The gut microbiome drives a process vital for protecting the colon against tissue injury, according to the findings of a study co-led by Cedars-Sinai Health Sciences University investigators. The discovery, published in Cell, has important implications for understanding how a wide variety of intestinal disorders may develop.
“Our research opens the door to treatments that focus on restoring key molecular signals in vulnerable regions of the colon,” said Ophir Klein, MD, PhD, executive director of Cedars-Sinai Guerin Children’s, executive vice dean of Children’s Health, and the David and Meredith Kaplan Distinguished Chair in Children’s Health. Klein is the senior author of the study.
Prior research has shown that the four sections of the colon – ascending, transverse, descending and sigmoid – have different functions and risks for disease, but it wasn’t clear why these variations exist.
In this study, the investigators showed that the identity of distinct regions of the colon are regulated by the gut microbiome. They identified nicotinic acid, a molecule produced by certain bacteria in the gut microbiome, as a main driver of these regional differences in the colon’s sections. Nicotinic acid, also known as niacin, part of the vitamin B3 family, helps the body convert food into energy and supports the health of cells.
The researchers compared laboratory mice with and without a microbiome. They found that production of nicotinic acid by bacteria in the upper colon activates a protective mechanism in colon cells. In mice without a microbiome, minimal nicotinic acid was produced, and cells in the upper colon became more vulnerable to damage and disease.
Investigators also studied human colon tissue samples. They found that the different sections of the human colon showedregional characteristics similar to patterns observed in mice. And in samples from human patients with the autoimmune disorder Crohn’s disease, this protective mechanism was reduced.
“Our work highlights the importance of studying hostmicrobiome interactions with careful attention to specific colon regions, rather than treating the colon as a uniform organ,” said Jeremie Rispal, PhD, a postdoctoral scholar at the University of California, San Francisco, and the first author of the study. “We learned that the microbiome controls regional differences and tissue protection.”
Further study will be needed to confirm the precise mechanisms behind this protective effect and to determine how these findings might be used in new therapies for intestinal disorders.
Ageing naturally weakens our muscles, but a new study published in the journal Gut have found a gut bacterium that may help turn the tide. The researchers Leiden University Medical Center and the Universities of Granada and Almería, found that Roseburia inulinivorans is linked to stronger muscles in both people and mice. The discovery hints at the potential for new probiotics to support muscle strength and healthy ageing.
While exercise and good nutrition remain important for maintaining muscle strength, scientists are now turning their attention to a lesser‑known player: the gut. “The bacteria living in our intestines help us process nutrients, regulate inflammation and manage energy,” Patrick Rensen, professor at the division of Endocrinology, notes. “All of these processes are essential for keeping our muscles healthy as we age.”
A gut bacterium linked to stronger muscles
In their new work, the researchers identified one particular gut bacterium, Roseburia inulinivorans, that appears to be linked to stronger muscles across the lifespan. “When we compared young adults aged 18 to 25 with older adults aged 65 and above, we noticed clear differences,” postdoc Borja Martínez-Téllez says. “Older adults who carried this bacterium had 29 percent stronger handgrip strength than those who didn’t.” In young adults, higher levels of Roseburia inulinivorans were associated with stronger muscles and better overall fitness. “It was remarkable to see the same pattern in both age groups,” Martínez-Téllez adds.
Testing the bacterium in mice
To find out whether this link was more than coincidence, the researchers carried out a series of experiments in mice. “We wanted to understand whether this bacterium actually causes improvements in muscle strength,” Rensen explains. After clearing the mice’s gut bacteria using antibiotics, they introduced human strains of Roseburia inulinivorans for eight weeks.
“The results were striking,” Rensen says. “The mice became 30 percent stronger, developed larger muscle fibres and produced more fast‑twitch fibres.”
The team also found that the bacterium changed how the muscles used certain building blocks and activated energy‑related pathways inside the muscle. “These metabolic changes may help explain why the muscles grew stronger,” according to Martínez-Téllez.
From discovery to potential probiotic treatment
Another key observation is that levels of Roseburia inulinivorans naturally decline with age. “This could partly explain why muscle strength drops as we get older,” Martínez-Téllez says. “If this bacterium supports muscle metabolism, then restoring it might one day help preserve muscle function later in life.”
Together, the findings suggest that Roseburia inulinivorans could become a future probiotic, developed into a safe, supplement‑like product aimed at preventing age‑related muscle‑wasting conditions. “A nutraceutical approach – using food‑based or naturally derived products – could offer a gentle and non‑invasive way to support healthy ageing,” Martínez-Téllez explains.
The researchers however caution that considerable work needs to be done before these findings can be turned into a treatment for humans.
Houston Methodist researchers find antibiotics aid recovery from traumatic brain injury
Source: CC0
What if healing the brain after traumatic injury starts in the gut? In a new study published in Nature Communications Biology, Houston Methodist researchers led by Sonia Villapol, PhD, found that short-term antibiotic treatment significantly reduced neuroinflammation and neurodegeneration following traumatic brain injury (TBI) by altering the gut microbiome in animal models.
“We found that antibiotic treatment following TBI can reduce harmful gut bacteria, decrease lesion size and limit cell death,” said Villapol, an associate professor in the Department of Neurosurgery at Houston Methodist. “Our results support a gut–brain mechanism in which microbiome changes influence peripheral immunity and, in turn, neuroinflammation after TBI.¨
Administering antibiotics cleans the gut of harmful bacteria, allowing beneficial bacteria to flourish. The study found that two helpful bacteria, Parasutterella excrementihominis and Lactobacillus johnsonii, are key to driving cell repair. According to Villapol, they could also be major regulators for peripheral inflammation in the body.
Notably, 70% of immune system regulation is generated by the gut microbiome. During gut imbalance, the bidirectional nature of the brain-gut axis can wreak havoc throughout the entire body.
“Our brains are constantly sending signals to the rest of our bodies. Following a traumatic brain event, those signals can get scrambled and disrupt other organs, including our digestive system,” Villapol said. “If the gut stays out of balance, the brain may have a harder time healing.”
Recent studies indicate that TBI-induced gut microbiome imbalance may even contribute to the development of neurodegenerative diseases like Parkinson’s, Alzheimer’s and dementia.
Villapol’s lab is focused on investigating and developing new neuroprotective treatments to fight inflammation linked with neurodegenerative disease. “If we can break neuroinflammation in the acute or chronic stage, we can reduce the risk of developing Alzheimer’s or dementia,” said Villapol.
The next phase of the research will focus on bioengineering P. excrementihominis and L. johnsonii to further develop precision therapies to reduce neuroinflammation.
Two bacteria working together to break down intestinal mucus are identified as a contributing factor to chronic constipation
Scientists at Nagoya University in Japan have found two gut bacteria working together that contribute to chronic constipation. The duo, Akkermansia muciniphila and Bacteroides thetaiotaomicron, destroy the intestinal mucus coating essential for keeping the colon lubricated and faeces hydrated. Their excess degradation leaves patients with dry, immobile stool. This discovery, published in Gut Microbes, finally explains why standard treatments often fail for millions of people with chronic constipation.
Notably, the study shows that Parkinson’s disease patients, who suffer from constipation decades before developing tremors, have higher levels of these mucus-degrading bacteria. While constipation in Parkinson’s disease has traditionally been attributed to nerve degradation, these findings suggest that bacterial activity also plays a crucial role in the development of their symptoms.
Why mucin matters for digestion
Constipation is a very common digestive problem. Doctors have assumed it happens because of slow gut movement when our intestines are not moving food along fast enough. However, this explanation does not work for everyone.
Some people have constipation with no identifiable cause, referred to as chronic idiopathic constipation (CIC). Parkinson’s disease patients also face severe, treatment-resistant constipation, though it is clinically categorized separately from CIC. Many struggle with severe constipation for 20 or 30 years before they develop tremors and movement problems, but researchers did not know why until now.
Instead of focusing on nerve and muscle movement in the gut, the researchers examined the protective gel-like coating called colonic mucin, a substance in the large intestine that lines the intestinal walls and is found within stool. Colonic mucin keeps stool moist, helps it move smoothly through our digestive tract, and protects the intestinal wall from bacteria.
They found that two gut bacteria work in sequence to break down this mucin. B. thetaiotaomicron uses enzymes to remove protective sulfate groups from the mucin, and A. muciniphila then breaks down and consumes the exposed mucin.
Sulfate groups attached to colonic mucin molecules normally prevent bacteria from degrading them. When too much mucin is destroyed, stool loses moisture and becomes hard and dry, causing constipation. Because the problem is mucin loss, not slow gut movement, standard laxatives and gut motility drugs are often ineffective.
Researchers have identified a two-step bacterial process driving a new type of constipation: one bacterium removes protective sulfate groups while another consumes the exposed colonic mucin. Credit: Tomonari Hamaguchi, Nagoya University
A new frontier for gut health treatment
“We genetically modified B. thetaiotaomicron so it could no longer activate the enzyme sulfatase that removes sulfate groups from mucin,” Tomonari Hamaguchi, lead author and lecturer from the Academic Research & Industry-Academia-Government Collaboration Office at Nagoya University explained.
“We put these modified bacteria into germ-free mice together with Akkermansia muciniphila, and surprisingly the mice did not develop constipation; the mucin stayed protected and intact.”
The experiment proved that blocking the sulfatase enzyme prevents the bacteria from degrading mucin. Therefore, drugs that block sulfatase could treat bacterial constipation in humans.
For millions of patients with treatment-resistant constipation, including those with Parkinson’s disease, this discovery offers hope for new therapies that address the root microbial causes of their condition.
A new randomised controlled study funded by the Crohn’s & Colitis Foundation found that time-restricted feeding, a form of intermittent fasting, significantly reduced symptomatic disease activity and systematic inflammation in adults with Crohn’s disease and overweight or obesity. The University of Calgary-led trial is the first to show that eating only within an 8-hour window can reduce Crohn’s disease activity by 40% and abdominal discomfort by 50% in just 12 weeks, compared to a standard eating schedule.
Participants practicing intermittent fasting not only lost about 2.5kg while controls gained approximately 1.7kg, but also showed notable improvements in blood markers of inflammation and immune health, including lower levels of leptin and PAI-1 – all without cutting calories.
Results of the study were published in Gastroenterology. People with IBD should talk with their healthcare team before changing their eating schedule to determine whether intermittent fasting is appropriate for them.
Time-restricted feeding (TRF) involves eating all meals within a set 8-hour window each day, followed by fasting for the remaining 16 hours. This 12-week randomised trial included 35 adults with Crohn’s disease and living with obesity or overweight, with 20 assigned to TRF and 15 to their regular diet. Researchers measured disease activity, inflammation, and body composition at the start and end of the study.
“This study shows that while weight loss is an important outcome in people with overweight and Crohn’s disease, time-restricted feeding offers additional benefits beyond just the scale,” said Maitreyi Raman, MD, Associate Professor of Medicine at the University of Calgary, the study’s senior author. “We saw meaningful improvements in disease symptoms, reduced abdominal discomfort, favourable shifts in metabolism and inflammation, and promising changes in gut bacteria – all suggesting that intermittent fasting may help patients maintain lasting remission from Crohn’s disease.”
The research was supported by the Crohn’s & Colitis Foundation’s Litwin IBD Pioneers program. “Time-restricted feeding is showing real promise as a new way to help people with Crohn’s disease manage not only their symptoms but also their overall health,” said Andres Lorenzo Hurtado, PhD, Senior Vice President of Translational Research & IBD Ventures at the Crohn’s & Colitis Foundation. “This research suggests that changing when we eat – not just what we eat – can improve metabolism, help the immune system work better, and support long-term remission from Crohn’s disease. We are excited to support studies like this that put patients at the centre of new solutions and encourage more research to make these benefits last for everyone living with IBD.”
“People with Crohn’s disease often look for practical tools to support their health alongside medication,” said Natasha Haskey, PhD, RD, Research Associate at the University of British Columbia and lead investigator in the study. “Our research suggests time-restricted eating may be a sustainable option grounded in biology, offering patients more ways to manage their own wellness.”
In addition to reducing Crohn’s disease activity, the study found a marked decrease in harmful visceral fat and key inflammatory signals in the blood of those who practiced intermittent fasting. The changes were not simply due to diet quality or calorie restriction, as both groups ate similar foods and amounts—indicating the timing of meals themselves may play a unique role in supporting digestive and immune health.
Researchers note that, while these results are promising, larger trials are needed to confirm the long-term safety and effectiveness of this approach for broader groups of patients with IBD.
Two Canadian clinical trials show poop pills could help patients respond to immunotherapy while also reducing toxic side effects of cancer drugs
Faecal microbiota transplants (FMT), can dramatically improve cancer treatment, suggest two groundbreaking studies published in the prestigious Nature Medicine journal. The first study shows that the toxic side effects of drugs to treat kidney cancer could be eliminated with FMT. The second study suggests FMT is effective in improving the response to immunotherapy in patients with lung cancer and melanoma.
The findings represent a giant step forward in using FMT capsules – developed at Lawson Research Institute (Lawson) of St. Joseph’s Health Care London and used in clinical trials at London Health Sciences Centre Research Institute (LHSCRI) and Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM) – for safe and effective cancer treatment.
A Phase I clinical trial was conducted by scientists at LHSCRI and Lawson to determine if FMT is safe when combined with an immunotherapy drug to treat kidney cancer. The team found that customised FMT may help reduce toxic side effects from immunotherapy. The clinical trial involved 20 patients at the Verspeeten Family Cancer Centre at London Health Sciences Centre (LHSC).
“Standard treatment for advanced kidney cancer often includes an immunotherapy drug that helps the patient’s immune system tackle cancer cells,” says Saman Maleki, PhD, Scientist at LHSCRI. “But, unfortunately, the treatment frequently leads to colitis and diarrhoea, sometimes so severe that a patient must stop life-sustaining treatment early. If we can reduce toxic side effects and help patients complete their treatment, that will be a gamechanger.”
Separate Phase II lung and skin cancer studies were led by researchers at CRCHUM in collaboration with Lawson and LHSCRI. The studies found that 80 per cent of patients with lung cancer responded to immunotherapy after FMT, compared to only 39-45 per cent typically benefiting from immunotherapy alone. Similarly, 75 per cent of patients with melanoma who received FMT experienced a positive response to treatment, compared to only 50-58 per cent response in patients who receive immunotherapy alone. Twenty patients participated in the lung cancer clinical trial and 20 patients participated in the skin cancer clinical trial.
“Our clinical trial demonstrated that faecal microbiota transplantation could improve the efficacy of immunotherapy in patients with lung cancer and melanoma,” says Dr Arielle Elkrief, co-principal investigator and Physician Scientist, Université de Montréal-affiliated hospital research centre (CRCHUM). “The results also uncovered one possible mechanism of action of faecal transplantation – through the elimination of harmful bacteria following the transplant. Our results open up a novel avenue for personalised microbiome therapies, and faecal transplant is now being tested as part of the large pan-Canadian Canbiome2 randomised controlled trial.”
“Faecal microbiota transplantation in melanoma and lung cancer opens an entirely new therapeutic avenue, made possible by the exceptional commitment of our patients and the teamwork,” adds Dr. Rahima Jamal, Director of the Unit for Innovative Therapies (UIT) at CRCHUM. “At the Unit for Innovative Therapies (UIT) of the CRCHUM, we have had the privilege of translating laboratory discoveries into early phase clinical trials and witnessing their concrete impact on people living with cancer.”
Both studies use advanced, world-leading FMT capsules, also known as LND101, produced by Lawson in London, Ont. The research reinforces London’s place as a global leader in FMT innovation and treatment. The capsules are processed from healthy donor stools and ingested to help restore a patient’s healthy gut microbiome and treat different types of cancer.
“To use FMT to reduce drug toxicity and improve patients’ quality of life while possibly enhancing their clinical response to cancer treatment is tremendous, and it had never been done in treating kidney cancer before this,” says Dr Michael Silverman, Scientist at Lawson and Head of St. Joseph’s Infectious Diseases Program. “And none of this would be possible if not for this close collaboration: innovating the FMT capsules in Lawson labs and introducing them at LHSCRI and CHUM to advance vital research initiatives. Also, because LND101 comes from healthy donors, production can be scaled up to eventually help large numbers of cancer patients.”
The studies build on earlier London and CHUM-generated Phase I research showing FMT can safely augment treatment for people with melanoma. FMT is also being studied in people with pancreatic cancer and triple-negative breast cancer, and is already a well-established treatment for serious gut infections such as C. difficile, which can cause severe diarrhoea.
“Our hope is that our research will one day help people with cancer live longer while reducing the harmful side effects of treatment,” adds Dr Ricardo Fernandes, Scientist at LHSCRI and Medical Oncologist at LHSC. “We are world leaders in FMT research and we’re excited about its potential.”
“Come on, little fella – we should get going now.” But my son was not listening. The sand in the playground was just right, so he kept digging with his new toy excavator.
As I drifted back to my list of to-dos, however, the laughter was suddenly replaced by sobs. My son was not hurt, just very upset. When I looked at my phone, I saw it was well past his regular mealtime – and he was feeling very hungry.
However old we are, we all have a tendency to grow irritated if our body lacks enough fuel. But while humans have experienced this for as long as we have been on the planet, a specific word to describe the phenomenon only entered the Oxford English dictionary in 2018. “Hangry: to be bad-tempered or irritable as a result of hunger.”
Perhaps more surprising is the scarcity of research into how hunger affects people’s everyday moods. Most studies on food and mood have focused on patients with metabolic or eating disorders – perhaps because many psychologists have traditionally understood hunger to be such a basic physiological process.
So, with colleagues from the fields of psychology and mental health, I decided to investigate how different people respond to feeling hungry. We wanted to see if (and why) some people are better at reacting calmly when hunger strikes. Perhaps there would be some lessons for those of us with young children, too.
Surprising results
In the animal world, hunger is frequently studied for its role as a key motivator. Hungry rodents, for example, will vigorously press a lever or climb over large walls to get to food rewards. In the wild, hungry animals often roam further to explore their environment, seeming restless as they seek to overcome the threat of low or no energy.
A Pallas’s cat (also known as a manul) gets increasingly hangry as it hunts for food. Video: BBC.
To investigate the relationship between energy levels, hunger and mood in people, we equipped 90 healthy adults with a continuous glucose monitor for a month. Glucose is the primary source of energy for the body and brain, and these monitors – used in clinical practice to help patients with diabetes regulate their blood sugar levels – report values every few minutes. (Participants could actively check their glucose levels using the sensor app, and we could see when they accessed them.)
We also asked our participants to complete mood check-ins on their smartphones up to twice a day. These included questions about how hungry or sated they felt on a scale from 0 to 100, as well as a rating of their current mood.
The results surprised us. First, people were only in a worse mood when they acknowledged feeling hungry – not simply when they had lower blood sugar levels. And second, people who more accurately detected their energy levels in general were less prone to negative mood swings.
This suggests there is a key psychological middle step between a person’s energy and mood levels, which scientists call interoception.
In the brain, hunger is signalled by neurons in the hypothalamus that detect a prolonged energy deficit. Conscious feelings of hunger are then linked to the insula, a part of the cerebral cortex that is folded deep within the brain, and which also processes taste and plays a role in feeling emotions.
In our recent study, people with high interoceptive accuracy experienced fewer mood swings. This does not mean they never felt hungry – they just seemed better at keeping their mood levels stable.
This is important, because a sudden change in mood can have knock-on effects on relationships with family, friends and colleagues. It can lead to bad decision-making and more impulsive behaviour – including buying fast-energy food that can be less good for you.
More generally, paying close attention to our bodies’ needs helps keep our minds at ease too, avoiding unnecessary wear and tear on both. Deviating too much from the body’s ideal state can pose a long-term risk to our health – mental as well as physical.
Caught off-guard
Young children find it hard to interpret all the signals from their rapidly developing body. They are also easily distracted by what is happening around them, and often fail to attend to their hunger or thirst without prompting – leading to a sudden meltdown like my son had in the playground.
Likewise for many adults in today’s fast-paced world full of digital distractions, it can be easy to be caught off-guard by dipping energy levels. One simple life hack is to keep a regular meal schedule, because hunger often kicks in when we skip a meal.
Everyone’s energy levels ebb and flow, of course. But it is possible to improve your interoceptive accuracy by allowing your inner systems to pay closer attention to your energy levels. In addition, exercise and physical activity can sharpen your hunger sensing and improve energy metabolism.
Most of the time, of course, our moods are only modestly affected by hunger, among the many other factors that can come into play. But one of the lessons of my time at the playground has been to take care of my son’s food needs long before they become obvious. Perhaps we all need to be more aware of the risk of getting hangry.
Microscopy image of intestinal lining in mice, shows CD4 (green), CD8 (magenta) and DAPI (blue). Ludivine Bersier 2025
In Nature Communications, researchers from Lusanne University reveal that chemotherapy alters gut microbes and bone marrow immune cell development, unexpectedly reprogramming systemic immunity in ways that help restrict metastatic progression.
Chemotherapy commonly damages the intestinal lining, a well-known side effect. But this injury does not remain confined to the gut. It reshapes nutrient availability for intestinal bacteria, forcing the microbiota to adapt.
The researchers report that chemotherapy-induced damage to the intestinal lining alters nutrient availability for gut bacteria, reshaping the microbiota and increasing the production of indole-3-propionic acid (IPA), a tryptophan-derived microbial metabolite.
Rather than acting locally, IPA functions as a systemic messenger. It travels from the gut to the bone marrow, where it rewires immune cell production. Elevated IPA levels reprogram myelopoiesis, reducing the generation of immunosuppressive monocytes that facilitate immune evasion and metastatic growth.
“We were surprised by how a side effect often seen as collateral damage of chemotherapy can trigger such a structured systemic response. By reshaping the gut microbiota, chemotherapy sets off a cascade of events that rewires immunity and makes the body less permissive to metastasis.” says Ludivine Bersier, first author of the study.
This immune reconfiguration enhances T-cell activity and remodels immune interactions within metastatic niches, particularly in the liver, resulting in a metastasis-refractory state in preclinical models.
Experimental findings are mirrored in patients. Clinical relevance is supported by patient data obtained in collaboration with Dr Thibaud Koessler (Geneva University Hospitals, HUG). In patients with colorectal cancer, higher circulating IPA levels following chemotherapy are associated with reduced monocyte levels, a feature of improved survival outcomes.
“This work shows that the effects of chemotherapy extend far beyond the tumor itself. By uncovering a functional axis linking the gut, the bone marrow and metastatic sites, we highlight systemic mechanisms that could be harnessed to durably limit metastatic progression.” says Tatiana Petrova, corresponding author of the study.
This research was supported by multiple funders, including the Swiss National Science Foundation and Swiss Cancer League. An ISREC Foundation Tandem Grant supported close collaboration between clinical and fundamental research, led at Unil by Professor Tatiana Petrova and Dr Thibaud Koessler at HUG. The project posits that chemotherapy can induce a form of biological “memory”, mediated by gut microbiome–derived metabolites that durably inhibit metastatic growth.
Together, these findings reveal a previously underappreciated gut–bone marrow–liver metastasis axis through which chemotherapy can exert durable systemic effects, opening new avenues to harness microbiota-derived metabolites as adjuvant strategies to limit metastasis.
Long-term use of medications for heartburn and acid reflux, known as proton pump inhibitors, does not appear to increase the risk of stomach cancer, according to a new study published in The BMJ. The results are based on extensive Nordic health data and may provide reassurance to patients who need long-term treatment, according to researchers at Karolinska Institutet.
The possibility that proton pump inhibitors could cause stomach cancer has been discussed since the 1980s. Overall, studies have shown a doubled risk, but the studies have had methodological shortcomings. To investigate the association, taking into account a number of possible sources of error in previous literature in the field, researchers analysed registry data from the five Nordic countries – Denmark, Finland, Iceland, Norway, and Sweden – over a period of up to 26 years.
The study included 17 232 people with stomach cancer and compared them with over 172 000 control subjects matched for age, sex, year, and country. The researchers investigated the use of proton pump inhibitors and another type of acid-suppressing drug, histamine-2 receptor blockers.
To avoid methodological errors, drug use in the last year before diagnosis was excluded, as were patients who had cancer in the upper part of the stomach, where heartburn is a risk factor. The results were also adjusted for factors such as Helicobacter pylori infection, stomach ulcers, smoking, alcohol-related diseases, obesity, diabetes, and certain medications.
By using this methodological approach, the researchers found no association between long-term use of these drugs and the risk of stomach cancer.
“Our results contradict the hypothesis that proton pump inhibitors cause stomach cancer,” says the lead researcher responsible for the study, Professor Jesper Lagergren at the Department of Molecular Medicine and Surgery, Karolinska Institutet. He continues:
“This provides reassurance for patients who need long-term treatment and is important for clinical decisions.”
The researchers emphasise that the study is observational, which means that no definitive conclusions can be drawn about cause and effect. Nor can it be completely ruled out that confounding factors that could not be adjusted for have influenced the results. However, the study design allows for more reliable results than previous research.
UCSF researchers discover that oestrogen can turn on pain signals associated with conditions like irritable bowel syndrome.
A zoomed in image of the lining of the colon. Cells that produce the hormone PYY (peptide YY) are in green. Cells that produce the neurotransmitter serotonin are in magenta. PYY triggers the release of serotonin, which activates pain-sensing nerve fibers. Image by Archana Venkataraman/UCSF
Women are dramatically more likely than men to suffer from irritable bowel syndrome (IBS), a chronic condition causing abdominal pain, bloating, and digestive discomfort. Now, scientists at UC San Francisco have discovered why.
Oestrogen, the researchers report in Science, activates previously unknown pathways in the colon that can trigger pain and make the female gut more sensitive to certain foods and their breakdown products. When male mice were given oestrogen to mimic the levels found in females, their gut pain sensitivity increased to match that of females.
The findings not only explain the female predominance in gut pain disorders but also point to potential new ways to treat the conditions.
“Instead of just saying young women suffer from IBS, we wanted rigorous science explaining why,” said Holly Ingraham, PhD, professor UCSF and co-senior author of the study. “We’ve answered that question, and in the process identified new potential drug targets.”
The research also suggests why low-FODMAP diets – which eliminate certain fermentable foods, such as onions, garlic, honey, wheat, and beans – help some IBS patients, and why women’s gut symptoms often fluctuate with their menstrual cycles.
“We knew the gut has a sophisticated pain-sensing system, but this study reveals how hormones can dial that sensitivity up by tapping into this system through an interesting and potent cellular connection,” said co-senior author David Julius, PhD. Julius won the 2021 Nobel Prize for Physiology or Medicine for his work on pain sensation.
Search for oestrogen
Previous research had hinted that oestrogen was to blame for higher rates of IBS in females, but not why. To understand how oestrogen might be involved, Ingraham’s and Julius’s teams first needed to see exactly where the hormone was working in the gut.
“At the time I started this project, we didn’t know where and how oestrogen signalling is set up in the female intestine,” said Archana Venkataraman, PhD, a postdoc in Ingraham’s lab and co-first author of the research. “So, our initial step was to visualise the oestrogen receptor along the length of the female gut.”
The team expected to see oestrogen receptors in enterochromaffin (EC) cells, which were already known to send pain signals from the gut to the spinal cord. Instead, they got a surprise: oestrogen receptors were clustered in the lower part of the colon and in a different cell type known as L-cells.
The scientists pieced together a complex chain reaction that occurs when oestrogen binds to the L-cells. First, oestrogen causes L-cells to release a hormone called PYY (peptide YY). PYY then acts on neighbouring EC cells, triggering them to release the neurotransmitter serotonin, which activates pain-sensing nerve fibres. In female mice, removing the ovaries or blocking oestrogen, serotonin, or PYY dramatically reduced the high gut pain observed in females.
For decades, scientists believed PYY primarily suppressed appetite – drug companies even tried developing it as a weight-loss medication. But those clinical trials failed due to a troubling side effect that was never fully explained; participants experienced severe gut distress. The new findings mesh with this observation and suggest a completely new role for PYY.
“PYY had never been directly described as a pain signal in the past,” said co-first author Eric Figueroa, PhD, a postdoc in Julius’ lab. “Establishing this new role for PYY in gut pain reframes our thinking about this hormone and its local effects in the colon.”
This video shows what happens to the enterochromaffin (EC) cells in the colon when they are treated with PYY. Upon PYY treatment, calcium activity increases in the EC cell, causing it to fluoresce more brightly as it releases serotonin that is detected by nearby pain-sensing nerve fibres. Video by Eric Figueroa/UCSF
A link between IBS and diet
Increased PYY wasn’t the only way that L-cells responded to oestrogen. Levels of another molecule, called Olfr78, also went up in response to the hormone. Olfr78 detects short-chain fatty acids – metabolites produced when gut bacteria digest certain foods. With more Olfr78 receptors, L-cells become hypersensitive to these fatty acids and are more easily triggered to become active, releasing more PYY.
“It means that oestrogen is really leading to this double hit,” said Venkataraman. “First it’s increasing the baseline sensitivity of the gut by increasing PYY, and then it’s also making L-cells more sensitive to these metabolites that are floating around in the colon.”
The observation may explain why low-FODMAP diets help some IBS patients. FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) are carbohydrates that gut bacteria ferment into those same fatty acids sensed by Olfr78. By eating fewer FODMAPs, patients may be preventing the activation of Olfr78, and, in turn, keeping L-cells from churning out more of the pain signalling PYY.
While men have this same cellular pathway, their lower oestrogen levels keep it relatively quiet. However, the pathway could engage in men taking androgen-blocking medications, which block the effects of testosterone and can elevate oestrogen in some cases, potentially leading to digestive side-effects.
The new work suggests potential ways to treat IBS in women and men alike.
“Even for patients who see success with a low-FODMAP diet, it’s nearly impossible to stick to long term,” Ingraham said. “But the pathways we’ve identified here might be leveraged as new drug targets.”
The researchers are now studying how such drugs might work, as well as asking questions about what other hormones, such as progesterone, might play a role in gut sensitivity and how pregnancy, lactation, and normal menstrual cycles affect intestinal function.
