Crohn's disease may develop from warped immune cell signaling during bile acid exposure Study reveals how T cells in the small intestine respond to bile acids, offering localized treatment direction for a cause of chronic illness.
April 07, 2021
JUPITER, FL People with Crohn's disease are typically treated with powerful anti-inflammatory medications that act throughout their body, not just in their digestive tract, creating the potential for unintended, and often serious, side effects. New research from the lab of Mark Sundrud, PhD, at Scripps Research, Florida suggests a more targeted treatment approach is possible.
Crohn's disease develops from chronic inflammation in the digestive tract, often the small intestine. More than half a million people in the United States live with the disease, which can be debilitating and require repetitive surgeries to remove irreversibly damaged intestinal tissue.
Writing in the journal Nature, Sundrud's team finds that certain immune cells in the small intestine have evolved a molecular sensing mechanism to protect themselves from the toxic effects of high bile acid concentrations in the small intestine. This sensory mechanism can be manipulated with small drug-like molecules, they find, and the treatment reduced small bowel inflammation in mice.
It seems that these immune cells, called T effector cells, have learned how to protect themselves from bile acids, Sundrud says. These T cells utilize an entire network of genes to interact safely with bile acids in the small intestine. This pathway may malfunction in at least some individuals with Crohn's disease.
Bile acids are made in the liver and released during a meal to help with digestion and absorption of fats and fat-soluble vitamins. They are actively recaptured at the end of the small intestine, in an area called the ileum, where they pass through layers of tissue that contain the body's dense network of intestinal immune cells, and ultimately re-enter the blood stream for return to the liver.
Because they are detergents, bile acids can cause toxicity and inflammation if the system becomes unbalanced. The whole process is kept humming along thanks to an intricate signaling system. Receptors in the nucleus of both liver cells and intestinal barrier cells sense the presence of bile acid and tell the liver to back off on bile acid production if there's too much, or to produce more if there aren't enough to digest a big steak dinner, for example.
Given how damaging bile acids can potentially be to cells, scientists have wondered how immune cells that live in or visit the small intestine tolerate their presence at all. Sundrud's team previously reported that a gene called MDR1, also known as ABCB1, becomes activated when an important subset of immune cells that circulate in blood, called CD4+ T cells, make their way into the small intestine. There, MDR1 acts in transitory T cells to suppress bile acid toxicity and small bowel inflammation.
In the new study, Sundrud's team uses an advanced genetic screening approach to uncover how T cells sense and respond to bile acids in the small intestine to increase MDR1 activity.
The basic discovery that T cells dedicate so much of their time and energy to preventing bile acid-driven stress and inflammation highlights completely new concepts in how we think about and treat Crohn's disease, Sundrud says. It's like we've been digging in the wrong spot for treasure, and this work gives us a new map showing where X marks the spot.
The T cells contain a receptor molecule in their nucleus known as CAR, short for constitutive androstane receptor. Acting in the small intestine, CAR promotes expression of MDR1, and also plays a role in activating an essential anti-inflammatory gene, IL-10, the team found.
When we treated mice with drug-like small molecules that activate CAR, the result was localized detoxification of bile acids and reduction of inflammation, Sundrud says.
Sundrud says exploring the therapeutic potential of CAR activation will require caution and creativity, because CAR is also critical for breaking down and eliminating other substances in the liver, including many medicines.
Ultimately, the Crohn's disease therapy that emerges from this work could be something that activates CAR locally in small intestinal T cells, or something that targets another gene that is similarly responsible for promoting the safe communication between small intestinal T cells and bile acids, Sundrud says.
Also interesting, the team found that the bile acid-inflammation feedback system worked somewhat differently in the colon in concert with gut microbiome factors. While gut flora had more influence on T cell development and function in the colon, it was the nuclear receptor CAR that had more influence on inflammation in the small intestine.
Inflammation plays both positive and negative roles in the body. It can damage tissue, but it also suppresses cancer growth and fights infections. The current anti-inflammatory treatments shut it down systemically, throughout the entire body. That can have potentially serious consequences, such as lowering resistance to infections or easing off the brake on cancer. Directing treatment for inflammatory diseases only to the affected tissue would be preferable whenever feasible, he says.
The roughly 50 million people living in the US with some sort of autoimmune or chronic inflammatory disease are all treated the same, medically, Sundrud says. The holy grail would be to come up with druggable approaches to treat inflammation in only specific tissues and leave the rest of the immune cells in your body untouched, and able to fend of cancer and microbial infections.
In addition to lead author Mark Sundrud, the authors of the study, CAR directs T cell adaptation
Europe Stories
22/04/2021
Barco Announces NEXXIS Partnership with Sigma - Jones AV in India to Accelerate ...
22/04/2021
ES Broadcast acquires archiving solutions specialist Memnon from Sony posted: 21/04/2021
ES Broadcast, a leading provider of end-to-end solutions to the p...
22/04/2021
Reaching a new galaxy: Lawo HOME revolutionizes management of IP broadcast infra...
21/04/2021
21 April 2021
Multi-channel broadcaster enjoys highest ever Q1 share of viewing at 4.73% - an 8.6% growth year-on-year
UKTVs share of commercial impacts (S...
21/04/2021
Maximize and protect your IP with the STN IP Protection Suite . From new users to expert searchers, at all stages of your innovation journey, STN has the soluti...
21/04/2021
Get bigger sound with Omnidirectional Party Sound on the SRS-XP700
Experience P...
21/04/2021
Tekst:
Penta and DADman Ready for Big Sur
Upon thorough testing, we are happy to announce that the most recent DADman version for macOS (v. 5.4.5 build 1) is...
21/04/2021
Etisalat and Nokia provide ultra-fast 5G broadband services in the UAE
Press Release
Etisalat and Nokia provide ultra-fast 5G broadband services in the UAE
...
21/04/2021
ITV named a Top 10 Inclusive Employer by the British LGBT Awards
ITV has been named as one of the top 10 most inclusive employers by the prestigious British LG...
21/04/2021
First look image of Marsha Thomason as DS Jenn Townsend
Guest cast announced The Bay Series 3
The Bay adds over one million viewers as an average of 8 milli...
21/04/2021
Fox Corporation Executives to Discuss Third Quarter Fiscal 2021 Financial Result...
21/04/2021
Let's celebrate the recent nominees and winners of this year's awards season.
Register now
FilmLight is hosting a discussion with the talents who have...
21/04/2021
Delphine Ernotte Cunci, EBU President, launches the TV Assembly 2021...
21/04/2021
Gestmusic, a Banijay Iberia company, confirms it will produce Onliners and Old Timers (Canvi de Xip) in collaboration with Catalan Ministry of Culture for TV3. ...
21/04/2021
Fall back dates for December are still in place, and an announcement on that is expected to be made in June
By Jenny Priestley
Published: April 21, 2021
Fa...
21/04/2021
Chamber music with a Baltic twist
Berlin-based sampling experts Orchestral Tools have just announced the release of Tallinn, a 43GB (92GB uncompressed) soft...
21/04/2021
Maximo Ibarra is due to leave the broadcaster this summer
By Jenny Priestley
Published: April 21, 2021
Maximo Ibarra is due to leave the broadcaster this s...
21/04/2021
All-in-one computer features a Dolby Atmos array
Apple have just announced a new iMac design - the first in their long line of all-in-one computers to be ba...
21/04/2021
Subsidiary of Kazakhstan's Ministry of Digital Development, Innovation and Aerospace Industry and SES will collaborate to deliver high-speed data services v...
21/04/2021
NASHVILLE, Tennessee - April 2021 - Although TobyMac's Hits Deep Tour has been an annual late-winter tradition for a number of years now, this year's tr...
21/04/2021
The full report can be downloaded here or from www.waterwise.org.uk
21 April 2021, UK, London: Fitting one million smart water meters in the UK each year for t...
21/04/2021
TRADING UPDATE 1Q21 Regulated information - Inside information Strong orderbook offers encouraging signs of recovery
Kortrijk, Belgium, 21 April 2021, 7:3...
21/04/2021
As the demand for video and content production grows worldwide, companies of all sizes and industries gradually increase their library of content or media archi...
20/04/2021
Photo credit: Amanda Demme Soleil Moon Frye became a household name upon starrin...
20/04/2021
Designed in a new Silent White colour to reflect the concept of silence and serenity of the noise cancelling headphones
WH-1000XM4 Silent White includes all ...
20/04/2021
The Newest Addition to Sony's E-mount Lens Lineup Offers Extraordinary Resol...
20/04/2021
Net Insight Annual Report 2020 published The Annual Report 2020 is now available on Net Insight's website.
The Annual Report 2020 can be downloaded in pdf ...
20/04/2021
RT reeled in the audience this weekend with an entertaining mix of the best of Irish. A tribute fit for a president, a look back at a year of highs and lows in...
20/04/2021
PIMP YOUR BRAND The evolution, and how it's worth more than money
Read the full article in FEED Magazine HERE
Not so long ago, there was a time when bro...
20/04/2021
Nokia provides 5G private wireless networking to KATCH Network, Japan
Press Release
Nokia provides 5G private wireless networking to KATCH Network, Japan
K...
20/04/2021
Nokia and Chunghwa Telecom accelerate 5G expansion in Taiwan
Press Release
Nokia and Chunghwa Telecom accelerate 5G expansion in Taiwan
Expansion will brin...
20/04/2021
Hugh Laurie To Adapt Agatha Christie's Why Didn't They Ask Evans?' Into BritBox's Biggest Original To Date Company News April 12, 2021
EXCLU...
20/04/2021
Shaun Evans and Roger Allam return for eighth series of Endeavour Company News April 20, 2021
Filming has begun on the eighth series of critically-acclaimed ...
20/04/2021
Shaun Evans and Roger Allam make a welcome return to Oxford to film the eighth series of the critically-acclaimed detective drama Endeavour
Filming has begun o...
20/04/2021
UN Race To Zero' Celebrates Mobile Breakthrough'
Almost Two-Thirds Mobile Industry Committed to Science-Based Carbon Reduction Targets
20 April 202...
20/04/2021
Back
PDF Version
Apr 20, 2021
Dolby Laboratories Announces Conference Call ...
20/04/2021
Broadpeak's CDN Selection Solution Now Available in AWS Marketplace April 20, 2021 umbrellaCDN Optimizes Video Streaming by Enabling Video Services Provider...
20/04/2021
Banijay today announces the acquisition of animation company, Monello Productions. The addition of this producer, alongside Zodiak Kids and Tiger Aspect Kids an...
20/04/2021
Filming has started in Bristol on Chloe, an original psychological thriller, fro...
20/04/2021
Arvato Systems Receives Five Awards as Leader for Microsoft Ecosystems
Top result for Arvato Systems in ISG Provider LensTM
Latest ISG Provider Lens Micros...
20/04/2021
Cupertino, California Apple today unveiled Apple Podcasts Subscriptions, a global marketplace for listeners to discover premium subscriptions offered by their f...
20/04/2021
Sponsored Content
Published: April 20, 2021
Everyone knows that the TV and film industry has gone through fundamental changes over the past 12 months. From ...
20/04/2021
Artist Edition Tracker unveiled
Polish hardware makers Polyend have teamed up with Londons hottest jungle producer Pete Cannon to release a limited Artists ...
20/04/2021
Stats Perform deploys DataMiner Service & Resource Management in the cloud to or...
20/04/2021
Live Captioning - TelVue SmartCaption LIVE posted: 18/04/2021
Introducing SmartCaption LIVE, the smart, affordable way to make your live channels and on...
20/04/2021
Work due to begin on new studios immediately
By Jenny Priestley
Published: April 20, 2021
Work due to begin on new studios immediately
target=_blank titl...
20/04/2021
League has reportedly held talks with the likes of Disney, Facebook and Amazon
By Jenny Priestley
Published: April 20, 2021
League has reportedly held talk...
20/04/2021
LS3/5A production resumes
Veteran UK speaker manufacturers Rogers have just restarted production of the legendary LS3/5A, alongside that of its bigger broth...
20/04/2021
Most affordable MPE synth ever?
West Country synth boffins Modal have released a new portable poly, called the SkulptSynth SE. Based on their 2018 Skulpt, t...
Crohn's disease may develop from warped immune cell signaling during bile acid exposure Study reveals how T cells in the small intestine respond to bile acids, offering localized treatment direction for a cause of chronic illness.
