Tag: gastrointestinal

Intestinal Nutrient Sensors Create ‘Gut Instincts’ for Digestion

Source: CC0

Rare hormone producing cells in the gut secrete hormones in response to incoming food and play key roles in managing digestion and appetite. Researchers have now developed new tools to identify potential ‘nutrient sensors’ on these hormone producing cells and study their function. This could result in new strategies to interfere with the release of these hormones and provide avenues for the treatment of a variety of metabolic or gut motility disorders.

The work, led by led by the Hubrecht Institute and Roche’s Institute of Human Biology, is reported in Science.

The intestine acts as a vital barrier. It protects the body from harmful bacteria and highly dynamic pH levels, while allowing nutrients and vitamins to enter the bloodstream. The gut is also home to endocrine cells, which secrete many hormones that regulate bodily functions. These enteroendocrine cells (endocrine cells of the gut) are very rare cells that release hormones in response to various triggers, such as stretching of the stomach, energy levels and nutrients from food. These hormones in turn regulate key aspects of physiology in response to the incoming food, such as digestion and appetite. Thus, enteroendocrine cells are the body’s first responders to incoming food, and instruct and prepare the rest of the body for what is coming.

Understanding hormone release

Medications that mimic gut hormones, most famously GLP-1, are promising for the treatment of multiple metabolic diseases. The ability to directly manipulate endocrine cells to adjust hormone secretion could open up new therapeutic options. However, it has been challenging to understand how gut hormone release can be influenced effectively. Researchers have had trouble identifying the sensors on cells.

Enteroendocrine cells represent less than 1% of cells in the intestinal epithelium. In addition, the sensors on these cells are expressed in low amounts. Current studies mainly rely on mouse models, but the signals to which mouse cells respond are likely different from those to which human cells respond. Therefore, new models and approaches were required to study these signals.

Enteroendocrine cells in organoids

The Hubrecht team has previously developed methods to derive large quantities of enteroendocrine cells in human organoids. Organoids contain the same cell types of the organ they are derived from. Therefore, they are useful to explore the development and function of cells. Using a special protein, Neurogenin-3, the researchers could generate high numbers of endocrine cells in organoids of the intestine.

Enteroendocrine cells have different sensors and hormone profiles in different regions of the gut. In order to study these rare cells, the researchers needed to make organoids of all these different regions.

Stomach organoids

In the current study, the team managed to enrich enteroendocrine cells in organoids of other parts of the digestive system, including the stomach. Like the real stomach, stomach organoids respond to known inducers of hormone release and secrete large amounts of the hormone Ghrelin. Ghrelin is also called the ‘hunger hormone’ because it plays a key role in signaling hunger to the brain. The Ghrelin production of the stomach organoids confirms that these organoids can be used to study hormone secretion in enteroendocrine cells.

Enteroendocrine cell sensors

Since enteroendocrine cells are rare, researchers have struggled to profile many of these cells. In the current study, the team identified a so-called surface marker, called CD200, on human cells. The researchers used this surface marker to isolate a large number of human enteroendocrine cells from organoids and study their sensors. This revealed numerous receptor proteins that had not yet been identified in enteroendocrine cells.

The team stimulated the organoids with molecules that would activate these receptors and identified multiple new sensory receptors that control hormone release. When the researchers inactivated these receptors using CRISPR-based gene editing, hormone secretion was often blocked.

Therapeutic applications

With these data, the researchers can now predict how human enteroendocrine cells respond when certain sensory receptors are activated. Their findings thus pave the way for additional studies to explore the effects of these receptor activations. The enteroendocrine cell-enriched organoids will allow the team to perform larger, unbiased studies to identify new regulators of hormone secretion. These studies may eventually lead to therapies for metabolic diseases and gut motility disorders.

Source: Hubrecht Institute

Routine Bloods can Improve Cancer Screening in Patients with Abdominal Symptoms

Risk of cancer by specific site based on blood test abnormalities in symptomatic patients can help guide referral strategies

Photo by National Cancer Institute on Unsplash

Incorporating information from common blood tests can enhance cancer risk assessment in patients with abdominal symptoms, according to a study publishing July 30th in the open-access journal PLOS Medicine by Meena Rafiq from University College London, UK, and colleagues.

Early cancer detection is key to successful treatment. However, many undiagnosed cancer patients present to their primary care provider with non-specific symptoms that can be a result of several other benign causes, making it difficult to determine who warrants additional diagnostic testing or referral. Most guidelines focus on “alarm” symptoms specific to a given type of cancer to guide referrals. There is limited guidance on non-specific symptoms to guide cancer assessment and referral decisions across different cancer types.

In this study, researchers used data from the UK Clinical Practice Research Datalink to identify more than 470 000 patients aged 30 years or older who had visited a general practitioner due to abdominal pain or bloating. Within a year of that visit, approximately 9000 patients with abdominal pain and 1000 patients with bloating were diagnosed with cancer. The researchers looked at 19 abnormal blood test results collected during the initial primary care visit to see if they could predict who was more likely to be diagnosed with cancer.

Several blood abnormalities were predictive of cancer risk across sex and age groups. For example, in patients aged 30–59 years with abdominal symptoms, anaemia, low albumin, raised platelets, abnormal ferritin, and increased inflammatory markers strongly predicted a risk of undiagnosed cancer. Among older patients (aged 60 years and above), the presence of abdominal pain or bloating alone was enough to warrant a cancer referral.

The study also showed which types of cancer were most common based on age, sex, and blood test abnormality. For example, among women aged 50–59 years with anaemia and abdominal bloating, the most common types of cancer were bowel and ovarian cancer. This level of granularity can help guide providers on which diagnostic strategies to prioritise.

The study shows that common, routine blood test results can provide additional context in patients with non-specific abdominal symptoms to improve cancer risk assessment and identify patients who warrant additional testing and/or referral to a specialist.

The authors add, “Using existing blood tests can be an effective and affordable way to improve early diagnosis of cancer in people who see their GP with vague symptoms. Our study identified several commonly used GP blood tests where abnormal results increase a patient’s risk of having cancer and these can be used to diagnose cancer earlier.”

Provided by PLOS

Probing the Gut’s Ability to Change Size According to Nutrient Intake

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The gut has considerable plasticity among animals, shrinking as much 50% in cases of fasting such as hibernating and able to rapidly return to normal size on refeeding. Now, scientists from the University of Copenhagen used fruit flies to investigate the signalling mechanisms and cellular changes that regulate this rapidly renewable tissue, which could reveal insights into diseases such as colorectal cancer. Their results are published in Nature Communications.

“Taking advantage of the broad genetic toolbox available in the fruit fly, we have investigated the mechanisms underpinning nutrient-dependent gut resizing,” says Dr Ditte S. Andersen.

The results show that nutrient deprivation results in an accumulation of progenitor cells that fail to differentiate into the mature cells causing the gut to shrink.

Upon refeeding these stalled progenitor cells readily differentiate into mature cells to promote regrowth of the gut.

Ditte S. Andersen continues: “We have identified activins as critical regulators of this process. In nutrient restrictive conditions, activin signalling is strongly repressed, while it is reactivated and required for progenitor maturation and gut resizing in response to refeeding. Activin-dependent resizing of the gut is physiologically important as inhibition of activin signalling reduces survival of flies to intermittent fasting.”

Regulators of organ plasticity are essential for host adaptation to an ever-changing environment, however, the same signals are often deregulated in cancers. Indeed, mutations affecting activin signalling are frequent in cancer cells in a variety of tissues. This study provides a starting point for investigating the link between aberrant activin signalling and the development of colorectal cancers and sets the stage for exploring the efficiency of anti-activin therapeutic strategies in treating colorectal cancers.

Source: University of Copenhangen

An Elusive Relationship Between The Gastrointestinal Immune System and Caffeine

Certain gut microorganisms are thought to contribute to the development of inflammatory conditions such as inflammatory bowel disease (IBD), but the sequence of events leading from microbes to immune cells to disease remains elusive. A new study published in Immunity explores exactly what leads to the generation of Th17 cells, an important subtype of cells in the intestine, and uncovers some of the underappreciated molecular players and events that lead to cell differentiation in the gut. One of those players is the purine metabolite xanthine – high levels of which are found in caffeinated foods such as coffee, tea and chocolate.

“One of the concepts in our field is that microbes are required for Th17 cell differentiation, but our study suggests that there may be exceptions,” said co-lead auhor Jinzhi Duan, PhD, of the Division of Gastroenterology, Hepatology and Endoscopy in the Department of Medicine at Brigham and Women’s Hospital,. “We studied the underlying mechanisms of Th17 cell generation in the gut and found some surprising results that may help us to better understand how and why diseases like IBD may develop.”

While illuminating the steps leading to Th17 cell differentiation, the researchers unexpectedly discovered a role for xanthine in the gut.

“Sometimes in research, we make these serendipitous discoveries – it’s not necessarily something you sought out, but it’s an interesting finding that opens up further areas of inquiry,” said senior author Richard Blumberg, MD, of the Division of Gastroenterology, Hepatology and Endoscopy in the Department of Medicine. “It’s too soon to speculate on whether the amount of xanthine in a cup of coffee leads to helpful or harmful effects in a person’s gut, but it gives us interesting leads to follow up on as we pursue ways to generate a protective response and stronger barrier in the intestine.”

Interleukin-17-producing T helper (Th17) cells are thought to play a key role in the intestine. The cells can help to build a protective barrier in the gut, and when a bacterial or fungal infection occurs, these cells may release signals that cause the body to produce more Th17 cells. But the cells have also been implicated in diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, and IBD.

Duan, co-lead author Juan Matute, MD, Blumberg and colleagues used several mouse models to study the molecular events that lead to the development of Th17 cells. Surprisingly, they found that Th17 cells could proliferate even in germ-free mice or mice that had been giving antibiotics wiping out bacteria. The team found that endoplasmic reticulum stress in intestinal epithelial cells drove Th17 cell differentiation through purine metabolites, such as xanthine, even in mice that did not carry microbes and with genetic signatures that suggested cells with protective properties.

The authors note that their study was limited to cells in the intestine. It’s possible that crosstalk between cells in the gut and other organs, such as the skin and lung, may have an important influence on outcomes. They also note that their study does not identify what causes Th17 cells to become pathogenic, and that further exploration is needed, including studies that focus on human-IBD Th17 cells.

“While we don’t yet know what’s causing pathogenesis, the tools we have developed here may take us a step closer to understanding what causes disease and what could help resolve or prevent it,” said Blumberg.

Source: Brigham and Women’s Hospital

Diverticular Disease Linked to Cancers outside the Gastrointestinal System

Anatomy of the gut
Source: Pixabay CC0

In a large-scale study of cancer among 75 000 patients with a diagnosis of diverticular disease and colorectal histopathology, researchers have reported an elevated cancer risk in patients with diverticular disease. Their findings were published in the Journal of the National Cancer Institute.

The data comes from the ESPRESSO cohort, which covers all histopathology reports from Sweden’s 28 pathology departments. Through linkage with the Swedish national patient register, researchers identified patients with diverticular disease. Diverticular disease can present through gastrointestinal bleeding, but also through diverticulitis when patients may have fever, nausea and abdominal pain. Previous research has focused on colorectal cancer development in diverticular disease but less has been know about cancer development elsewhere. The researchers found a 33% increased risk of overall cancer in Swedish patients with diverticular disease.

“This is the first nationwide cohort study to demonstrate that diverticular disease is associated with an increased, long-term risk of overall cancer”, says first-author Wenjie Ma from Massachusetts General Hospital. “Diverticular disease is associated with an increased risk of specific cancers, including liver cancer and lung cancer.”

She also adds that “Given the high prevalence of diverticular disease, our results highlight the need for awareness for cancer, not only for colorectal cancer, in patients with diverticular disease.”

Patients with diverticular disease had significantly increased overall cancer incidence (24.5 vs 18.1 cancer cases per 1000 person-years). After adjusting for covariates, these rates corresponded to 1 extra cancer case in 16 individuals with diverticular disease followed for ten years.

“There has been a lot of research on extraintestinal cancer in other bowel disorders such as inflammatory bowel disease (IBD) and celiac disease, but less is known about diverticular disease”, says senior author Jonas F Ludvigsson, professor at Karolinska Institutet.

“These data suggest that patients with diverticular disease are at increased risk of other cancers than colorectal cancer, but it should also be emphasized that the absolute risk for cancer was moderate”, adds Ludvigsson. “I hope other researchers are inspired by our findings and explore the biological mechanisms underlying the association between diverticular disease and cancer”, he concludes.

Source: Karolinska Institutet

IBD and Depression is a Two-way Street

Photo by Andrea Piacquadio on Pexels

While irritable bowel disease (IBD) and depression are known to occur together, scientists report a clinical overlap of these conditions in the Journal of Gastroenterology and Hepatology, implying the existence of a two-way relationship. Patients diagnosed with IBD were nine times as likely to develop depression than the general population. Their siblings who did not suffer from IBD were almost two times as likely to develop depression.

Conversely, patients with depression were two times as likely to develop IBD, and their siblings without depression were more than one and a half times as likely to develop IBD.

“This research reveals a clinical overlap between both conditions, and is the first study to investigate the two-way association between IBD and depression in siblings,” said Bing Zhang, MD, a gastroenterologist with Keck Medicine and co-lead author of the study.

The researchers drew on the data of more than 20 million people from Taiwan’s National Health Insurance Research Database. For 11 years, they tracked patients with either IBD or depression and their siblings without either condition, comparing onset of depression or IBD with a control group of people without either condition, but with similar age, sex and socioeconomic status.

Zhang hypothesises that many factors may contribute to the bidirectional nature of the disorders, including environmental stressors, the gut microbiome and genetics.

“The finding that people with IBD are more prone to depression makes sense because IBD causes constant gastrointestinal symptoms that can be very disruptive to a patient’s life,” he said. “And the elevated depression risk among siblings of IBD patients may reflect caregiver fatigue if the siblings have a role in caring for the patient.”

What surprised researchers was that patients with depression were prone to IBD. Zhang speculates that this discovery may have to do with what is known as the gut-brain axis, a scientifically established connection between the gastrointestinal system and the central nervous system, which consists of the spinal cord and the brain.

For example, he said, inflammation of the brain, which plays a role in depression, may be linked to the inflammation of the gastrointestinal tract, a hallmark of IBD.

The researchers are not sure why siblings of patients with depression are more likely to be diagnosed with IBD. Zhang surmises that there may be a shared genetic susceptibility for either disease that presents differently in family members.

Zhang hopes that the study findings will encourage health care professionals to take both family history and the relationship between gastrointestinal and mood disorders into consideration when evaluating or treating patients with either IBD or depression.

Through more research and better understanding of the gut-brain axis, he envisions leveraging the newfound connection between the conditions to improve the prevention, diagnosis and treatment of IBD and mental disorders.

Source: University of Southern California – Health Sciences

Using Ablation Therapy to Treat Stomach Disorders

Photo by Andrea Piacquadio on Pexels

Researchers have shown that ablation therapy, often used to correct an abnormally beating heart, could be used to correct disorders of the stomach such as ‘stomach dysrhythmias’. They outline the results of their work in AJP Gastrointestinal and Liver Physiology.

In normal circumstances the stomach is coordinated by underlying bioelectrical ‘slow wave’ activity, which coordinates the contraction of the muscles that mix and move contents into and through the gastrointestinal (GI) tract.  When these electrical slow waves don’t work as they should, described as ‘stomach dysrhythmias’, it can lead to severe GI disorders and symptoms of nausea, vomiting, pain and bloating, and is often untreatable.

When dysrhythmic activity occurs in the heart it results in atrial fibrillation, which is often treated with ablation therapy in which tissues are precisely ‘burnt’ to control the naturally occurring electricity in the heart. Dr Tim Angeli-Gordon and PhD student Zahra Aghababaie of the ABI have shown that the technique could also be applied to control the naturally occurring bioelectrical “slow wave” activity in the stomach.

With last year’s publication of the team’s initial research using ablation in the stomach, they demonstrated that it was possible to use the technique to block the electrical activation of the stomach in localised regions. “The more recent paper builds on that foundational work and is an important advance because we have now shown that we can eliminate abnormal electrical activation with ablation, and also that the normal electrical activation of the stomach can be restored after ablation,” said Dr Angeli-Gordon. “Although these studies were done in our pre-clinical lab, they demonstrate the powerful potential of ablation in the stomach which may now be able to be translated as a therapy for patients suffering from gastrointestinal disorders.”

Source: EurekAlert!

GI Issues and Anxiety Linked in Children with Autism

Male doctor with young girl patient
Photo by National Cancer Institute on Unsplash

A new study has found a bi-directional relationship between gastrointestinal (GI) issues and internalised symptoms such as anxiety in children and adolescents with autism, which means the symptoms seem to be affecting each other. The findings could inform future precision medicine research aimed at developing personalised treatments for people with autism experiencing gastrointestinal issues. The study appears in the Journal of Autism and Developmental Disorders.

Autism is known to be often associated with GI issues, and is often overlooked in children despite being a source of pain and anxiety. Food preferences are often for carbohydrates and processed foods. The most common cause of GI issues in children with autism are abdominal pain, constipation, chronic diarrhea and gastroesophageal reflux disease (GERD).

“Research has shown gastrointestinal issues are associated with an increased stress response as well as aggression and irritability in some children with autism,” said Brad Ferguson, an assistant research professor. “This likely happens because some kids with autism are unable to verbally communicate their gastrointestinal discomfort as well as how they feel in general, which can be extremely frustrating. The goal of our research is to find out what factors are associated with gastrointestinal problems in individuals with autism so we can design treatments to help these individuals feel better.”

In the study, Ferguson and his team analysed health data from more than 620 under-18 patients with autism who experience gastrointestinal issues. Then, the researchers examined the relationship between the GI issues and internalised symptoms. Ferguson explained the findings provide more evidence on the importance of the ‘gut–brain axis’ in GI disorders in individuals with autism.

“Stress signals from the brain can alter the release of neurotransmitters like serotonin and norepinephrine in the gut which control gastrointestinal motility, or the movement of stool through the intestines. Stress also impacts the balance of bacteria living in the gut, called the microbiota, which can alter gastrointestinal functioning,” Ferguson said. “The gut then sends signals back to the brain, and that can, in turn, lead to feelings of anxiety, depression and social withdrawal. The cycle then repeats, so novel treatments addressing signals from both the brain and the gut may provide the most benefit for some kids with gastrointestinal disorders and autism.”

Ferguson is collaborating with David Beversdorf, a neurologist who also studies gastrointestinal problems in individuals with autism. Beversdorf had recently helped identify specific RNA biomarkers linked with gastrointestinal issues in children with autism.

“Interestingly, the study from Beversdorf and colleagues found relationships between microRNA that are related to anxiety behaviour following prolonged stress as well as depression and gastrointestinal disturbance, providing some converging evidence with our behavioural findings,” Ferguson said.

Ferguson and Beversdorf are now together investigating the effects of a stress-reducing medication on GI issues in a clinical trial. Ferguson cautioned that treatment could be effective for certain people with autism but not others.

“Our team uses a biomarker-based approach to find what markers in the body are common in those who respond favourably to certain treatments,” Ferguson said. “Our goal is to eventually develop a quick test that tells us which treatment is likely to work for which subgroups of patients based on their unique biomarker signature, including markers of stress, composition of gut bacteria, genetics, co-occurring psychological disorders, or a combination thereof. This way, we can provide the right treatments to the right patients at the right time.”

Source: University of Missouri-Columbia

A Touch-sensing Protein Helps the Gut to ‘Feel’

Anatomy of the gut
Source: Pixabay CC0

New research published in the journal Gastroenterology has discovered that a touch-sensing protein is present in the gut, with its presence likely playing a key role in constipation. The protein, called Piezo2, was found using both human gut samples and mice is not just in our fingers, but also in our gut.

“Many people suffer from digestive issues on a daily basis, such as chronic constipation, however we still don’t understand the cause which underlies most of them,” said Lauren Jones, lead author and final year PhD student.

“Our research identified Piezo2 in cells that line the human digestive tract, allowing them to sense physical stimuli, such as touch or pressure, that would occur when food is present. The cells then respond by releasing serotonin to stimulate gut contractions and push the food along.”

Last year, international researchers Ardem Patapoutian and David Julius were awarded the Nobel Prize in Physiology or Medicine for their research on receptors responsible for the perception of touch and temperature, including the discovery of Piezo2, now known to be responsible for sensing light touch on our skin.

Of potential clinical importance, the Flinders research team also discovered that the levels of Piezo2 decrease in the gut with age, and found that if the protein was removed only from gut serotonin cells, gut motility slowed down in mice, causing constipation.

The authors say this could be a potential contributing factor to age-related constipation and provide a possible path to treatment.

Researchers discover a nuclear import mechanism essential for organ growth and development

“Age-related constipation affects 1 in 2 adults over the age of 80, whilst constipation generally affects almost everyone at some point throughout their life,” says Ms Jones.

“It’s therefore extremely important we increase our understanding of the underlying mechanisms, so that we can find targeted solutions to improve the quality of life of the many people who suffer daily from various gut disorders, including constipation.

“This research provides the building blocks for both further research and the development of highly specific treatments to reduce the impacts of constipation.”

The authors say that, though more studies are needed to firmly link Piezo2 to constipation, the research overall is an important advancement into our understanding of gut physiology, opening up new targets for the treatment of digestive issues.

The insights allow for reduced side effects, explained Ms Jones: “More specifically, we now have the potential to create treatments that are taken orally and only directly impact these cells that line the gut, therefore significantly reducing side effects typically seen with many of the current medications.”

Source: News-Medical.Net

A New Understanding of the Fundamental Order of the Abdomen

Source: Pixabay

In a research paper published in Communications Biology, researchers from the University of Limerick have detailed the development and structure of the mesentery. In doing this, they uncovered a new order by which all contents of the abdomen are organised or arranged – or the “fundamental order of the abdomen”, where organs are in one of two compartments.

Professor Calvin Coffey, Foundation Chair of Surgery at UL’s School of Medicine in Ireland, whose major discovery led to the reclassification of the mesentery as a new organ in 2016, has published new research on the makeup and structure of the abdomen.

The importance of these findings on the mesentery and the impact these have on our understanding of the abdomen have been further explained in a review article just published in the Lancet Gastroenterology and Hepatology.

Prof Coffey explained that his team have been looking at the development and structure of the mesentery since 2016.

“We showed how the mesentery is a single and continuous organ in and on which all abdominal digestive organs develop and then remain connected to throughout life,” he explained.

“These findings revealed a simplicity in the abdomen that was not apparent in conventional descriptions of anatomy.”

The international team of researchers used cutting edge techniques to clarify how the mesentery develops and the shape it has in adults.

Their work revealed that the organisation of the abdomen has a remarkably simple design.

“The abdomen is not the dauntingly complex collection of separate organs it was previously thought to be,” said Prof Coffey.

“Instead, all digestive organs are neatly packaged and arranged by the mesentery into a single digestive engine. That simplicity lay hidden until clarification of the nature of the mesentery.”

The model itself was described by the team in the most recent edition of Gray’s Anatomy. The supportive evidence was published in Communications Biology and the clinical importance was explained in the review in The Lancet Gastroenterology and Hepatology.

“The most important finding here was the discovery of the fundamental order of the abdomen. At the foundation level, all contents of the abdomen are simply organised into one of two compartments,” explained Prof Coffey.

“The fundamental order of any structure is of considerable importance, in particular when it comes to diagnosing patients with illness and treating their disease. The fundamental order is the foundation from which all science launches and clinical practice is based.

“The organisational simplicity of the abdomen now immediately explains the behaviours of viral and bacterial infections, cancer, inflammatory bowel disease, obesity, diabetes and many others,” he added.

Improvements in surgery have been made to surgery by a better understanding of the mesentery and its functions, and the new research builds on those advances. There are also exciting areas for future investigation, according to Prof Coffey.

“Patients are already benefiting from what we now call mesenteric-based approaches to the diagnosis and treatment of most abdominal conditions. The Mesenteric Model of Abdominal Anatomy – or the description of the order of the abdomen – is being incorporated into numerous reference curricula at this moment,” he said.

“Regarding the future, it is being argued that we are seeing a paradigmatic shift from old to new order. Already, intriguing questions are emerging that we can call ‘legitimate or admissible’ in the strictest scientific sense. Science can approach numerous questions in a new light.  Clinicians can design diagnostic and treatment approaches based on a new foundation,” Prof Coffey concluded.

Source: EurekAlert!