11 ms·
Researchers identify major driver of inflammatory bowel and related diseases
- datameta 2y agoUndoubtedly several different factors in the BioPsychoSocial model contribute to epigenetic changes like those described in the article.
- sva_ 2y ago> Lee’s research team “stumbled” on the discovery after investigating a “gene desert”, a stretch of DNA on chromosome 21 that does not code for proteins, which has previously been linked to IBD and other autoimmune diseases. Writing in Nature, they describe how they found a section of DNA that behaves like a volume control for nearby genes. This “enhancer” was seen only in immune cells called macrophages where it boosted a gene called ETS2 and ramped up the risk of IBD. > Through gene editing experiments, the scientists showed that ETS2 is central to the inflammatory behaviour of macrophages and their ability to damage the bowel in IBD. Sounds like a win for CRISPR-Cas9
- w10-1 2y agoPartly. The "model" for inflammation that confirms a causal relation doesn't look like it's ever been used before. > To directly confirm that ETS2 was causal, we used CRISPR–Cas9 to delete the 1.85 kb enhancer region in primary human monocytes before culturing these cells with inflammatory ligands, including TNF (a pro-inflammatory cytokine), prostaglandin E2 (a pro-inflammatory lipid) and Pam3CSK4 (a TLR1/2 agonist) (TPP model; Fig. 1d and Extended Data Fig. 2a–c). This model was designed to mimic chronic inflammation16, and better resembles disease macrophages than classical IFNγ-driven or IL-4-driven models17 (Extended Data Fig. 2). i.e., gene editing (by whatever means) is not really a win any more than changing bits in memory is. The win comes from having an in-vitro model that replicates the in-vivo disease, or from correctly identifying the relevant genes (e.g., here ETS2 is the furthest gene considered, and could easily have been excluded).
- ejstronge 2y ago> i.e., gene editing (by whatever means) is not really a win any more than changing bits in memory is. The win comes from having an in-vitro model that replicates the in-vivo disease I take your point, but this would have been a challenging, expensive endeavor before CRISPR-Cas9. Likely, the perturbation would not have been done in the same paper as the announcement of the locus due to the challenge of deletion work before CRISPR-Cas systems became readily available
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- lawrence1 2y agoevery holy grail is 5 years away. i've been reading this for 20 years now.
- deleted 2y ago[deleted]
- spondylosaurus 2y agoHonestly IBD is one area where we've made massive progress in the past few decades. We went from having zero biologics (which means your only options were mediocre oral meds, long-term steroid use, or various -ectomies) to having dozens of biologics that each target one of a handful of major inflammatory pathways. Remicade was the first holy grail :)
- kbf 2y agoI started on Remicade, but sadly I was one of the few who didn’t see results and I managed to get a lot sicker while waiting for it to do its thing. I got put on Upadacitinib and so far I feel a lot better, if it keeps working this well then I’m very happy to just have a pill to take daily. It’s pretty new, but from what I’m hearing it’s very effective.
- spondylosaurus 2y agoFingers crossed for the new pill! I've also heard that JAK inhibitors work wonder for a lot of people who didn't get results from TNF inhibitors. And it's probably way easier to tinker with the dose if need be :P
- jpm_sd 2y agoUpadacitinib has been a huge success for someone in my family. Spectacularly effective. This is after trying the Specific Carbohydrate Diet, 5-ASAs, adalimumab, ustekinumab, and vedolizumab, none of which offered more than minor relief.
- jjtheblunt 2y agoi often thing such claims are progress updates from research groups dependent on government grants for funding, so they need to assert they will still need a next round of funding.
- w10-1 2y agoFor auto-immune diseases, the question is always whether suppressing over-activity will cause more disease than it prevents. In this case, the pathway affects macrophages, leucocyte activation and migration, and production of 3 inter-leukin's and other cytokines -- which doesn't offer much hope at avoiding off-target effects. As they mention, this gene is shared as far back as other proto-humans, so it's likely essential. And they didn't really need this finding to consider targeting (toxic) MEK at macrophages using antibodies, particularly since GI drugs can be made relatively non-absorbable, further reducing off-target effects. But since these are chronic diseases with wide variations between patients of severity and tissue involvement, and since macrophage activity is relatively acute, the narrow therapeutic range of a MEK-based drug is far from ideal: too much opportunity for overdose. So I hope this stimulates more investigation of the ETS2-mediated pathways, but I don't hold out much hope for a MEK + Ab drug for IBD.
- incomingpain 2y agoThe major breakthrough is that perhaps a genetic test will be able to identify you. That perhaps there's a drug in a decade from now that might help?
- bpodgursky 2y agoI haven't looked in depth but the risk allele info here is probably enough for embryo screening.
- hi41 2y agoMy son has Crohn’s disease. He was very thin and underweight and under height compared to his peers. My wife and I tried to understand what we did wrong raising our son. Did we feed him too much cheerios. Did we give him too much sugar, bread. Somehow the modern diet is not suiting my son. I feel very guilty for giving the chronic disease to my son with the food choices I made as a parent.
- ceejayoz 2y agoNothing in this research appears to indicate fault of any kind; rather, a genetic cause. > Lee’s research team “stumbled” on the discovery after investigating a “gene desert”, a stretch of DNA on chromosome 21 that does not code for proteins, which has previously been linked to IBD and other autoimmune diseases. Writing in Nature, they describe how they found a section of DNA that behaves like a volume control for nearby genes. This “enhancer” was seen only in immune cells called macrophages where it boosted a gene called ETS2 and ramped up the risk of IBD. As parents we make plenty of real mistakes; blaming ourselves for unavoidable stuff isn't worth adding to the pile.
- Projectiboga 2y agoDon't feel bad there are huge corporations and even the government pushing some foods. And the risk gene is rare, like less than 2% Have you tried getting your son off all milk products for a few weeks? And really try and avoid non organic wheat, as it is harvested with roundup which is implicated with leaky gut syndrome.
- Turing_Machine 2y ago> And really try and avoid non organic wheat, as it is harvested with roundup That appears to overwhelmingly not be the case, at least in the United States. https://www.snopes.com/fact-check/wheat-toxic/ https://www.snopes.com/fact-check/wheat-toxic/
- extragood 2y agoI have Crohn 's disease and it's never occurred to me to fault my parents. It is a genetic disease, and I can only hope that the doctors you've worked with have helped you to understand the basics so you can educate yourself and help your son. There's been a lot of really encouraging progress in the 15+ years since my diagnosis, but there are still a lot of unknowns. I got very little support in the dietary side of things other than the infamous elimination diet approach. It took a while for me to dial it in, but I did and am very rarely sick these days, now that I've discovered my own food sensitivities. As much as you may want to solve this problem for him, it will take an immense amount of maturity on his part to want to discover and understand his limitations and to create and stick to a sustainable lifestyle.
- surfsvammel 2y agoAnyone got a link for the actual study paper?
- breezeTrowel 2y agoHere you go: https://www.nature.com/articles/s41586-024-07501-1 https://www.nature.com/articles/s41586-024-07501-1
- solfox 2y agoI was diagnosed with Crohn's disease when I was 13. I was on various 3x-daily anti-inflammatory medications; doctors said I would be on them the rest of my life. I started going to therapy as an adult and made a lot of progress in my mental health. I went off my medications 5 years ago and have been healthy since without intervention - I give a lot of credit to this work. I don't think we fully understand the role of the mind/emotions in health; my advice to anyone suffering from IBS and the like is not to forget the mind component to overall health. When you're suffering in your head, it can sometimes manifest in your body. Gabor Maté talks a lot about this connection: https://www.youtube.com/watch?v=1fPQ7Oc44SU https://www.youtube.com/watch?v=1fPQ7Oc44SU
- voisin 2y agoCan you speak more about the type of therapy you undertook? I have a few non-threatening but otherwise annoying autoimmune disorders and my bloodwork, diet, and exercise are all good but have wondered if there is some underlying stress that could be exacerbating things. I’ve considered therapy but honestly have no idea where to start as there are a lot of different modalities and each are expensive (both in money and time) to spend 12-26 weeks exploring with sufficient depth before determining whether or not it “worked” and then trying another. After reading Pollan’s “How to Change your Mind” I have wondered if Psychedelics could be the answer to resetting pathways.
- bwb 2y agoYou might look at aip diet. It is more gut centric but good results for MS and similar.
- solfox 2y agoI think you have to actually try out a modality or two before landing on the therapy that works best for you. Somatic trauma work was truly incredible for me because I was so locked in my mind - but it’s less evidence-based than say CBT which is proven to work for all sorts of mental health. Pollan is great! I’d be happy to chat more with you - send me a PM.
- kunai 2y ago
- JohnMakin 2y agoGod I hope something comes out of this. I have IBD, and it's very difficult to put into words people can relate to how debilitating, uncomfortable, inconvenient, embarrassing, and painful these conditions are.
- Spod_Gaju 2y ago[dead]
- wittystick 2y agoWhat about Arthiris? There's some link between UC and RA. I get both flare up at the same time, and I use the same medication (Azathioprine) to keep both in remission.
- spondylosaurus 2y agoIt sounds like ETS2 for sure has implications for spondylitis, although unclear to me whether it's a direct link or just because a lot of people who have IBD also have spondylitis. If it's the former, then my guess would be that there's a link to other types of arthritis as well.
- dillutedfixer 2y agoI was diagnosed with UC in my mid-30's, am in my early 40's now. I used to deal with flare-ups about twice a year that always coincided with allergy season (May and October/November). I was living in Colorado at the time and was drinking lots of heavy craft beer quite regularly. Three years ago, I cut out about 98% of alcohol from my life, and when I drank, I only drank clear things - hard seltzers and gin. But only once or twice a month at the most. I hadn't had a flare-up in that entire time, until this last holiday weekend when I drank whiskey and was hit with horrible UC symptoms immediately. As someone in the throes of a flare-up right now, I have to say that research like this is promising. But yeah, for me alcohol, primarily darker alcohol like whisky and red wine, are an absolute trigger for me.
- careless_lisper 2y agoHave you ever looked into histamine intolerance?
- marmadukester39 2y agoSeconding this. Low histamine diet has been a game changer, combined with fasting to give my gut a break.
- archsurface 2y ago"More than half a million people in the UK have inflammatory bowel disease, the two main forms of which are Crohn’s disease and ulcerative colitis, with at least 7 million affected globally" - either "at least" is doing a lot of work, or something is going on in the UK.
- erehweb 2y agoMaybe because of race. From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130615/#:~:text=Crohn's%20disease%20is%20found%20in,3%5D%E2%80%93%5B12%5D https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130615/#:~:tex.... "Crohn's disease is found in all racial groups worldwide. However, historically, the highest prevalence rates have been reported in white populations, particularly those of North America and Europe, with significantly lower rates seen in black and Asian populations within these or any other foreign country"
- Spod_Gaju 2y ago[dead]
- jononomo 2y ago[flagged]
- JohnMakin 2y agoI have noticed high amounts of animal protein and fat sometimes alleviates my symptoms, but sometimes makes them worse.
- naasking 2y agoMaybe it's cured or other processed meats that are worse? It was thought that red meat was linked to prostate cancer but it turned out to be all due to processed and cured meats. Perhaps the high salt content.
- hombre_fatal 2y agoOr look for a dietary pattern that helps your IBD but isn't atherogenic and doesn't require you to dismiss the science on saturated fat and CVD like Shawn Baker / Revero. Else you're just trading one problem for another.
- jononomo 2y agoPlease read The Big Fat Surprise by Nina Teicholz to get the "science on saturated fat and CVD". You will find that it supports my perspective. Phenomenal book -- deeply researched over ten years and well-written.
- kunai 2y agoIt's better to attempt elimination diets rather than a single type (low-fodmap, specific carb, carnivore, etc.) What works for one person may not work for everybody.
- jononomo 2y agoThe carnivore diet is the ultimate elimination diet. The strict version (in which you eat nothing but ribeye steak) is nutritionally 100% complete and there are people who have been thriving on this diet for over a decade now. Meat is the food that human beings evolved on. Just try it and see for yourself.
- jononomo 2y ago[flagged]
- dsjoerg 2y agocan you provide a link to the research in support of this?
- kunai 2y agoThis is irresponsible advice. Some people find that meat alleviates their symptoms while other people find more relief from going vegetarian. Recommending a single type of diet (especially a "fad" diet like the carnivore diet, rather than one with some type of scientific basis like low-fodmap or specific carbohydrate diets) as a panacea is not going to work for most people. People can and should try elimination diets instead, where you eliminate all but the most basic of foods and slowly reintroduce foods over time to see which ones are triggers. It's entirely possible you or someone you know saw great success with a carnivore diet, but others trying it might not see the same results and need one tailored to their specific gut microbiome.
- amanaplanacanal 2y agoIt’s not uncommon to start your elimination diet with meat only.
- seattle_spring 2y agoCan you share some links or literature backing this claim up? I've done a few elimination diets and they did not start anywhere close to "meat only."
- jononomo 2y agoBeef-only is the ultimate elimination diet. You literally eliminate absolutely everything except beef. And beef contains 100% of the nutrients you need in order to thrive in life. There are people who have literally eaten nothing but ribeye steaks for over ten years now. Also, consider the fact that agriculture is only about 12,000 years old, but human beings have been living on Earth for about 200,000 years (in our current form -- a couple million if you include Homo Erectus and the other variations). We were basically 99% meat-eaters for the vast vast majority of human history. I follow a diet that is basically 100% beef, eggs, salmon, and milk (planning to cut out the milk) and I can assure you that it is the easiest possible diet for your digestive system. (For one thing, you completely stop farting.). You have never known poops so small, easy, and quick (because 99% of what you eat is simply absorbed - this diet has no fiber). Note that there is no truly satisfactory "literature" on ANY diet, because double-blind randomized controlled trials that are of a long enough duration and over a large enough sample size are basically impossible to conduct. The human body is the most complex thing that we know of in the universe. However, you can follow the work of Dr. Ken Berry or Dr. Shawn Baker to learn more about the carnivore diet -- they've been neck deep in it for years. And the anecdotal evidence is becoming overwhelming -- check ou the success stories at the carnivore.diet website.
- blastadon 2y agoI was diagnosed with colitis in my early 20s. Since I was 13, I had been using an acne medication containing benzoyl peroxide daily. Once I stopped using this medication, my symptoms drastically improved. While I can't prove it, I believe the acne medicine may have triggered my colitis.
- kunai 2y agoDoesn't seem like that far of a stretch given that Accutane (another acne medication) has been linked to IBD as well. There are a lot of drugs that interfere with the gut microbiota, of which its dysbiosis is often linked to the development of IBD. We're still in the infancy of understanding the pharmacokinetics of drugs as far as they relate to the gut and the ability of drugs to modulate the microbiome.
- jnwatson 2y agoIsotretinoin and benzoyl peroxide are not remotely similar drugs. They have completely different mechanisms of action. That they both treat acne is essentially a coincidence.
- marmadukester39 2y agoI went down a rabbit hole looking for something I could take now that would influence this pathway and came across a study suggesting a particular flavonoid, cumaroyl, might work; if I'm interpreting this right it appears in ginko leaves, so I'm going to see if they have any effect.
- ElijahLynn 2y agoSource: https://www.nature.com/articles/s41586-024-07501-1 https://www.nature.com/articles/s41586-024-07501-1