Tag: inflammatory bowel disease

Categories : GastrointestinalTags :

Research Uncovers Why IBD Causes Blood Clots – and How to Prevent Them

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Irritable bowel syndrome. Credit: Scientific Animations CC4.0

Rates of inflammatory bowel disease are rising, and there’s currently no cure. IBD can also be deadly: up to 8% of people with the disease develop blood clots, which can lead to heart attack and stroke. New research has uncovered why blood clotting malfunctions in IBD – and identified drugs that normalise blood clotting in human cells and animal models of IBD.

“We think we can leverage these findings to reduce inflammation and the risk of blood clots,” says senior author Aaron Petrey, PhD, assistant professor of microbiology and immunology at University of Utah Health, associate director of the U’s Molecular Medicine Program.  “This could be lifesaving.”
 
The results are published in Blood.

Clotting with the brakes off

Most research into IBD has focused on immune cells. But blood cells called platelets are another key contributor to IBD symptoms. In healthy people, platelets clump together into clots in response to injuries to stop bleeding, and don’t form clots otherwise. But in patients with IBD, platelets are on a hair trigger, ready to form clots at the slightest provocation.

Surprisingly, platelets from IBD patients weren’t clotting via the normal pathways that trigger clotting, says first author Rebecca Mellema, PhD, pathology postdoc. “It’s completely independent of what we would expect.”

“There’s an innate mechanism by blood vessels to tell platelets to stay quiet and not form a clot yet,” Petrey explains. “Once there’s injury or inflammation, that signal can switch over and tell them to form a clot. That’s the process that’s broken in IBD patients.”

IBD platelets appear to clot more often because they don’t have enough of a key protein called layilin, the researchers found. In healthy people, layilin acts as a molecular brake for clotting: it senses the difference between healthy and injured blood vessels and prevents platelets from clotting as long as blood vessels are intact.

But when the researchers deleted the layilin gene in mice, the brakes came off. Without layilin, platelets were extra sticky, forming clots when they shouldn’t.

The researchers also found that platelets from IBD patients only had about 60% of the layilin protein that they should, leaving them constantly on the verge of clotting. 

A promising drug target

Layilin prevents unwanted clotting by tamping down the activity of a clot-triggering molecule called Rac1. In mice without the layilin gene – and in people with IBD – Rac1 is always a little bit too active, which means platelets are too prone to forming clots.

But there’s good news. Drugs that prevent Rac1 activity are already in clinical trials for other conditions, and the researchers’ results suggest that these Rac1 inhibitors could be powerful therapeutics for IBD.

One Rac1 inhibitor reduced excessive clotting in human platelets in a dish. The inhibitor also decreased the level of tissue damage in the gut in a mouse model of IBD.

Promisingly, the drug decreased clotting in platelets from IBD patients even more strongly than it affected healthy cells. “We have shown a hyperactivation pathway in resting IBD patient platelets, but they’re also incredibly sensitive to treatment, moreso than those from a healthy person,” Mellema says.

Normalizing Rac1 activity might not only reduce the risk of heart attack and stroke—it could also help alleviate day-to-day IBD symptoms, the researchers say. Excessive clotting can block blood flow in the gut and make inflammation worse, which means that preventing clotting could reduce inflammation.

Unlike established anti-clotting drugs, the researchers say, Rac1 inhibitors shouldn’t lead to an increased risk of dangerous bleeding, which is a serious concern for IBD patients with chronic inflammation. Blocking Rac1 won’t interfere with other, independent pathways that can trigger platelet clotting, so the cells should still be able to form needed clots in response to injury. 

“We’re targeting a pathway that is not pre-activated in healthy people,” Petrey says. “So we can address that step of the pathway, and if there’s a significant injury, the platelets can overcome that inhibition.”

Other groups had been looking into the potential of Rac1 inhibitors to reduce inflammation in IBD. The new work emphasises the potential of these drugs to address multiple symptoms. “Paying more attention to what we can do to address these blood clotting risks could significantly improve patient lives,” Petrey says.

Source: University of Utah Health

Categories : Diet and Nutrition GastrointestinalTags :

Plant-based Diets Must Also Be Healthy to Reduce IBD Risk

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Irritable bowel syndrome. Credit: Scientific Animations CC4.0

A large prospective study published in Molecular Nutrition and Food Research reveals that a healthy plant-based diet is linked with a reduced risk of inflammatory bowel disease (IBD).

For the study, 143 434 individuals in the UK reported on their dietary intake. During an average follow-up of 14.5 years, 1117 participants developed inflammatory bowel disease – 795 cases of ulcerative colitis and 322 cases of Crohn’s disease.

A healthy plant-based diet was associated with an 8% lower risk of ulcerative colitis, and a 14% lower risk of Crohn’s disease. An unhealthy plant-based diet was associated with a 15% higher risk of Crohn’s disease, with results suggesting that this was in part due to higher intake of vegetable oils and animal fats. Fruits and vegetables were identified as protective factors against inflammatory bowel disease.

Blood analyses suggested that the benefits seen in this study might be explained by the anti-inflammatory properties of plant-based foods.

“Our research indicates that a healthy plant-based diet may protect against inflammatory bowel disease, with its anti-inflammatory properties playing a key role,” said corresponding author Zhe Shen, MD, of the Zhejiang University School of Medicine, in China.

Source: Wiley

Categories : GastrointestinalTags :

Could Strawberry Tree Extract Prevent and Treat Ulcerative Colitis?

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Irritable bowel syndrome. Credit: Scientific Animations CC4.0

New research in rats indicates that a Mediterranean plant may be an effective treatment for ulcerative colitis, a type of inflammatory bowel disease. The findings are published in the Journal of the Science of Food and Agriculture.

Various antioxidant and anti-inflammatory medications are used to treat ulcerative colitis, but they can cause numerous side effects. To test the potential of the Arbutus unedo plant (often referred to as the strawberry tree) that is native to the Mediterranean region, investigators gave rats doses of an extract from the plant before exposing the animals to acetic acid, a chemical that induces ulcerative colitis.

The pretreatment prevented changes in the colon’s lining and led to fewer colonic lesions compared with no pretreatment. The pretreatment also caused decreased expression of various proteins that promote oxidative stress and inflammation.

“Our findings suggest that Arbutus unedo should be studied further in preventative and therapeutic approaches to gastrointestinal disorders,” said corresponding author Soumaya Wahabi, PhD, of the University of Jendouba, in Tunisia.

Source: Wiley

Categories : Cancer GastrointestinalTags :

New Findings Reveal Immune Molecules that Drive Inflammatory Bowel Disease

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Irritable bowel syndrome. Credit: Scientific Animations CC4.0

Chronic inflammatory bowel disease is challenging to treat and carries a risk of complications, including the development of bowel cancer. Young people are particularly affected: when genetic predisposition and certain factors coincide, diseases such as ulcerative colitis or Crohn’s disease usually manifest between the ages of 15 and 29 – a critical period for education and early career development. Prompt diagnosis and treatment are crucial. Researchers at Charité – Universitätsmedizin Berlin have now discovered a therapeutic target that significantly contributes to halting the ongoing inflammatory processes. Their findings are published in the current issue of the journal Nature Immunology*.

Sometimes gradually, sometimes in flare-ups – accompanied by severe abdominal cramps, diarrhoea, weight loss, fatigue and a high level of emotional stress – this is how the two most common chronic inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, often begin. While ulcerative colitis only affects the inner lining of the large intestine, Crohn’s disease can involve the entire thickness of the intestinal wall, most commonly in the small intestine, but sometimes also the stomach and oesophagus. Ongoing inflammation can cause lasting tissue damage and increase the risk of cancer. While traditional treatments aim to suppress the immune system as a whole, newer therapies are more targeted: they interrupt the inflammatory process by blocking specific messenger substances that drive inflammation in the body.

The exact causes of severe systemic diseases are still not fully understood. In addition to genetic factors, environmental influences are also believed to play an important role in their development. Prof Ahmed Hegazy has been studying inflammatory processes in the gut and the immune system’s defence mechanisms at Charité’s Department of Gastroenterology, Infectiology and Rheumatology for several years. Together with his team, he has now succeeded in identifying the interaction between two messenger substances of the immune system as the driving force behind chronic intestinal inflammation: Interleukin-22, a protein that supports the cells lining the inside of the gut and helps maintain the protective barrier, and oncostatin M, a signalling molecule that plays a significant role in tissue repair and cell differentiation.

Uncontrolled chain reaction

“At the clinic, we mainly see young patients who just beginning their professional lives. So far, we have only been able to slow down the progression of the disease and alleviate symptoms. But not all patients respond well to existing treatments, so new therapeutic approaches are urgently needed,” says Ahmed Hegazy. In previous work, the research team closely examined the effects of oncostatin M, an inflammation-promoting messenger molecule. This protein, produced by certain immune cells, activates other inflammatory factors – setting off a chain reaction that triggers an excessive immune response. “It was especially interesting for us to see that patients with high levels of oncostatin M do not respond to several common therapies,” Ahmed Hegazy explains. “This means that Oncostatin M levels could help predict treatment failure and may serve as a biomarker for more severe disease. That’s exactly where we focused our efforts: we wanted to understand this signaling pathway better and find ways to block it with targeted treatments.”

The research team spent five years uncovering how the immune messenger oncostatin M triggers inflammatory responses. They began by using animal models, and later studies tissue samples from patients, to examine the different stages of chronic intestinal diseases, State-of-the-art single-cell sequencing showed that – compared to healthy tissue – a much larger number of unexpected cell types in the inflamed gut have receptors for oncostatin M. At the same time, additional immune cells start producing the inflammatory protein. Interestingly, interleukin-22, which normally protects tissue, also makes the gut lining more sensitive to oncostatin M by increasing the number of its receptors. “These two immune messengers work together and amplify the inflammation, drawing more immune cells into the intestine, like a fire that keeps getting more fuel and spreads,” as Ahmed Hegazy relates. “In our models, we specifically blocked the binding sites for oncostatin M and saw a clear reduction in both chronic inflammation and the associated of cancer.”

Targeted therapy for high-risk patients in sight

The researchers found a particularly high number of receptors for the messenger molecule oncostatin M around the tumours in tissue samples from patients with colorectal cancer caused by chronic intestinal inflammation, but not in the surrounding healthy tissue. This observation suggests that this signalling pathway may help promote cancer development. But chronic inflammation does not always lead to bowel cancer, and not every patient is affected in the same way, making treatment and prognosis difficult. With an understanding of oncostatin M’s amplifying effect on interleukin-22, new therapies may be possible.

The team’s experimental findings may soon translate into a real-world therapy: by specifically disrupting the harmful interaction between the immune messengers interleukin-22 and oncostatin M. “Our results provide a strong scientific basis for developing targeted treatments against this inflammation-promoting mechanism in chronic inflammatory bowel disease — particularly in patients with more severe forms of the illness,” explains Ahmed Hegazy. A clinical trial is already underway to test an antibody that blocks the receptors for Oncostatin M.

Source: Charité – Universitätsmedizin Berlin

Categories : GastrointestinalTags :

Compound in Ginger might be a Treatment for Inflammatory Bowel Disease

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Irritable bowel syndrome. Credit: Scientific Animations CC4.0

An international team led by researchers at the University of Toronto has found a compound in ginger, called furanodienone (FDN), that selectively binds to and regulates a nuclear receptor involved in inflammatory bowel disease (IBD).

Through a screen to identify chemical components of ginger that bind to receptors associated with IBD, the team observed a strong interaction between FDN and the pregnane X receptor (PXR). FDN reduces inflammation in the colon by activating PXR’s ability to suppress the production of pro-inflammatory cytokines in the body. While researchers have been aware of FDN for decades, they had not determined its functions or targets in the body until now.

“We found that we could reduce inflammation in the colons of mice through oral injections of FDN,” said research associate Jiabao Liu. “Our discovery of FDN’s target nuclear receptor highlights the potential of complementary and integrative medicine for IBD treatment. We believe natural products may be able to regulate nuclear receptors with more precision than synthetic compounds, which could lead to alternative therapeutics that are cost-effective and widely accessible.”

The study was published recently in the journal Nature Communications.

IBD patients typically start to experience symptoms early in life; around 25% of patients are diagnosed before the age of 20. There is currently no cure for IBD, so patients must adhere to life-long treatments to manage their symptoms, including abdominal pain and diarrhoea, enduring significant psychological and economic consequences.

While patients with IBD have found some relief through changes to their diet and herbal supplements, it is not clear which chemical compounds in food and supplements are responsible for alleviating intestinal inflammation. With FDN now identified as a compound with potential to treat IBD, this specific component of ginger can be extracted to develop more effective therapies.

An additional benefit of FDN is that it can increase the production of tight junction proteins that repair damage to the gut lining caused by inflammation. The effects of FDN were demonstrated in the study to be restricted to the colon, preventing harmful side effects to other areas of the body.

Nuclear receptors serve as sensors within the body for a wide range of molecules, including those involved in metabolism and inflammation. PXR specifically plays a role in the metabolism of foreign substances, like dietary toxins and pharmaceuticals. Binding between FDN and PXR needs to be carefully regulated because over-activating the receptor can lead to an increase in the metabolism and potency of other drugs and signaling metabolites in the body.

FDN is a relatively small molecule that only fills a portion of the PXR binding pocket. The study shows that this allows for an additional compound to bind simultaneously, thereby increasing the overall strength of the bond and its anti-inflammatory effects in a controlled manner.

“The number of people diagnosed with IBD in both developed and developing countries is on the rise due to a shift towards diets that are more processed and are high in fat and sugar,” said Henry Krause, principal investigator on the study and professor of molecular genetics. “A natural product derived from ginger is a better option for treating IBD than current therapies because it does not suppress the immune system or affect liver function, which can lead to major side effects. FDN can form the basis of a treatment that is more effective while also being safer and cheaper.”

Source: University of Toronto

Categories : GastrointestinalTags :

Growing up with Dogs (But not Cats) Protects Against Crohn’s Disease

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Photo by Snapwire on Pexels

Young children who grow up with a dog or in a large family appears to confer some protection later on in life from Crohn’s disease, according to a study presented at Digestive Disease Week® (DDW) 2022.

Crohn’s disease is a common type of inflammatory bowel disease that often develops in young adults, smokers, and those with a close family member who has IBD. Symptoms include diarrhoea, abdominal pain and weight loss. Treatments currently aim to prevent symptom flare-ups through diet modification, medication, and surgery.

“Our study seems to add to others that have explored the ‘hygiene hypothesis’ which suggests that the lack of exposure to microbes early in life may lead to lack of immune regulation toward environmental microbes,” said Williams Turpin, PhD, the study’s senior author and a research associate with Mount Sinai Hospital and the University of Toronto.

Researchers used an environmental questionnaire to collect information from nearly 4300 first-degree relatives of people with Crohn’s disease enrolled in the Crohn’s and Colitis Canada Genetic, Environmental, and Microbial (CCC-GEM) project. Using responses to the questionnaire and historical data collected at the time of recruitment, Dr Turpin and his team analysed several environmental factors, including family size, the presence of dogs or cats as household pets, the number of bathrooms in the house, living on a farm, drinking unpasteurised milk and drinking well water. The analysis also included age at the time of exposure.

The study found that exposure to dogs, especially from ages 5 to 15, was associated with healthy gut permeability and balance between the microbes in the gut and the body’s immune response, which may all help protect against Crohn’s disease. Similar effects were observed with exposure to dogs across all age groups.

“We did not see the same results with cats, though we are still trying to determine why,” Dr Turpin said. “It could potentially be because dog owners get outside more often with their pets or live in areas with more green space, which has been shown previously to protect against Crohn’s.”

Another protective factor seemed to be living with three or more family members in the first year of life, which was associated with microbiome composition later in life. The gut microbiome is believed to play a role in a number of health conditions, such as inflammatory bowel disease, colorectal cancer, diabetes, and high blood pressure.

Dr Turpin and his colleagues hope their findings may assist physicians in asking detailed questions of patients to determine who is at highest risk. However, he noted that the early life environmental factors were assessed by questionnaires, so caution is warranted in interpreting these results due to possible recall bias at recruitment. The reasons dog ownership and larger families appear to provide protection from Crohn’s remain unclear.

Source: Digestive Disease Week

Categories : GastrointestinalTags :

Damaging Candida Strains in Inflammatory Bowel Disease

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Anatomy of the gut
Source: Pixabay CC0

In the human gut, individual strains of Candida albicans are incredibly varied, and some C. albicans strains may damage the gut of patients with inflammatory bowel disease (IBD), according to a new study published in Nature. The findings suggest a possible way to tailor treatments to individual patients in the future.

The researchers used an array of techniques to study Candida strains from the colons of people with or without ulcerative colitis, a chronic, relapsing and remitting inflammatory disorder of the colon and rectum and one of the main forms of IBD. They found that certain strains, which they call “high-damaging,” produce candidalysin, a potent toxin that damages immune cells.

“Such strains retained their “high-damaging” properties when they were removed from the patient’s gut and triggered pro-inflammatory immunity when colonised in mice, replicating certain disease hallmarks,” said senior author Dr Iliyan Iliev, an associate professor of immunology in medicine at Weill Cornell Medicine.

IBD is estimated to affect between one in 11 and one in 26 people worldwide. The condition can significantly impact patients’ quality of life. There are a handful of available therapies, but treatments may not always be effective. The study showed that steroids, one of the common treatments, may not work. Treating mice with steroids to suppress intestinal inflammation failed in the presence of “high-damaging” C. albicans strains.

“Our findings suggest that C. albicans strains do not cause spontaneous intestinal inflammation in a host with intact immunity,” Dr Iliev said. “But they do expand in the intestines when inflammation is present and can be a factor that influences response to therapy in our models and perhaps in patients.”

Most studies of the human microbiome in healthy individuals and those with IBD have focused on bacteria and viruses, but recent studies  by Dr Iliev and others has highlighted the role of fungi. Intestinal fungi play an important role in regulating immunity at surfaces exposed to the outside, such as the intestines and lungs, due to their potent immune-stimulating characteristics. While the mycobiota – the body’s fungi community – has been linked to IBD, the pro-inflammatory of gut the mycobiota was not understood.

In the new study, the investigators initially found that Candida strains, while highly diverse in the intestines of both patients with and without colitis, were on average more abundant in the patients with IBD. But that did not explain disease outcomes in individual patients. So, the investigators set out to identify the characteristics of these strains that cause damage and how they relate to individual patients.

The researchers observed that in the patients with ulcerative colitis, severe disease was associated with the presence of “high-damaging” Candida strains, all of which produce the candidalysin toxin. The scientists showed that the toxin damages immune cells called macrophages, prompting a storm of the pro-inflammatory cytokine IL-1β.

The researchers then grew macrophages in the presence of Candida strains and found that the ability of the strains to induce IL-1β corresponded closely to the severity of colitis in the patients.

“Our finding shows that a cell-damaging toxin candidalysin released by “high damaging” C. albicans strains during the yeast-hyphae morphogenesis triggers pathogenic immunological responses in the gut,” said first author Dr Xin Li.

Experiments in mice delineated that candidalysin-producing “high-damaging” strains induced the expansion of a population of T cells called Th17 cells and other inflammation-associated immune cells, such as neutrophils.

“Neutrophils contribute to tissue damage and their accumulation is a hallmark of active IBD,” said Dr Ellen Scherl, a professor of inflammatory bowel disease. “The indication that these processes might in part be driven by a fungal toxin released by yeast strains in specific patients could potentially inform personalized treatment approaches.”

Consistent with this finding, blocking IL-1β signalling had a dramatic effect in reducing colitis signs in mice that harboured these highly pro-inflammatory strains. The researchers noted that other recent studies have linked IBD to IL-1β in a general way, prompting ongoing investigations of drugs targeting related pathways as potential IBD therapies.

“We do not know whether specific strains are acquired by specific patients during the course of disease or whether they have been always there and become a problem during episodes of active disease” Dr Iliev said. “Nevertheless, our findings highlight a mechanism by which commensal fungal strains can turn against their host and overdrive inflammation.”

The team’s next steps are to investigate the persistence candidalysin-producing strains in the inflamed colon of specific IBD patients, as well as ways to choose patients for mycobiome therapy.

Source: Weill Cornell Medicine

Categories : AgeingTags :

For Older IBD Patients, Vedolizumab is a Safer Option

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Vedolizumab appeared to be safer than tumour necrosis factor (TNF) inhibitors in older adults with inflammatory bowel disease (IBD), according to the results of a large retrospective study.

Vedolizumab is a fully humanised monoclonal antibody which targets α4β7 integrin, and prevents leukocyte movement from the blood into inflamed gut tissue.

At the virtual Crohn’s and Colitis Congress, Bharati Kochar, MD, of Massachusetts General Hospital in Boston, presented data showing that all-cause hospitalisation during the 12 months after initiating biologic treatment was lower in new users of vedolizumab than in those starting TNF inhibitors, with a hazard ratio of 0.81 (95% CI 0.68-0.96)

“The American population is rapidly aging, and the number of Americans 65 and older in 2060 will be more than double what it was in 2014,” Dr Kochar said. “The combination of increasing IBD incidence, improvements in disease treatment-related knowledge, and decreasing IBD mortality is resulting in a high prevalence of older adults with IBD,” she added.

It is estimated that a quarter of Americans over 65 have IBD, yet are less likely to receive adequate immunosuppression. Over 65s are underrepresented in IBD clinical trials, creating a lack of understanding over what medications work or not in this age group.

To answer this question, Dr Kochar and her team analysed a 20% sample of Medicare claims database. Patients were included if they were diagnosed with Crohn’s disease or ulcerative colitis and if they initiated treatment with vedolizumab, infliximab, adalimumab, golimumab, or certolizumab from 2014 to 2018 after being on Medicare for 12 months while not receiving any of those medications.

There were 488 new users of vedolizumab and 2213 initiators of TNF inhibitors in the analysis group, with an average age of 71. More than half were women and most were white, 44% had ulcerative colitis and over half of patients had Carlson Comorbidity Index scores of 2 or higher.

There was otherwise no significant difference between vedolizumab and TNF for IBD-related hospitalisation (HR 0.77, 95% Ci 0.53-1.12), IBD-related surgery: (HR 0.78, 95% CI 0.49-1.22), or new steroid prescription within 60 days of starting the biologic (HR 1.01, 95% CI 0.86-1.18).

In the 6-month period prior to biologic initiation, nearly one-third had a prescription for budesonide, 58% had a prescription for a systemic corticosteroid, and nearly one-third were being prescribed immunomodulators.

“In conclusion, I think it’s important to use your clinical judgment to treat the patient in front of you, and these data should simply help contextualise risk for older IBD patients newly initiating vedolizumab or TNF inhibitors,” said Dr Kochar.

“There is a vast need for additional large and robust comparative effectiveness and safety studies for older adults with IBD, with the rapid proliferation of new IBD medications,” she concluded.

Source: MedPage Today

Presentation information: Kochar B, et al “Comparative effectiveness and safety of vedolizumab and anti-tumor necrosis factor agents in older adults with inflammatory bowel diseases in Medicare administrative claims database” CCC 2021