Thread by @Mucus_Man

🚨🚨I’m very excited (and terrified) to share our lab’s first work (and my first as PI😱)!! We asked a seemingly fundamental question; how do mucus-secreting cells “know” how much mucus they need to secrete? Answering this taught us a lot about susceptibility to #IBD. A 🧵 /1

https://twitter.com/biorxivpreprint/status/1530840872371240960

Mucus is a great solution to separate yourself from the environment (and the potentially harmful microbes in it). Just think of how many organisms secrete mucus, from corals to snails. Luckily, evolution made us non-slimy on the outside. But we use this trick inside our body. /2

Everywhere in our body where there are cells that face the outside world you can find mucus. Our eyes, lungs, mouth, mammary glands, GI and urogenital tracts are all covered in mucus. This mucus limits microbial invasion. It also limits immune response to the environment. /3

How important is this mucus? Well, mice who are genetically engineered to not produce mucus in their gut suffer from chronic inflammation because there is no separation between the gut cells and the microbes in their gut lumen. But how about humans? /4

We know from pioneering work by the @MucinBiology group, and others, that people who suffer from chronic inflammation in their guts (called inflammatory bowel diseases, or IBD) have a penetrable mucus layer. There’s something wrong with their mucus. /5

Because of those mucus defect, bacteria can move across the mucus and trigger inflammation. While we don’t know exactly why the gut produces this flawed mucus in IBD patients, we can get some clues from the genetics of IBD patients. GWAS studies have shown that /6

People with IBD tend to have mutations in genes that are involved in the #autophagy and ER stress response pathways. What do autophagy and ER stress have to do with inflammatory diseases? This is where our original question comes in. /7

How do goblet cells (the cells that secrete mucus) “know” how much mucus they need to secrete? Cells usually have feedback that tells them how much they need to produce of a certain protein. Usually, a secreted protein will lead to a response that stops its further secretion. /8

But mucus is secreted outside of the body. So how do goblet cells know when to stop? Well, we found that an intracellular switch controls mucus secretion, ER stress. This makes sense because constantly producing a lot of proteins will lead to accumulation of misfolded proteins./9

Now, goblet cells can’t just stop producing mucus because of ER stress. Here comes #autophagy to the rescue. We found that activating autophagy reduces ER stress to facilitate mucus production. We even found that we can force excess production of mucus via this axis. /10

When we treated mice with TUDCA, a bile acid that acts as a chemical chaperone, we saw a FLOOD of mucus secreted into the gut lumen. What happens if we limit autophagy activation? We found that inhibiting Beclin1-induced autophagy via Bcl-2 puts a break on mucus secretion. /11

And now for some physiological relevance (just to satisfy @OdedRechavi). We found that boosting mucus production completely changes the microbiome, with enrichment of bacteria that feed on mucus, and protection from chemical- and infection-induced intestinal inflammation. /12

I think it’s very clever to limit protein secretion by ER stress. Making mucus is very costly, and if a cell doesn’t know when to stop secreting, the cell will end up dying from ER stress-induced apoptosis. And without autophagy, the ER stress will stop mucus production. /13

If mucus production is defective, bacteria will come in contact with the gut cells and trigger inflammation. This might explain why mutations in autophagy genes are so prevalent in IBD patients. /14

Now for the credits: This work was spearheaded by the amazing @MariaNaama95 with incredible help from @tel_paz @shirabens @PoranMic @meytaln and all the other Bel lab members who are not on Twitter. We enjoyed a wonderful collaboration with the great @bo_schroeder /15

I must say that we are standing on the shoulders of giants. Our work was only possible because of the works of others that paved the way: Gunnar Hansson and all the @MucinBiology, Arthur Kaser, Richard Blumberg, Timon Adolph, @TheXavierLab, @TStappenbeckMD, @CadwellLab /16

@PhilipCRosensti and many other. Shoutout to @BrianKCoombes for hooking us up with a nasty bug (AIEC) and for providing much needed advice. This work was funded by the ISF, @ERC_Research, ECCO and @azrielifdn. /17

Finally, this work is dedicated to the memory of Beth Levine @UTSWNews, a pioneer and a kind mentor, who is sorely missed. /end