Thread by @Mucus_Man

🚨🚨I'm proud to present our lab's first peer-reviewed paper, out at @cellhostmicrobe🥳. We started out by asking a basic question about mucus secretion, and discovered something surprising about genetic risk to inflammatory bowel diseases (#IBD). A🧵/1
cell.com/cell-host-micr…

Every cell that secretes something needs to have some kind of control over how much it secretes. We asked how goblet cells in the intestine "know" how much mucus they need to secrete. I wrote about it here when we published our #preprint 👇🏻. /2

https://twitter.com/Mucus_Man/status/1530877941638479872?s=20&t=Hhf9XRWDy2UR3g_Vg846Vw

We found that ER stress is the cell-intrinsic switch that tells the goblet cell when to stop producing mucus, and that autophagy is tasked with relieving this stress to allow secretion. /3

Just before we submitted our manuscript to review, @MariaNaama_ tested whether this mechanism works in germ-free mice as well. To our surprise, it turned out that without bacteria, this control of mucus secretion doesn't work, and the mice have a very thin mucus layer 😱. /4

So during the revision process the entire lab rose to the challenge of finding out how the host senses the microbiota to facilitate mucus secretion. We pretty much threw the kitchen sink at this problem, with more than 10 new in vivo experiments. The answer shocked us. /5

Let's take a little break here to talk about genetic susceptibility to IBD. THE most common mutations that predispose to IBD are in the gene #NOD2. It encodes an intracellular sensor of bacteria that activates an inflammatory response to infection. But there is a paradox here: /6

Why do inactivating mutations in a gene that activates inflammation lead to chronic inflammation?? This is counterintuitive. Well, we found out that without Nod2, mice do not respond to reduced ER stress and don't secrete the proper amount of mucus!! /7

We are very excited about this finding because work by @CadwellLab has identified goblet cell abnormalities in Nod2-deficient mice. We think we can now explain why this goblet cell dysfunction occurs, and provide a new hypothesis for the prevalence of NOD2 mutations in #IBD. /8

I want to thank @galette86, the editor at @cellhostmicrobe who first handled our manuscript. Dr Lim always made me feel that her only goal is improving our manuscript and strengthening our conclusions. We often complain about editors, so I want to give credit when it's due. /9

This work was a heroic effort by all lab members and collaborators (@bo_schroeder lab) who worked day and night. and I could not be prouder of this incredible team ☺️ @tel_paz @SoniaModilevsky @PoranMic @meytaln @Mor_Zigdon @shirabens and Twitterless others /10

Finally, we dedicate this work to the memory of Dr Beth Levine. I wish she was here too see it. /end