBD patients, some bacteria strains increase, some decrease. In general, diversity of microbiota in these patients gone down!
Everyone born with a microbiome from mom, a baby doesn’t have a complete microbiome = and it develops in 4-5 years after birth. And every individual gets their own unique microbiome, it’s stable, but can be effected by diet, antibiotics etc., if you don’t continuously disturb it with these factors it’s going to stay like that.
To alter the microbiome in a good way as a therapy: Introduce good bacteria, (probiotics) = hard to get a new good strain established in a microenvironment, since it’s already established.
Prebiotics = try to alter the composition by useful nutrients like fibers.
You can introduce good bacteria with fecal transplantation = used for certain intestine diseases, not used for IBD that frequent, since we don’t know clearly the good healthy microbiome, there’s not only bacteria there as well, also viruses, fungi etc. You have to sequence everything.
In some diseases it really works no matter what, eg. Cdiff caused disease.
In IBD, you take feces from a donor that’s not obese = obese people usually don’t have a good microbiome, and you transplant it. There’s superdonors with really good composition which can cure patients.
Remove bad ones. = Antibiotics. Certain ones that aren’t good for sure.
Role of diet in IBD - Vit. A - fiber diet
Vitamin A: Comes with diet, not made in body, it’s converted by intestinal epithelia/DCs to Retinoic acid.
Retinoic acid turns DC into a tolerogenic one, and this tolerogenic DC can convert Vitamin A to Retinoic acid again, and that’s needed for Gut homing molecules, alpha 4 beta 7, Isotype switch to IgA, induce Foxp3 + Tregs. = All immune regulatory events. So you need to get Vitamin A from your diet.
Fibers / no fibers: And composition of microbiome is really different. Check short chain fatty acid production = all three fatty acids they measured reduced with synthetic diet.
SCFAs increase the production of Vitamin A to Retinoic acid converting enzyme! - ALDH
If you have a lot of them = you get more Tregs, IgA, become more toleragenic. And it allows you to home more diverse of a microbiome. So eat fibers!
