US Pharm. 2023;48(12):23-27.
Gastrointestinal Viruses Surged After Decline During COVID-19
Following the first stay-at-home orders issued in the United States to curb the spread of COVID-19, gastrointestinal viruses such as norovirus, rotavirus, and adenovirus all but disappeared from California communities and remained at very low levels for nearly 2 years. The research was published in the Journal of Clinical Microbiology, a journal of the American Society for Microbiology.
Interestingly, these viruses surged back to prepandemic levels in late 2022, said Niaz Banaei, MD, professor of pathology and medicine (infectious diseases), Stanford University, and medical director of the Clinical Microbiology Laboratory, Stanford Health Care. “Adenovirus F40/41, the adenovirus strains most frequently associated with gastroenteritis, actually jumped to levels twofold higher than prepandemic levels.”
Dr. Banaei suspects that the surge in viral infections was enabled by the waning of collective community immunity from lack of exposure during the pandemic. “Something similar has been described for the surge in respiratory syncytial virus infections in 2022,” he said.
To identify changes in the prevalence of gastrointestinal pathogens, the investigators compared detection rates for community-acquired gastrointestinal pathogens before, during, and after California’s COVID-related shelter-in-place. They used a polymerase chain reaction (PCR) panel test called the BioFire FilmArray Gastrointestinal Panel, which tests for 22 of the most common pathogens that cause diarrhea, and analyzed about 18,000 tests that were taken from January 2018 to December 2022.
The motivation for the research was the change in the rate of positives for certain pathogens during the COVID-19 pandemic, said Dr. Banaei. “It immediately became clear that the pandemic lockdown and shelter-in-place had created a natural experiment to investigate the transmission dynamics of pathogens causing gastroenteritis.”
The research offers a unique window into the biology of gastrointestinal pathogens, raising some new research questions, said Dr. Banaei. “Why did some disappear while others persisted unaffected during lockdown? Why are some now surging to levels we haven’t seen before?”
Improved understanding of these phenomena could lead to ways to interrupt pathogens’ spread, particularly in low- to middle-income countries where gastroenteritis remains a major cause of illness and death, especially among children. “It may also help us prepare for future unforeseen pandemics,” he added.
Genetics Links in Endometriosis and IBS
University of Queensland (UQ) researchers in Brisbane, Australia, have shown that endometriosis and irritable bowel syndrome (IBS) share genetic risk factors, explaining why patients with one condition may also have the other.
Grant Montgomery and Sally Mortlock at UQ’s Institute for Molecular Bioscience found a significant relationship between the risks for endometriosis and common gastrointestinal disorders, such as IBS, peptic ulcer disease, and gastroesophageal reflux disease (GERD).
“This genetic finding supports the clinical observation of an increased incidence of gastrointestinal disorders in women with endometriosis,” Dr. Montgomery said. “We hope that this study will raise more awareness about the overlap of these conditions.”
Endometriosis is a severe condition affecting one in seven women that is caused by tissue that resembles the uterine lining growing outside the uterus. Women with endometriosis are twice as likely to have an IBS diagnosis compared to women without the disease and 1.4 times more likely to have a diagnosis of GERD.
“Sufferers can find it difficult to distinguish the source of their pain, leading to confusion or misdiagnosis and years of delay in treatment during which time the endometriosis can progress to more severe disease,” Dr. Montgomery said.
“Endometriosis should be considered as a possible cause if a woman presents to her GP [general practitioner] with abdominal pain and gastrointestinal symptoms. As our knowledge of risk factors for endometriosis increases, we hope to move closer to understanding how the disease develops and improve treatments and diagnosis,” he added.
Older Adults With Digestive Diseases Have More Loneliness, Depression
While life expectancy rates for older Americans are rising, nearly 40% of adults report living with a digestive disease of some kind.
“Many people don’t realize that these conditions are very common in ambulatory care,” said Michigan Medicine gastroenterologist Shirley Ann Cohen-Mekelburg, MD, who specializes in conditions such as inflammatory bowel disease, Crohn’s disease, and ulcerative colitis.
“Ultimately, this creates an excess in healthcare spending in the U.S. Not only are these conditions debilitating for the millions of people living with them, but they’re also very expensive to treat.”
Dr. Cohen-Mekelburg says that in recent years there has been a greater emphasis among providers in detecting why so many Americans are developing digestive diseases. However, she notes that current approaches often fail to consider how things like psychosocial factors contribute to these conditions.
“As physicians, it’s important for us to pay attention to psychosocial factors involved in the lives of our patients, but they often go overlooked,” she said. “These factors have the potential to significantly impact gastrointestinal health, and they also play a crucial role in the overall well-being of our patients.”
This notion inspired Dr. Cohen-Mekelburg and a team of fellow gastroenterologists and hepatologists to examine the rates of loneliness, depression, and social isolation in older adults both with and without digestive diseases. Their findings were published in Clinical Gastroenterology and Hepatology.
Dr. Cohen-Mekelburg noted that the team also “wanted to quantify these numbers with self-reported rates of poor health. Our research involved analyzing data from 2008 to 2016 from the University of Michigan Health and Retirement Study. This is a longitudinal panel study that involves a representative sample of approximately 20,000 individuals in the U.S. who are 50 years and older, as well as their spouses,” she said.
“It’s important to note that loneliness refers to the subjective distressed feeling of being alone or lacking companionship. The correlation between loneliness and depression is well established.” However, Dr. Cohen-Mekelburg adds that social isolation refers to the “objective physical separation from other people, which is independent of psychological well-being.
“Therefore, there are people who live in isolation but are well-adapted, not lonely, and report high psychological well-being. But on the other hand, there are also people who are socially connected, yet suffer from low psychological well-being and loneliness. This, despite having a strong social network.”
Out of a pool of 7,110 participants, the team identified 56% of individuals with a digestive disease and 44% without one. “Overall, 60.4% and 55.6% of respondents with and without digestive diseases reported loneliness, while 12.7% and 7.5% reported severe depression, and 8.9% and 8.7% reported social isolation, respectively,” said Dr. Cohen-Mekelburg.
“We found that individuals with a digestive disease were more likely to report ‘poor-or-fair’ health when compared to those without one. And among patients with a digestive disease, loneliness as well as moderate-to-severe depression were associated with greater odds of self-reporting ‘poor-or-fair’ health.”
Dr. Cohen-Mekelburg said that she hopes these findings eventually empower gastroenterologists to “screen patients for depression and loneliness” in addition to their physical symptoms. “By doing this, providers can better establish care pathways for mental health treatment for their patients, which is hugely important,” she said.
“Our research shows that gastroenterologists are in a unique position to help their patients achieve good overall health. If you’re a clinician who also happens to treat older adults, even better. Being aware of the link between loneliness, depressive symptoms, and digestive diseases can really benefit your patients from a holistic perspective.”
Early Broccoli Exposure Protects Against Colitis in IBD
High-fiber diets, such as those that include broccoli sprouts or other cruciferous vegetables, may reduce disease symptoms and improve quality of life in patients with inflammatory bowel disease (IBD), according to a study conducted in mice. The study was published in mSystems, a journal of the American Society for Microbiology.
In the study, the investigators used a popular interleukin-10-knockout (IL-10-KO) mouse model of Crohn’s disease to investigate the interactions between mice and their immune systems, as well as the broccoli sprout diet, microbes within the Crohn’s-afflicted gut, and how those microbes would use an inactive compound in the broccoli sprouts to make an anti-inflammatory compound in the gut. They also wanted to determine if, and by how much, a diet containing broccoli sprouts alleviates Crohn’s symptoms, given the anti-inflammatory metabolites innately present in the sprouts.
The researchers used four groups of IL-10-KO mice in the study. In the first round, they had younger mice enrolled at age 4 weeks that ate their standard mouse diet the whole time, as well as mice that ate the mouse food with raw broccoli sprouts mixed in. In the second round, they had the same two diet groups, but mice were enrolled at age 7 weeks. The researchers were particularly interested in understanding the development of IBDs in early life, which is why they studied the Crohn’s mouse models at the juvenile stage (age 4-6 weeks) and at the adolescence stage (age 7-9 weeks) to better understand how host-diet-microbial community interactions and disease severity differ by age.
The mice were fed for 7 days to acclimate to their respective diets before the researchers triggered symptoms, and the mice stayed on their diets for the following 2 weeks while the disease progressed. To trigger symptoms, new healthy mice that host more microbes were added to the cage. Since the IL-10-KO mice in the study cannot produce IL-10, their immune systems have trouble tolerating gut microbiota, and the new microbes in the cage triggered colitis and Crohn’s symptoms. For the next 15 to 16 days after infection, the researchers regularly weighed the mice and collected fecal samples to assess for signs of colitis development.
At the end of the study, the researchers examined the gut tissues of the euthanized mice and microbial communities present throughout their intestines, as well as the presence of certain markers of inflammation and broccoli metabolites in the blood. The researchers wanted to know what types of microbes were living in particular parts of the gut to understand how the broccoli sprout diet affected microbial biogeography in the Crohn’s models.
DNA was extracted from the intestinal tissue samples collected from the mice and sent for sequencing to identify the bacteria present. Once the sequencing data were returned, the researchers used bioinformatics software and human ingenuity to study the gut microbial ecology of mouse models.
“We found many exciting results from this study. First, we show that the mice that ate the broccoli sprout diet had a greater concentration of an anti-inflammatory metabolite called sulforaphane in their blood. Even though our mice were immunocompromised and had colitis, this increase in sulforaphane protected them from severe disease symptoms like weight loss, fecal blood, and diarrhea,” said Lola Holcomb, lead author and a PhD candidate in the Graduate School of Biomedical Sciences and Engineering at the University of Maine.
Body Changes Up to 8 Years Ahead of IBD Diagnosis
Researchers at the Francis Crick Institute and Aalborg University in Copenhagen, Denmark, have shown that changes can be detected in blood tests for up to 8 years before a diagnosis of Crohn’s disease and up to 3 years before a diagnosis of ulcerative colitis.
This means that the beginnings of inflammatory bowel disease start long before symptoms occur and, in the future, may provide an opportunity for doctors to take preventative action before symptoms begin or prescribe medication when it will be most effective.
Crohn’s disease and ulcerative colitis are collectively known as IBD. They are incurable conditions that involve excessive inflammation in the gut, leading to symptoms like abdominal pain and diarrhea. Early diagnosis and treatment are key to improving outcomes, but nearly a quarter of the 25,000 people diagnosed each year in the UK wait over a year.
In their study published in Cell Reports Medicine, the team used electronic health records from people in Denmark, comparing 20,000 individuals with an IBD diagnosis with controls from 4.6 million people without IBD.
It was previously thought that most people have symptoms for about a year before diagnosis, but significant bowel damage is often seen, suggesting that changes have been taking place for a lot longer.
The researchers confirmed this by looking at 10 years of test results before diagnosis. They observed changes in a series of minerals, cells in the blood, and markers of inflammation, such as fecal calprotectin, a molecule released into the gut during inflammation and currently used to determine which people with bowel symptoms need further investigation. These changes were observed up to 8 years before diagnosis in Crohn’s disease and 3 years in ulcerative colitis.
Importantly, most of the observed changes were subtle and would have appeared within a normal range for standard blood tests, so these would not have been flagged as a cause for concern. It required a huge dataset to be able to detect these changes across many different markers.
The researchers’ next steps are to investigate if treatment or prevention has an impact before people exhibit symptoms and whether the findings from this research could be developed further to predict who will develop IBD.
First author Marie Vestergaard, PhD student at the Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT) at Aalborg University, said, “So many young people are affected by IBD. Their lives, hopes, and aspirations for the future are turned upside down by a diagnosis and trying to live with a chronic disease. As a young person myself, it gets me. I am happy that our research might help predicting who could potentially suffer from IBD and thus start treatment earlier, which would greatly improve their quality of life.”
Study Examines How the Gut Signals to the Brain
The gut-brain connection is a complicated, two-way signaling cascade that is responsible for keeping the digestive system working properly, and it can cause problems when it breaks down. A key part of that axis is the colon, which extracts water and nutrients from food and transports waste out of the body. This crucial organ is implicated in a range of gastrointestinal conditions, including constipation, diarrhea, pain, and inflammation.
Researchers at Harvard Medical School (HMS) have defined five distinct subtypes of sensory neurons in the colon that carry signals to the brain. In a new study, conducted in mice and published in Cell, the researchers found that some neurons are dedicated to sensing gentle forces, such as substances moving through the colon, while others sense more intense ones, such as pain.
The researchers say that if confirmed in humans, their findings could help scientists develop more effective therapies to treat conditions that arise when this colon-brain sensing system goes awry. “Patients often complain about sensation and pain in the gastrointestinal system, yet we don’t know a lot about the sensory neurons that innervate the gut and allow us to respond to different stimuli,” said lead author Rachel Wolfson, a research fellow in neurobiology at HMS and a gastroenterology fellow at Massachusetts General Hospital.
David Ginty and scientists in his laboratory have spent many years studying how sensory neurons in the skin communicate with the brain to form our sense of touch. They have developed precise genetic tools that label subtypes of sensory neurons and have used these tools to uncover basic information about the structure, organization, and function of skin-sensing neurons.
Yet, even as scientific knowledge about touch neurons has grown, very little research has focused on understanding the neurons in other parts of the body, including the gastrointestinal system. “We’ve learned a lot about the neurons that go to the skin, but the properties of neurons that project to other organs like the colon have remained poorly understood,” said Dr. Ginty, the Edward R. and Anne G. Lefler Professor of Neurobiology in the Blavatnik Institute at HMS and senior author of the article.
To tackle this understudied area, Dr. Ginty teamed up with Dr. Wolfson, a neurobiologist and clinical expert on the gastrointestinal system. Dr. Wolfson took genetically labeled mouse models developed in the Ginty laboratory and repurposed them to study neurons in the colon. She discovered that five subtypes of sensory neurons in the skin are also found in the colon. However, colon and touch neurons had distinct shapes, and the subtypes of colon neurons also varied from each other in form.
“We know that form underlies function, so the fact that the colon neurons look different from each other made us think that they have different functions,” Dr. Wolfson said.
To investigate function, she stretched the mice’s colons with a balloon, mimicking naturally occurring distension, and recorded activity in the distinct types of neurons. Two types responded to gentle forces, similar to the slight stretching that might happen when digested food or stool moves through the colon. Two other types responded to intense forces, such as more extreme stretching. When Dr. Wolfson artificially activated these high-force neurons, the mice behaved as if they were in pain. When she removed the neuron with the highest force threshold, the pain response diminished. Triggering inflammation in the mice caused one of the pain-sensing neuron subtypes to become even more reactive.
Study Links Chronic Psychological Stress With IBD
For the first time, cells involved with the communication between stress responses in the brain and inflammation in the gastrointestinal (GI) tract have been identified in animal models, according to findings from the Perelman School of Medicine at the University of Pennsylvania, published in Cell.
Glial cells, which support neurons, communicate stress signals from the CNS to the semiautonomous nervous system within the GI tract, called the enteric nervous system (ENS). These psychological stress signals can cause inflammation and exacerbate symptoms of inflammatory bowel disease (IBD).
An estimated 1.6 million Americans have IBD, which refers to two conditions, Crohn’s disease and ulcerative colitis, characterized by inflammation of the GI tract, and can cause symptoms such as persistent diarrhea, abdominal pain, and bloody stools. Prolonged inflammation can also lead to permanent damage to the GI tract. Current treatments consist of anti-inflammatory drugs, immune suppressants, dietary changes, and steroids.
“Clinicians have long observed that chronic stress can worsen IBD symptoms, but until now, no biological connection has been identified to explain how the digestive system knows when someone is stressed,” said senior author Christoph Thaiss, PhD, an assistant professor of microbiology.
In the study, researchers found that like humans, mice with IBD developed severe symptoms when stressed. They traced the initial stress response signals to the adrenal cortex, which releases glucocorticoids—steroid hormones that activate the physiological responses to stress throughout the body. The researchers found that neurons and glia in the ENS responded to chronically elevated glucocorticoid levels, suggesting that they are the link between stress perception by the brain and intestinal inflammation.
While glucocorticoids typically have an anti-inflammatory effect in the body, the researchers found that when glia in the ENS were exposed to the steroid hormones for a prolonged period, such as during chronic stress, they attract white blood cells to the GI tract that increase inflammation. The researchers also found that when exposed to chronic stress, the neurons in the ENS in the GI tract stop functioning as they normally do, which can lead to impaired bowel movements and exacerbated IBD symptoms.
Dr. Thaiss and collaborators verified the connection between psychological stress and IBD symptoms in humans using the UK Biobank and a patient cohort from the IBD Immunology Initiative at Penn Medicine. They found that in patients with an IBD diagnosis, the level of reported stress correlated with an increased severity of IBD symptoms.
“This finding highlights the importance of psychological evaluations in patients being treated for IBD, as well as to inform treatment protocols,” said Maayan Levy, PhD, an assistant professor of microbiology and cosenior author of the study. “One of the most common treatments for IBD flare-ups is steroids, and our research indicates that in patients with IBD who experience chronic stress, the efficiency of this treatment could be impaired.”
Researchers underscore the opportunity for more research into the biology of enteric glial cells and the role they play in many regulatory systems within the body, including the communication between the nervous system and the immune system.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.To comment on this article, contact rdavidson@uspharmacist.com.
