investigators linked higher coffee consumption with lower risk of cirrhosis, liver cancer and liver-related death.

“Previous studies suggested that coffee might benefit the liver, but most were smaller or looked at only one piece of the puzzle,” said hepatologist Hyunseok Kim, MD, MPH, PhD, assistant professor of Medicine at Cedars-Sinai and corresponding author of the study. “We followed hundreds of thousands of people for more than a decade and looked at their health outcomes along with liver MRI scans and blood protein analyses. Together, those findings help explain the biological mechanisms behind coffee’s association with better liver health.”

A Cedars-Sinai study of more than 355,000 adults found that drinking coffee was associated with lower risks of cirrhosis, liver cancer and liver-related death. The investigators analyzed data from 354,957 UK Biobank participants who did not have cirrhosis or liver cancer at the start of the study. Over a median follow-up of 13 years, researchers tracked new diagnoses of cirrhosis, liver cancer and liver-related death through linked health records.

Compared with people who did not drink coffee, those who drank five or more cups of coffee a day had a 32% lower risk of cirrhosis, a 47% lower risk of liver cancer and a 42% lower risk of liver-related death. Participants who drank more coffee also had lower levels of liver fat, liver iron, fibrosis and liver inflammation in MRI scans. And coffee drinkers’ blood tests showed higher levels of proteins tied to healthy liver function and lower levels of proteins linked to scarring and inflammation.

While liver health risk decreased as coffee consumption increased, researchers noted that benefits were seen even at one to two cups per day and appeared strongest around three to four cups per day. They emphasized that while the highest intake group (five or more cups daily) showed benefit, they would not recommend increasing consumption to that level specifically.

Similar protective associations were observed for caffeinated and decaffeinated coffee, suggesting that caffeine itself is unlikely to be the only active component, and that other naturally occurring compounds in coffee may contribute to the benefits. Because the study was observational, investigators noted it does not prove that coffee itself prevents liver disease. And they emphasized that coffee should complement—not replace—established strategies for preventing liver disease.

“Our findings support moderate coffee consumption for people who already enjoy and tolerate it well,” said study senior author Ju Dong Yang, MD, medical director of the Liver Cancer Program at Cedars-Sinai. “However, we would not recommend that someone begin drinking coffee solely for liver protection based on this study alone. Prevention should continue to focus on maintaining a healthy weight, limiting alcohol, exercising regularly, and managing blood sugar, blood pressure and cholesterol.”

Because caffeine isn’t appropriate for everyone, people with uncontrolled high blood pressure, certain heart rhythm disorders, severe anxiety, insomnia or other conditions that require limiting caffeine should consult their healthcare provider before increasing their coffee consumption.

“The next step in our research is to identify the specific compounds in coffee that are responsible for these liver-protective associations,” said study author Shelly Lu, MD, the Women’s Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Our findings point to biological pathways involving inflammation and scarring and highlight molecular targets that future research can explore to better understand how coffee may influence liver health and who stands to benefit the most.”

Additional Cedars-Sinai authors include Yufeng Wang, Abdelrahman M. Attia, Minsun Kwak, Seungwon Burm, Derin Celtik, Daniel Legaspi, Osama Khattab, Naomy Kim, Beza M. Mengistu, Kelsey N. Larios, Walid Ayoub, Alexandar Kuo, Paul Martin, Aarshi Vipani, Yun Wang, Debiao Li and Stephen Pandol.

Other authors include Mohammad Saeid Rezaee-Zavareh, David Sooik Kim and Suthat Liangpunsakul.

Conflicts of Interest: Ju Dong Yang reports the following conflicts of interest: consulting service for AstraZeneca, Eisai, Exact Sciences, and Fujifilm Medical Sciences.

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Digestive Disease Week is the largest international gathering of physicians and scientists in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

Cedars-Sinai is a nationally recognized leader in gastroenterology and gastrointestinal surgery. Digestive and liver disease experts attending the conference are available to discuss a wide variety of research, including these presentations.

Late-Breaking Trial Shows Progress in Difficult Ulcerative Colitis

Maria T. Abreu, MD, executive director of the F. Widjaja Inflammatory Bowel Disease Institute, will present late-breaking results from a clinical trial evaluating two targeted biologic therapies for ulcerative colitis used together. The study focused on patients whose disease had not responded to multiple advanced treatments and found that the combination led to higher rates of clinical remission and healing of the intestinal lining compared with either drug alone.

“We studied patients whose disease has already proven difficult to treat and found that using two therapies together led to stronger outcomes than either alone, without increasing side effects,” Abreu said.

Irritable Bowel Syndrome (IBS)

Ali Rezaie, MD, medical director of the GI Motility Program, will present research that found palatable elemental diet nutrition replacement reduced abdominal pain and related symptoms in people with irritable bowel syndrome after two weeks.

Zoe Krut, MHDS, a clinical research coordinator with the Center for Outcomes Research and Education at Cedars-Sinai Health Sciences University, will present research from a multicenter randomized trial showing that virtual reality-delivered cognitive behavioral therapy improved symptoms of IBS and was well accepted by patients. Study leader Christopher Almario, MD, MSHPM, assistant professor of Medicine and Health Systems Research, will also be on hand to discuss the research.

Interventional Gastroenterology

Barham K. Abu Dayyeh, MD, MPH, director of Interventional Gastroenterology, will share results of a study in which a less invasive laparoscopic procedure for hiatal hernia-associated GERD (gastroesophageal reflux disease) was used. It achieved results similar to standard surgery, with fewer complications. The abstract has been selected for the “Best of DDW” session held at the end of the meeting, highlighting 6 of the top studies presented.

Abu Dayyeh will also share results of another study in which a novel endoscopic therapy used pulsed electric fields to treat the lining of the small intestine. Results reveal improvements in blood sugar control and weight management for nearly one year in adults with Type 2 diabetes.

Inflammatory Bowel Disease

Talin Haritunians, PhD, a research associate professor of Medicine, will present results of a study that found patients with inflammatory bowel disease (IBD) have distinct genetic variants linked to an increased risk for cardiovascular disease, independent of traditional risk factors.

Allistair Clark, MA, a clinical research data specialist at Cedars-Sinai Health Sciences University, will share results of an investigation that found an AI-powered virtual reality therapy reduced pain and anxiety in patients with inflammatory bowel disease (IBD) in both inpatient and outpatient settings.

Small Intestinal Bacterial Overgrowth (SIBO)

Ruchi Mathur, MD, an endocrinologist, and Gabriela Leite, PhD, a research scientist, will present research linking changes in the small bowel microbiome to Type 2 diabetes. These include strong associations with small intestinal bacterial overgrowth (SIBO) and higher glucose levels. Mathur and Leite are with the Medically Associated Science and Technology (MAST) Program.

Diagnostics: Breath Testing

Mark Pimentel, MD, gastroenterologist, and project scientist Maria Jesus Villanueva-Millan, PhD, of the MAST program, are available to discuss their research t directly comparing breath and small-intestine gases in the same patients, showing that hydrogen sulfide levels reflect those in the small intestine and are linked to specific microbes and diarrhea severity.

Liver Disease

Hyunseok Kim, MD, MPH, PhD, hepatologist and assistant professor, Medicine, will present results of research examining biomarkers that may help predict cirrhosis and liver disease progression in people with alcohol-associated liver disease.

Ju Dong Yang, MD, medical director of the Liver Cancer Program, and clinical research data specialist Osama Khattab, MD, are available to discuss their research showing that transarterial radioembolization (TARE) achieved survival outcomes comparable to ablation in early-stage liver cancer, suggesting it may offer an alternative treatment option for patients.

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To schedule an interview with a Cedars-Sinai expert during the conference, please contact Laura Coverson Laura.Coverson@cshs.org or 310-562-1112.

The findings, published in Communications Medicine, are based on nearly two decades of electronic health records from more than 650,000 U.S. adults with IBS, making it the largest real-world study to examine the long-term safety of IBS treatments.

IBS is a chronic gastrointestinal condition affecting about 10% of the U.S. population. There is no cure, but dietary modifications, behavioral therapy and medications can help manage symptoms.

“Many patients are diagnosed with IBS at a young age and may remain on medications for years,” said Ali Rezaie, MD, medical director of the GI Motility Program at Cedars-Sinai and senior author of the study. “However, most clinical trials of these medications last less than a year, so we know very little about their long-term safety. This study begins to address that gap.”

Researchers assessed patients taking Food and Drug Administration-approved IBS medications, as well as antidepressants, antispasmodics and opioid-based antidiarrheal drugs, such as loperamide and diphenoxylate—widely used and recommended in IBS care. They found that long-term antidepressant use was associated with a 35% higher risk of death, and that loperamide and diphenoxylate use were associated with roughly double the risk of death.

The study does not establish that these medications directly cause death; rather, the observed associations may reflect higher rates of adverse outcomes, such as cardiovascular events, falls and stroke, which were more frequent among exposed patients.

Although antidepressants are not FDA-approved for IBS, they are commonly prescribed for IBS patients to help reduce pain, calm symptoms and make the condition easier to manage. The study found that other recommended treatments, including FDA-approved medications and antispasmodics, were not associated with increased mortality risk.

Researchers emphasized that while the increase in risk is significant and may sound concerning, the overall risk to any individual patient is small.

“IBS patients should not panic, but they do need to understand and weigh the small but meaningful risks when considering long-term treatments,” said Rezaie, the director of Bioinformatics at the Medically Associated Science and Technology (MAST) Program at Cedars-Sinai. “Patients should speak with their healthcare provider about the safest and most effective options for managing their symptoms.”

Rezaie said more research is needed to confirm these findings and identify which patients may be at greatest risk. He also called for future treatment guidelines to better address the long-term safety of medications commonly used to manage IBS.

In the meantime, he emphasized a more personalized approach to IBS patient care.

“Treatment for IBS patients should focus on identifying the underlying causes and using the safest, evidence-based options available rather than relying on a single class of medications for long-term management,” Rezaie said.

Additional Cedars-Sinai authors include Sepideh Mehravar, MD, Yee Hui Yeo, MD, and Mark Pimentel, MD.

Other authors include Parnian Naji, MD, Wee Han Ng, Nils Burger, PhD, and Will Takakura, MD.

Conflicts of Interest: Mark Pimentel is also a consultant for and received grant support from Bausch Health. Ali Rezaie reports serving as a consultant for Bausch Health and Ardelyx. In addition, Cedars-Sinai Medical Center has a licensing agreement with Gemelli Biotech. Ali Rezaie and Mark Pimentel have equity in Gemelli Biotech and Good LFE. The remaining authors disclose no conflicts.

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The findings are published in the journal Gastroenterology.

“Among Hispanic patients, higher African ancestry was associated with more severe Crohn’s disease throughout the digestive tract, while higher Amerindian ancestry was linked to disease affecting primarily the colon,” said Talin Haritunians, PhD, the corresponding author of the study and a research associate professor of Medicine at Cedars-Sinai.

Many Hispanic individuals have mixed genetic ancestry that can include Indigenous American ancestry, plus European and African contributions that are the result of centuries of migration and colonization. Amerindian Hispanics have ancestry from indigenous Maya, Aztec and Inca civilizations—and from Spain. 

“Our findings show that genetic ancestry can help explain important differences we see in how inflammatory bowel disease affects patients, even within a single ethnic group,” Haritunians said.

An estimated 3 million people in the U.S. have inflammatory bowel disease, according to the Centers for Disease Control and Prevention. The disorder can produce chronic, painful and often destructive inflammation in the digestive tract. The two most common forms of IBD are Crohn’s disease, which can impact any part of the gastrointestinal system, and ulcerative colitis which affects just the colon and rectum.

Ancestry-Aware Analysis

Investigators analyzed genetic and clinical data from more than 7,300 Hispanic patients from the U.S., including Puerto Rico, who had IBD. They also analyzed the same data from patients without the disease. Using a new method of genomic analysis that takes specific ancestry into account, investigators examined how genetic risk and disease presentation and severity varied across ancestral backgrounds.

Hispanic populations often include individuals with mixed genetic ancestry, reflecting a mosaic of Indigenous American, European, and African genetic contributions, the result of centuries of migration and colonization.

“Our group has had a longstanding commitment to extending studies to include diverse populations. Here, we were able to identify ancestry-specific variations in IBD patterns that may be overlooked in broader genetic studies, which often focus on European populations,” said Dermot McGovern, MD, PhD, a co-author of the study and director of Translational Research in the Inflammatory Bowel and Immunobiology Research Institute.

One group in the genetic study was found to be at higher risk for developing a serious and painful form of inflammatory bowel disease.

“Increased risk of penetrating Crohn’s disease was associated with higher African ancestry among Hispanic patients. It is a severe form of IBD in which inflammation extends through the layers of intestinal wall and increases the risk of complications that often require surgery,” McGovern said.

The findings also highlight the importance of examining genetic risk alongside other factors, such as diet and environment, to better understand inflammatory bowel disease across diverse populations.

“Largescale genetic studies that include diverse patients and populations historically underrepresented in research are essential for advancing our understanding of IBD and helping patients,” Haritunians said. “Expanding research in this way will help us move toward more inclusive approaches with the potential to improve treatment options and the lives of patients.”

Additional Cedars-Sinai authors include Dalin Li, PhD; Shaohong Yang, MD; Sweta Sinha, MPH; Emebet Mengesha; Maria A. Quintero, MD; Stephan R. Targan, MD; Shervin Rabizadeh, MD; and Maria T. Abreu, MD.

Other authors include Ashley H. Beecham, PhD; Steven W. Brugger, PhD; Mary F. Davis, PhD; Esther A. Torres, MD; Lissette Gomez, MSc; Paola Lopez-Marte, MD; Mark Daly, PhD; Christine R. Stevens; James S. Leavitt, MD; Oriana M. Damas, MD; Ksenija Sabic; Judy H. Cho, MD; and Jacob L. McCauley, PhD.

Funding: This work was supported by the F. Widjaja Foundation Inflammatory Bowel Disease Institute; the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) through grants U01 DK062413, U24 DK062429-18, U01 DK062422-18, U01 DK062431, and DK062432; the Leona M. and Harry B. Helmsley Charitable Trust; the Fred L. Hartley Family Foundation; the Micky & Madeline Arison Family Foundation Crohn’s & Colitis Discovery Laboratory; the Sanford J. Grossman Charitable Trust; and the National Institutes of Health through grants U54HG003067 and 5UM1HG008895.

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highlight a potential link between pandemic-related stress on the gut-brain axis.

“Using data from a national online study, we found that rates of digestive issues such as irritable bowel syndrome and chronic idiopathic constipation rose significantly,” said Christopher V. Almario, MD, MSHPM, lead author and gastroenterologist at Cedars-Sinai. “These findings underscore the significant toll the pandemic has taken on digestive health.”

Also known as disorders of gut-brain interaction, conditions like irritable bowel syndrome and chronic idiopathic constipation are common gastrointestinal disorders driven by complex interactions between the gut and nervous system.

Nearly 40% of people in the U.S. are estimated to meet diagnostic criteria for at least one disorders of gut-brain interaction, making these conditions a major source of healthcare burden and reduced quality of life.

“These disorders involve chronic gastrointestinal symptoms that are often triggered or worsened by psychological stress,” said Almario.

To better understand how the viral infection might be linked with digestive health, researchers analyzed data from over 160,000 adults across the U.S. who participated in a national online survey conducted from May 2020 to May 2022.

Participants completed detailed questionnaires covering digestive symptoms, mental health and lifestyle changes. By tracking responses over time, the researchers observed a steady rise in gut-related health issues that began early in the pandemic and persisted throughout the survey period.

Key findings showed that:

• Rates of irritable bowel syndrome increased from around 6% among U.S. adults in May 2020 to about 11% in May 2022.
• Chronic idiopathic constipation rose slightly from 6.0% to 6.4%.
• Among adults who reported IBS, investigators noted that the prevalence of mixed IBS, a subtype of IBS where a person experiences both diarrhea and constipation, was most commonly reported. The investigators did not observe significant increases in other types of functional digestive disorders.

As doctors uncover the long-term health effects of COVID-19, study investigators hope this study may draw attention to how the virus’ impact on mental health may affect the gut—potentially triggering or worsening disorders like IBS and other gut-brain conditions.

“This research calls for a renewed focus on gastrointestinal health in the post-pandemic era,” said Brennan Spiegel, MD, MSHS, corresponding author of the study and director of Health Services Research for Cedars-Sinai.

Spiegel, director of the Cedars-Sinai Master's Degree Program in Health Delivery Science and the George and Dorothy Gourrich Chair in Digital Health Ethics, says even those who did not get COVID-19 but endured significant psychological distress also may have had alterations in their gut-brain axis.

“Healthcare providers must be vigilant in recognizing and addressing the long-term effects of the pandemic on digestive health,” said Spiegel.

Other Cedars-Sinai authors include So Yung Choi. Other authors include William D. Chey.

Funding: Support for this study was received from Ironwood Pharmaceuticals and Salix Pharmaceuticals in the form of institutional research grants to Cedars-Sinai. Brennan M.R. Spiegel, MD, MSHS is the guarantor of this article.

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The monoclonal antibody therapy, developed at Cedars-Sinai, is called tulisokibart. The experimental treatment also recently showed promising results in a separate Phase II study in treating ulcerative colitis.

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases that affect the digestive tract and impact approximately 1% of the U.S. population. There is no cure, and response to current treatments is variable.

“These findings, together with the recently published positive results in ulcerative colitis, strongly support this approach as a completely new therapy for people with inflammatory bowel diseases,” said clinician-scientist and geneticist Dermot McGovern, MD, PhD, director of Translational Research in the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai and senior author of the study.

McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and the director of Precision Health at Cedars-Sinai, together with colleagues at Cedars-Sinai, helped develop tulisokibart.

“This mechanism was identified through both genetic and immunological work, the vast majority of which came from the inflammatory bowel diseases group at Cedars-Sinai,” he said.

In the Phase II-A trial, called APOLLO-CD, 55 adults with Crohn’s disease received tulisokibart in varying doses over 12 weeks. The results showed that nearly 50% of patients achieved clinical remission, compared to about 16% in historical studies.

The investigational therapy also may target fibrosis—a process that leads to narrowing in the gut and often requires surgery. Fibrosis is a major problem in Crohn’s disease and other diseases and cannot currently be prevented or reversed.

Stephan Targan, MD, former executive director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai and a study author, said the therapy’s ability to target fibrosis has broad implications.

“Fibrosis is a major issue in many chronic medical conditions and can cause serious complications,” said Targan, the Feintech Family Chair in Inflammatory Bowel Disease. “So, there is great interest in seeing whether the drug we developed may have benefits even beyond inflammatory bowel disease.”

McGovern added that data from the APOLLO-CD study indicated that response to tulisokibart was rapid—patients’ inflammatory markers dropped within a week of beginning the therapy.

“This is promising news, because in addition to getting people well and helping them stay in remission, we want to help them get well as quickly as possible,” he said.

Also promising: Tulisokibart was developed with a diagnostic tool to help identify people who are most likely to benefit from the drug, which would introduce precision medicine to inflammatory bowel disease care.

McGovern, Targan and a team of researchers at Cedars-Sinai, including Janine Bilsborough, PhD, director of Inflammatory Bowel Disease Drug Discovery and Development, have long studied the role of TL1A in contributing to inflammation and fibrosis in inflammatory bowel disease patients. 

Bilsborough, also a study author, said, “We’ve dedicated our careers to pursuing innovative therapies for people affected by inflammatory bowel disease. It’s very fulfilling to see scientific progress that could help Crohn’s and ulcerative colitis patients reach lasting remission and live a life without limitation.”

Further studies are in progress in larger groups of people with both Crohn’s disease and ulcerative colitis: The double-blind, placebo-controlled Phase III trials will determine the effectiveness and safety of tulisokibart as a treatment to bring about and maintain remission in people with IBD.

Other authors involved in the study include Prof. Brian G. Feagan, MD; Prof. Bruce E. Sands, MD; Prof. Corey A. Siegel, MD; Prof. Marla C. Dubinsky, MD; Randy S. Longman, MD, PhD; João Sabino, MD; Olivier Laurent, PhD; Allison Luo, MD; Jiandong Lu, PhD; Deanna D. Nguyen, MD; Ernesto J. Muñoz-Elias, PhD; Heather Llewellyn, PhD; Tony (Yong) Wang, PhD; InSock Jang, PhD; Ron Marchelletta, PhD; Fadi Towfic, PhD; Mark Yen, MD; Jaclyn K. Anderson, DO; Aaron DuVall, MD; Prof. Jaroslaw Kierkus, MD; Prof. Marek Woynarowski, MD; and Houssam Al Kharrat, MD.

This research was supported by Prometheus Biosciences, a subsidiary of Merck & Co.

Conflicts of Interest: McGovern, Targan and Bilsborough have consulted for Merck, Prometheus Biosciences (acquired by MERCK) and Prometheus Labs. Cedars-Sinai has a financial interest due to the right to receive future royalties for patient rights from MERCK, Inc.

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Excessive fat in the liver is an early characteristic of alcohol-associated liver disease, which is the most frequent underlying cause of alcohol-associated deaths, according to the U.S. Centers for Disease Control and Prevention. The new study found that a specific cellular signaling pathway, which helps maintain normal fat levels in the liver, was suppressed in alcohol-associated liver disease mice. The findings were published in the peer-reviewed journal Signal Transduction and Targeted Therapy.

“Therapeutic approaches that control fat accumulation may be able to stop liver disease from progressing to a more advanced state,” said Komal Ramani, PhD, associate professor of Medicine and Biomedical Sciences, member of the Karsh Division of Gastroenterology and Hepatology in the Department of Medicine at Cedars-Sinai and corresponding author of the study. “Based on our research, one possible treatment could involve creating a drug to mimic the interaction that is integral to the signaling pathway, to normalize fat levels in the liver.”

Other Cedars-Sinai authors include Chandana Thimme Gowda, Mallikarjuna Siraganahalli Eshwaraiah, Jiaohong Wang, Youngyi Lim, and co-corresponding authors Maria Lauda Tomasi and Nirmala Mavila.

Funding: This work was supported by NIH grant R01AA029988 (PI: Komal Ramani, Co-I’s-Nirmala Mavila, and Maria Lauda Tomasi).

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Liver fibrosis can be triggered by many factors, including viruses that cause hepatitis (infection and inflammation in the liver), long-term alcohol use or some metabolic disorders. Because it produces few or no symptoms at first, the condition typically progresses slowly for years, going undetected until it has caused serious organ damage. At that stage, liver transplantation may be the only effective treatment. The ability to undo the scarring would be a major breakthrough for patient care.

In their study, published in the peer-reviewed journal Nature Communications, Cedars-Sinai investigators examined three genes and the proteins that they made. One of them, FOXM1, is known to cause liver cancer, inflammation and fibrosis when it becomes overactive in hepatocytes, a type of liver cell. The two other genes, MAT2A and MAT2B, are required to activate another type of cell, hepatic stellate cells, which plays a key role in liver fibrosis. The study demonstrated that the proteins coded by these three genes interact and that all three are needed to produce liver fibrosis.

“We discovered that these proteins ‘talk’ with each other inside liver cells,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and corresponding author of the study. “They even influence nearby cells through extracellular vesicles—fat molecules filled with genetic fragments, proteins and other biological materials that act as messengers between cells. Working together, that is how these proteins stimulate each other, driving liver inflammation and fibrosis.”

These discoveries raised the possibility that inactivating just one of the three proteins might block liver fibrosis. To test that theory, the team induced liver inflammation and fibrosis in laboratory mice and treated them with a substance known as FDI-6 that blocks the FOXM1 protein. In a series of experiments, they showed that FDI-6 could prevent liver fibrosis from developing, halt further progression and even reverse the condition, resulting in the scarring disappearing.

Although both mice and humans have all three genes, and these genes also are more highly expressed in human liver fibrosis and cirrhosis, the study did not prove that a similar treatment would work in patients with liver fibrosis. Reaching that conclusion would require additional research and testing, Lu said. 

“What we achieved was to unveil the axis of FOXM1, MAT2A and MAT2B as a potential target for developing drugs to treat liver fibrosis,” Lu said. “Our findings suggest that blocking any of these proteins might be useful in treating this condition.”

Peter Chen, MD, professor of Medicine, the Medallion Chair in Molecular Medicine and interim chair of the Cedars-Sinai Department of Medicine, said, “This highly original study significantly advances our understanding of an insidious condition that too often leaves patients and doctors with few treatment options. It is emblematic of Cedars-Sinai’s innovative scientific work.”

Other Cedars-Sinai authors include Bing Yang, Liqing Lu, Ting Xiong, Wei Fan, Jiaohong Wang, Lucía Barbier-Torres, Jyoti Chhimwal, Sonal Sinha, Takashi Tsuchiya, Nirmala Mavila, Maria Lauda Tomasi, DuoYao Cao, Jing Zhang, Hui Peng, Komal Ramani, Jenny Han, Ekihiro Seki and Heping Yang. Additional authors include Jose M. Mato, Ting Liu, Xi Yang and Vladimir V. Kalinichenko.

Funding was provided by the National Institutes of Health grant P01CA233452 to S.C. Lu, H. Yang and E. Seki; Plan Nacional of I + D SAF2017-88041-R to J.M. Mato; and the National Natural Science Foundation of China 82070632 to Liu T.

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“The ACG annual meeting is an important opportunity for our expert researchers and clinicians to share their innovative research with other leaders in this space to drive the field forward and continue improving patient care,” said Shelly Lu, MD, the Women’s Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai.

Cedars-Sinai is ranked #1 in California and #2 in the nation for Gastroenterology and GI Surgery, according to U.S. News & World Report’s “Best Hospitals 2024-2025” rankings.

Cedars-Sinai Highlights at ACG 2024

Brennan Spiegel, MD, MSHS, the George and Dorothy Gourrich Chair in Digital Health Ethics and director of Health Services Research at Cedars-Sinai, co-authored a series of new books for ACG titled, Guide to the Guidelines, and is hosting an educational session to enhance knowledge of ACG guidelines and improve clinicians’ medical practice.

Ali Rezaie, MD, medical director of the Cedars-Sinai GI Motility Program and director of Bioinformatics at the Medically Associated Science and Technology (MAST) program at Cedars-Sinai, is receiving the ACG Outstanding Research Award in the Small Intestine Category for his research, “Achieving Organoleptic Acceptability With Elemental Formula: A Prospective Single-Blind Comparative Study.” Rezaie also is presenting research into the effects of GLP-1 agonists on surgical outcomes.

Srinivas Gaddam, MD, associate director of Pancreatic Biliary Research at Cedars-Sinai, is presenting a poster on the risk of pancreatic cancer after a diagnosis of gallbladder disease.

Andres Yarur, MD, a gastroenterologist and associate professor of Medicine at Cedars-Sinai, is lecturing in the postgraduate course, giving an oral abstract presentation and exhibiting several posters about inflammatory bowel disease.

Amrit K. Kamboj, MD, a gastroenterologist at Cedars-Sinai, is presenting research data on esophageal conditions including Barrett’s esophagus, which is caused by damage from stomach acid.

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Results from the multicenter Phase II study, ARTEMIS-UC, were published in The New England Journal of Medicine.

Ulcerative colitis is a type of inflammatory bowel disease (IBD) that damages the digestive tract, causing stomach cramping, diarrhea, weight loss and rectal bleeding. It affects as many as 900,000 people in the U.S., and current treatments are often only minimally effective.

“Findings from this study are poised to have a remarkable impact on treatment for ulcerative colitis and IBD overall,” said study senior author and IBD research pioneer Stephan Targan, MD, the Feintech Family Chair in Inflammatory Bowel Disease and executive director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai. “The investigational therapy was generated based on the concept of precision medicine; it shows promise as being both anti-inflammatory and anti-fibrotic; it represents a potential turning point in drug development and discovery; and it could change how this complex disease is treated in the future.”

The study evaluated a therapy developed by Cedars-Sinai clinician-scientists called tulisokibart (previously PRA023)—a man-made monoclonal antibody that acts like endogenous antibodies. It is designed to target and block a protein called TL1A, which can contribute to the severity of ulcerative colitis. The antibody reduces inflammation and targets fibrosis, which causes many of the complications and severity of disease.

“Unlike other IBD treatments that can exacerbate inflammation or suppress the body’s natural anti-inflammatory responses, our findings suggest that tulisokibart modulates inflammation and the body's anti-inflammatory mechanisms,” Targan said. “This dual action could lead to more balanced and effective management of ulcerative colitis.”

Notably, the role of TL1A as a master regulator of inflammation was discovered by Targan and collaborators at Cedars-Sinai. In groundbreaking work spanning two decades, the researchers found that while TL1A protects against invading pathogens, at high levels it also contributes to inflammation and fibrosis in IBD.  

ARTEMIS-UC was a 12-week study involving 178 adults from 14 countries. It also included a genetic-based companion diagnostic test to help predict response to the therapy.

A Phase III study will further examine safety and test effectiveness of tulisokibart in patients who take it longer than 12 weeks.

Clinician-scientist and geneticist Dermot McGovern, MD, PhD, director of Translational Research in the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai and one of the study authors, has focused his career on identifying genetic variants associated with ulcerative colitis and other autoimmune diseases, exploring drug targets and working to revolutionize treatment through a precision medicine approach.

Nearly 20 years ago at Oxford University, McGovern and colleagues, in the first-ever genome-wide association study in IBD, identified that a variation in the TNF superfamily 15 (TNFSF15) gene was associated with developing both ulcerative colitis and Crohn’s disease. The protein TL1A, simultaneously being studied by Targan at Cedars-Sinai, is encoded by TNFSF15. McGovern left Oxford to collaborate with Targan and team at Cedars-Sinai in the effort to bring scientific breakthroughs to IBD.

“Findings from the ARTEMIS-UC study exemplify how combining genetics and biology can transform IBD care,” said McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and the director of Precision Health at Cedars-Sinai.

McGovern, who was recently awarded the prestigious Sherman Prize for his pioneering work in advancing understanding of the genetic architecture of IBD in diverse populations, says the uniqueness of this target and the way tulisokibart was designed to interact with that target represent significant advancements in how clinicians approach IBD treatment.

“Previously we have only been able to prescribe a medication to a patient that we think will work well, but going forward we could imagine telling the patient, ‘Actually, the genetic test suggests that you would be more likely to respond to this therapy,’” McGovern said.

Targan and McGovern also noted that ARTEMIS-UC involved multiple countries and diverse populations, reflecting the global nature of IBD. The F. Widjaja Inflammatory Bowel Disease Institute has invested significant resources in extending genetic research in IBD to diverse populations.

“It’s taken a village—supported by Cedars-Sinai’s integrated science culture—to reach this point,” said Targan, a 2017 recipient of the Sherman Prize. “We’ve devoted our careers to getting better treatments to IBD patients, and now we’re closer than ever to helping all patients with ulcerative colitis get their disease into remission so they can get back to enjoying life.”

Other authors involved in the study include Bruce E. Sands, MD; Brian G. Feagan, MD; Laurent Peyrin-Biroulet, MD, PhD; Silvio Danese, MD; David T. Rubin, MD; Olivier Laurent, PhD; Allison Luo, MD; Deanna D. Nguyen, MD; Jiandong Lu, PhD; Mark Yen, MD; Jaroslaw Leszczyszyn, MD, PhD; Radosław Kempiński, MD, PhD; Christopher Ma, MD; and Timothy E. Ritter, MD.  

This research was supported by Prometheus Biosciences, a subsidiary of MERCK.

Conflict of Interest: Targan and McGovern have consulted for MERCK, Prometheus Biosciences (acquired by MERCK) and Prometheus Labs.

Read more on the Cedars-Sinai Blog: Is It IBS or IBD?

McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and director of Precision Health at Cedars-Sinai, is one of two 2024 Sherman Prize recipients. The Prize, established by the Bruce and Cynthia Sherman Charitable Foundation, recognizes visionary clinicians, surgeons, researchers and academics who have made exceptional contributions in transforming IBD research and improving patient care.

“Receiving the Sherman Prize is an incredible honor,” McGovern said. “To be listed alongside previous awardees, people I greatly admire, is very special to me. Much of the credit for this honor goes to my outstanding team—I’m very lucky to be working with such smart and dedicated people to help improve the lives of those with IBD.”

Over the past 15 years, McGovern has been a key driver in many pivotal IBD genetic studies.  

“Dr. McGovern is a brilliant researcher who is working to elucidate the complexities of IBD to meaningfully improve the lives of people around the world who suffer from the disorder,” said Shlomo Melmed, MB, ChB, executive vice president of Medicine and Health Sciences, dean of the Medical Faculty and distinguished professor of Medicine at Cedars-Sinai. “Our institution is an international leader in IBD research and treatment, largely due to our talented faculty—exemplified by Dr. McGovern’s visionary leadership and dedication. Heartiest congratulations on his receipt of the distinguished Sherman Prize.”

McGovern began his career at Oxford University. He remembers a patient asking how he knew the treatment being prescribed was the right one. That question sparked McGovern’s yearslong quest to identify drug targets and associated biomarkers so he could match each patient with the most effective medicine.

While at Oxford, McGovern and collaborators identified a gene involved in IBD pathophysiology called TNF Superfamily 15. At the same time, Stephan Targan, MD, the Feintech Family Chair in Inflammatory Bowel Disease and director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai—also a past recipient of the Sherman Prize—had discovered and was studying a protein encoded by the TL1A  gene.

After a chance meeting between the two, McGovern joined Targan and team at Cedars-Sinai.

Today, McGovern leads his own lab, the Translational Genomics Group, at Cedars-Sinai. After 20 years of collaboration with Targan on an anti-TL1A therapy, McGovern’s dream of delivering personalized medicine to IBD patients is gaining momentum. A new investigative treatment that differs from existing therapies while also addressing fibrosis (excessive scar tissue) in Crohn’s disease and ulcerative colitis—forms of IBD—is being studied in Phase III clinical trials. And, for the first time in IBD care, the disease has a companion diagnostic tool, which matches a patient to a specific medication.

If the therapy is approved, it will be the first approved personalized medicine for people with IBD.

McGovern says collaborations enable advances for patients. Now, he is working on other game-changing projects in his lab—such as improving the IBD classification system—with an eye toward broad global application.

He believes that the most pressing challenge for the field is bringing IBD advances to all parts of society. To that end, he has led the effort to extend largely European ancestry studies and advances to African American, Hispanic/Latino and East Asian populations. He also recently created a consortium to conduct genetic studies in sub-Saharan Africa.

“The Sherman Prize will allow me to enhance our collaborations across sub-Saharan Africa so that we can study the evolution of IBD in African populations,” McGovern said.

Improving patients’ quality of life, regardless of where they live, their ethnicity, social status or gender, inspires McGovern.

“A fundamental aspect of our work to advance our understanding of the causes of Crohn’s disease and ulcerative colitis and develop strategies to translate these discoveries into the clinic is our philosophy that these advances should be available to all populations,” McGovern said. “This has motivated us to invest resources and pioneer studies in diverse populations and ensure we are addressing disparities in research and clinical care.”

Read more from the Cedars-Sinai Blog: A Good Grip on Crohn’s Disease

The study, published in Clinical Gastroenterology and Hepatology, showed that disruption in a patient’s gut flora, specifically the overgrowth of archaea—unique microorganisms in the gut microbiome that produce methane—could be the cause.

Researchers hope the study’s findings will help experts root out the cause of constipation instead of merely treating patients’ symptoms. These findings could also aid in developing a personalized treatment plan for a subgroup of patients who experience severe constipation due to intestinal methanogen overgrowth (IMO)—a condition in which archaea excessively grow in the intestines.

“Our study found that patients with IMO are more likely to have constipation, particularly severe constipation, and less likely to have unyielding diarrhea,” said the study’s corresponding author, Ali Rezaie, MD, medical director of the Cedars-Sinai GI Motility Program and director of Bioinformatics at the Medically Associated Science and Technology (MAST) program at Cedars-Sinai. “Patients, however, also reported several other gut-related symptoms, including bloating, diarrhea, abdominal pain and flatulence.”

Constipation is one of the most common gut-related issues in the United States. About 16% of adults experience bloating, abdominal pain, and difficulty having bowel movements; the numbers nearly double for people over 60. While many things, like medication side effects or lack of dietary fiber, can cause constipation, historically, there has been a shortage of research on the gut microbiome’s role in constipation and other digestive issues. 

“When there is an excessive amount of archaea in your gut, they produce more methane, and some of that methane makes its way to your bloodstream, then to your lungs, and you breathe it out, where it can measured as a diagnostic test,” Rezaie said. “Essentially, people who have excessive amounts of methane have a lot of GI symptoms, including constipation, flatulence, bloating and diarrhea.”

For context, the gut microbiome consists of trillions of microorganisms, such as the community of bacteria, yeast and fungi in the digestive system. When there is an imbalance among the microorganisms populating the gut, it is associated with a host of GI symptoms and diseases.

Experts used electronic databases to identify 19 studies—11 conducted in the U.S. and eight conducted in six other countries—that assessed symptoms for patients with IMO.

“Historically there has been a paucity of information regarding the role of archaea in health and disease. Unique symptom patterns related to IMO should be taken into account when measuring patient-reported outcomes and should be further studied in relation to the microbiome,” said Peter Chen, MD, interim chair of the Department of Medicine at Cedars-Sinai.

For example, taking over-the-counter or prescription laxatives often relieves constipation, but won’t always address other GI symptoms, such as bloating, abdominal pain and diarrhea. In fact, in some cases, taking a laxative could potentially worsen coexisting diarrhea and bloating. 

Researchers explain that the optimal solution for IMO-induced severe constipation is to suppress the archaea overgrowth and keep the organism at bay. This generally involves a combination of antibiotics and a specialized diet to reset the gut microbiome. However, the first step is to diagnose the archaea overgrowth through a noninvasive hydrogen/methane breath test.

According to Rezaie, the study's findings are crucial and will hopefully encourage healthcare providers to utilize precision medicine, conduct clinical trials that target microbiome research and develop strategies to optimize patient care.

“The goal is to move toward developing specific therapies and personalized treatment for a subgroup of people who experience constipation due to IMO,” Rezaie said. “We can start by using breath tests to identify excessive methane production, which can be the first step to detecting archaea overgrowth and could ultimately lead to developing more targeted therapies. It's a big step to move away from the common reflex use of laxatives.”

Additional Cedars-Sinai authors include Sepideh Mehravar, MD; Jiajing Wang, PhD; Jason Nasser, MD; and Mark Pimentel, MD.

Funding: This study was supported in part by funds provided by Nancy Stark and Stanley Iezman in support of the MAST Program's Innovation Project.

Read more on the Cedars-Sinai Blog: Is It IBS or IBD?

Investigators found glucagon-like peptide-1 receptor agonists (GLP-1RAs)—medications like Ozempic and Wegovy that are used to treat diabetes and obesity—are associated with an increased risk of aspiration pneumonia following endoscopy. The large, population-based study is published in the leading peer-reviewed journal Gastroenterology. 

Aspiration pneumonia is caused by inhaling foreign materials—including food in the stomach, or secretions from the mouth and nose—into the lungs. Endoscopy is a medical procedure in which a physician puts a tube-like scope down a patient’s throat and into the body to look inside.

One way the new obesity medications work is by slowing digestion, so people feel full longer, causing them to eat less. This also means that food sits in the stomach longer. As a result, the stomach may not empty completely during the usual duration of fasting that is recommended ahead of a surgical procedure to decrease risk of aspiration, explained the study’s corresponding author, Ali Rezaie, MD, medical director of the GI Motility Program and director of bioinformatics at the MAST Program at Cedars-Sinai.

“Aspiration during or after endoscopy can be devastating,” Rezaie said. “If significant, it can lead to respiratory failure, ICU admission and even death. Even mild cases may require close monitoring, respiratory support and medications including antibiotics. It is important we take all possible precautions to prevent aspiration from occurring.” 

The study analyzed data from nearly 1 million de-identified U.S. patients who underwent upper or lower endoscopy procedures between January 2018 and December 2020. Patients who were prescribed GLP-1RA medications had a 33% higher chance of experiencing aspiration pneumonia than those who did not take these medications before the procedure. This comparison also considered other variables that could influence the outcome to ensure a fair comparison between the two groups.

“When we apply this risk to the more than 20 million endoscopies that are performed in the U.S. each year, there may actually be a large number of cases where aspiration could be avoided if the patient safely stops their GLP-1RA medication in advance,” Rezaie said.

“The results of this study could change clinical practice,” said Yee Hui Yeo, MD, first author of the study and a clinical fellow in the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Patients taking these medications who are scheduled to undergo a procedure should communicate with their healthcare team well in advance to avoid unnecessary and unwanted complications.”

Additional Cedars-Sinai authors involved in the study are Srinivas Gaddam, MD, MPH; Ruchi Mathur, MD; Rabindra Watson, MD; and Jamil Samaan, MD. Additional authors include Wee Han Ng; Pin-Chia Huang, BS; and Kevin Sheng-Kai Ma, DDS.

Read more from the Cedars-Sinai Blog: Weight-Loss Drugs – What to Know Now

The study is published in the journal Gastroenterology.

“We found that being female, smoking, or having a history of surgeries to treat Crohn’s disease or ulcerative colitis puts patients more at risk for developing other serious inflammatory conditions,” said Talin Haritunians, PhD, co-senior author of the study and an associate professor of Medicine at Cedars-Sinai.

“Genetic variations of IBD, as well as the location of the disease in the gastrointestinal tract, were also associated with developing debilitating extraintestinal manifestations of the disease affecting the eyes, joints, skin, liver and spine,” Haritunians said.

The multi-center study involved over 12,000 subjects: the largest study of extraintestinal manifestations of IBD to date, according to investigators. The scientists looked at patients who had at least one of seven different conditions occurring outside the gut, including psoriasis, inflammation of the eye, and ankylosing spondylitis, a condition which can degrade the spine or hips.

Investigators also identified genetic, clinical and immunological factors associated with primary sclerosing cholangitis—a condition which damages the liver—and with painful peripheral arthritis that affects both the small and large joints of the body.

“These inflammatory manifestations outside the gut impact about 40% of our patients with IBD. The disorders can have a very significant effect on quality of life and, in some instances, are life-threatening. Our findings will help us identify those at risk of developing these related conditions,” said Dermot McGovern, MD, PhD, the corresponding author of the study and director of Translational Research in the Cedars-Sinai F. Widjaja Inflammatory Bowel Disease Institute. 

McGovern expects the findings will also provide a guide to developing novel therapeutic treatments for the other disorders and may also address the underlying gut inflammation.

“Our clinical findings in this study shed light on the risk factors for morbidity associated with IBD. Our genetic findings highlight pathways that are targets for existing drugs or therapeutics in development. These discoveries are critical for developing more personalized approaches to the management of IBD and its various manifestations,” said McGovern, who holds the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and is the director of Precision Health at Cedars-Sinai.

Other Cedars-Sinai authors involved in the study include Michelle Khrom, Shishir Dube, Gregory J. Botwin, Shaohong Yang, Emebet Mengesha, Dalin Li, Takeo Naito, Nirupama N. Bonthala, Christina Ha, Gil Melmed, Shervin Rabizadeh, Gaurav Syal, Stephan R. Targan Eric Vasiliauskas and David Ziring. Other authors include Millie Long, Lori Robbins, Steven R. Brant, Judy Cho, Richard H. Duerr, John Rioux, Phil Schumm, Mark Silverberg, Ashwin N. Ananthakrishnan, William A. Faubion, Bana Jabri, Sergio A. Lira, Rodney D. Newberry, Robert S. Sandler, Ramnik J. Xavier, Subra Kugathasan, David Hercules and R. Balfour Sartor.

This research was supported in part by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute. The Cedars-Sinai MIRIAD IBD Biobank is supported by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) grants (P01 DK046763 and U01 DK062413), and The Leona M and Harry B Helmsley Charitable Trust (DPBM and SHARE Consortium).

Conflict of Interest: Dermot McGovern is a consultant for MERCK, Prometheus Biosciences (acquired by MERCK), Takeda and Prometheus Labs.

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Read more in Discoveries Magazine: Ancestry Matters in IBD

The findings of the single center randomized controlled trial are published in Scientific Reports.

“We found that Cedars-Sinai patients in the P.A.I.N.-Sparing group received significantly less opioids and had greater physical activity during their hospitalization, when compared with IBD patients whose pain was treated with as-needed opioids. Also, those receiving the P.A.I.N. protocol tended to have lower overall pain scores while in the hospital,” said Gil Melmed, MD, principal investigator of the study and director of Inflammatory Bowel Disease Clinical Research at Cedars-Sinai.

The P.A.I.N.-Sparing treatment approach developed by investigators was based on a review of the literature on pain management and included scheduled, non-opioid pain medications tailored to the severity of a patient’s reported discomfort. Melmed said that if this approach were not sufficient to control pain, the IBD patients could request opioid pain medications, as needed.

Inflammation, severe diarrhea, malnutrition and acute and chronic pain are leading causes of repeat hospitalizations for IBD patients. Pain is rated by these patients as one of the most burdensome aspects of the disease, yet there is insufficient evidence to support a pain management strategy that is effective.

“Opioid use is more prevalent in IBD than in any other chronic gastrointestinal condition. In spite of the widespread use of these medications, our previous studies have found that opioids do not meaningfully reduce the pain these patients experience. Additionally, there are the known risks associated with using these medications for chronic conditions, including misuse, overdose, infection, hospital readmission and even death,” said Melmed, a professor of Medicine.

Larger, multicenter trials would be useful to further validate the efficacy of the P.A.I.N.-Sparing protocol for IBD patients, Melmed said. He is also encouraged by the emergence of new tools for managing pain.

“There are novel, non-pharmacologic strategies being rigorously studied for their potential to control acute and chronic pain. Biofeedback, virtual reality and other modalities could be incorporated into a proactive approach for addressing the pain and quality of care of our hospitalized IBD patients,” Melmed said.

Additional (current) Cedars-Sinai investigators: Devin Patel, MD; Rajalakshmi Govalan, MD; Shao-Chi Greg Huang; Catherine Bresee; and Teryl K. Nuckols, MD.

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Their findings, published today in the peer-reviewed journal Cell Reports, could aid future studies looking at the effects of diet and the microbiome, especially the process of fiber metabolism by gut microbes.

The team of investigators—led by Ivan Vujkovic-Cvijin, PhD, assistant professor in the department of Biomedical Sciences and department of Gastroenterology at Cedars-Sinai—are among the first to find that looking for fiber metabolites—molecules that strengthen gut barrier integrity and immune function—in blood samples, versus traditional stool samples, provides a more accurate representation of production of these metabolites by the gut microbiome.  

With this knowledge, investigators also discovered that gut microbial production of these fiber metabolites is related to the prevention of heart disease and death in people with HIV, the virus that causes acquired immunodeficiency syndrome (AIDS).

“This is an important step in the human microbiome field because the high-fiber diet has been shown to protect from a remarkable number of diseases, but the field has struggled to quantify the immediate effects of such diets,” said Vujkovic-Cvijin, corresponding and senior author of the study. “We anticipate our discovery will allow better quantification of microbial fiber metabolism and will lead to a greater understanding of the precise pathways that link fiber metabolites to protection from diseases and early death in people with HIV.”

People with HIV have long been known to experience higher rates of many diseases and premature death, despite being treated with optimal antiretroviral therapy. The medical field also knows, based on past studies from Vujkovic-Cvijin and team, that the gut microbiota of people with HIV is different from that of those who are HIV-negative.

This latest research sheds light on the “why.”

Investigators found that an abundance of microbial enzymes involved in fiber deprivation correlates more strongly with fiber metabolite levels in blood than in stool.

Through this research, the team also found that significantly higher levels of these microbial enzymes were found in people who did not later succumb to heart disease or death, suggesting the importance of this pathway in the health of people with HIV.

“Thanks to this important research, we now understand that a lack of ability of the gut microbiome to digest fiber precedes medical conditions like heart disease, suggesting this function of the microbiome may also contribute to their development,” said David Underhill, PhD, chair of the Department of Biomedical Sciences, who was not involved in the research study.

Underhill said future studies may also gain more information by examining blood levels of fiber metabolites, instead of examining stool samples.

“Blood samples appear to paint a clearer picture of who might best benefit from fiber, and which types,” said Underhill.

Looking ahead, Vujkovic-Cvijin also plans to focus future research efforts on the precise pathways that may link fiber metabolites to protection from disease and early death in people with HIV.

“There are several likely candidates, and we hope to uncover which of these pathways might have the greatest impact on health,” said Vujkovic-Cvijin.

Additional Cedars-Sinai authors include Alice Lo and Jacob Gifford. Other authors include Irini Sereti, Myrthe L. Verburgh, Anders Boyd, Eveline Verheij, Aswin Verhoeven, Ferdinand W.N.M. Wit, Maarten F. Schim van der Loeff, Martin Giera, Neeltje A. Kootstra, and Peter Reiss.  

DOI: 10.1016/j.celrep.2023.113336

Funding: Vujkovic-Cvijin was funded by the Crohn’s & Colitis Foundation Career Development Award. This work was supported in part by The Netherlands Organization for Health Research and Development and AIDS Fonds and by the intramural research program of NIAID/NIH.

Read more from the Cedars-Sinai Blog: Cedars-Sinai Investigators Exploring the Connection Between the Microbiome and Diabetes

The gastrointestinal tract includes the organs that digest food, absorb nutrients and process the body’s waste. A protein called mucin is essential to the proper functioning of these organs, which are basically a long, coiled tube. When combined with water, mucin forms mucus, a slippery substance that lubricates the gut’s lining. Mucus creates a sticky barrier that catches and traps harmful particles. 

When the body produces too much or too little mucin, the result can be unhealthy levels of bacteria, trouble digesting food and absorbing nutrients, and other issues. By better understanding the cellular and molecular processes involved in mucus formation, scientists aim to uncover how to treat gastrointestinal-related diseases. 

FINDINGS

Because of this study, investigators now have a better understanding of how mucin is created and regulated. The epithelium, the type of tissue that covers internal and external surfaces on the body, is made up of cells that produce a protein called tumor necrosis factor (TNF). Investigators learned that this protein contributes to cell differentiation and communication that result in a healthy balance of mucin production and turnover.  

The research was published in the Journal of Clinical Investigation. 

METHODS

Investigators observed the effect of removing TNF from laboratory mice and examined tissue samples from people with inflammatory bowel disease on anti-TNF therapy. A lack of TNF led to an increased number of cells called goblet cells that produce mucin. The absence of TNF also resulted in mucus accumulation, unhealthy bacterial levels and slower gut movement. 

IMPACT

“Epithelial TNF is a vital regulator of mucin production, and when this process is optimal, it contributes to a healthy gastrointestinal tract,” said Ophir Klein, MD, PhD, executive director of Cedars-Sinai Guerin Children’s, the David and Meredith Kaplan Distinguished Chair in Children’s Health and a corresponding author of the study. “With these findings, we can study how to manipulate mucin production to treat diseases of the gastrointestinal tract.”

AUTHORS

Efren A. Reyes, PhD, University of California, San Francisco; David Castillo-Azofeifa, PhD, University of California, San Francisco, and Genentech, Inc.; Jérémie Rispal, PhD, University of California, San Francisco; Tomas Wald, PhD, University of California, San Francisco; Rachel Zwick, PhD, University of California, San Francisco; Brisa Palikuqi, PhD, University of California, San Francisco; Angela Mujukian, MD, Cedars-Sinai; Shervin Rabizadeh, MD, MBA, Cedars-Sinai; Alexander R. Gupta, MD, University of California, San Francisco; James M. Gardner, MD, PhD, University of California, San Francisco; Dario Boffelli, PhD, Cedars-Sinai; Zev J. Gartner, PhD, University of California, San Francisco; Ophir Klein, MD, PhD, Cedars-Sinai.

FUNDING

This research was supported in part by the National Institutes of Health, the Center for Cellular Construction and a UCSF/NIGMS IMSD Fellowship.

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In a new study published in the journal IBD, investigators used a novel statistical approach to identify three new regions of the genome associated with developing IBD. They also discovered other areas that were specifically associated with developing IBD in only one sex.

“We observed sex differences in the prevalence of specific clinical characteristics. Females were more likely to have Crohn’s disease affecting only the colon. In males, on the other hand, we saw a higher risk for perianal complications in Crohn’s disease as well as more extensive disease in ulcerative colitis,” said Talin Haritunians, PhD, the senior author of the study and a research associate professor of Medicine at Cedars-Sinai.

Haritunians, a research scientist in the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, noted the study was the first international investigation into sex-stratified genetic associations in IBD containing more than 70,000 subjects.

“Most genetic association studies analyze males and females together. Our study highlighted the need to move beyond the conventional sex-combined analyses in order to fully appreciate the complex genetic architecture of IBD,” said Dermot McGovern, MD, PhD, a co-author of the study and director of Translational Research in the Inflammatory Bowel and Immunobiology Research Institute.

The sex-dimorphic analytic approach used by the investigators identified associations in three new genetic loci (chr9q22, CARMIL1 and UBASH3A) as well as distinct sex-specific patterns of association for several variants, including on chromosome-2 and in the major histocompatibility complex on chromosome-6.

“This is of particular interest given the well-established role of the major histocompatibility complex and HLA locus in IBD and immune-mediated diseases, in general,” said Haritunians.

The investigators say they are continuing the collaboration with the IBD international consortium and are currently expanding the study to include a cohort of more than 100,000 people.

“We plan to also develop sex-specific IBD genetic risk scores to better evaluate the genetic ‘burden’ in males and females,” said Haritunians.

This novel approach to genetic research of sex differences in IBD will also be used in Cedars-Sinai’s large-scale studies of the disease in Black and Hispanic populations, according to the scientists.

“These types of studies are critical if we are to build on our previous success employing genetics to develop new, personalized therapeutics for IBD and using them to treat those most likely to respond well. In other words, getting the right therapy to the right patient at the right time,” said McGovern, who holds the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai.

Funding: This work was supported in part by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grants P01 DK046763 and U01 DK062413), and The Leona M. and Harry B. Helmsley Charitable Trust.

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The findings are published in the journal Gastroenterology.

“Even though biologic medications have significantly improved outcomes for our patients with Crohn’s disease or ulcerative colitis, some people do not respond well to these therapies. In our study, we found that the patients with higher amounts of internal abdominal fat were less likely to improve and experience remission from their disease,” said gastroenterologist Andres J. Yarur, MD, the corresponding author of the study.

Unlike some conventional anti-inflammatory drugs which treat inflammation in a non-selective way, biologics work by blocking specific targets that cause inflammation in the body.

Patients in the study with higher visceral fat levels had lower concentrations of the biologic medications in their blood after treatment, and lower rates of steroid-free remission and bowel healing.

“It may not be body weight or body mass index [BMI] that is the reason some of our patients benefit from these approved biologic medications. It seems the fat tissue on the inner side of the abdomen, in particular, impacts treatment, so we may need to use higher doses of the drugs to help these patients,” said Gil Melmed, MD, a co-author of the study and director of Inflammatory Bowel Disease Clinical Research at Cedars-Sinai.

Investigators treated 141 IBD patients with one of three biologic medications: infliximab, ustekinumab or vedolizumab. Reliable body composition measurements were taken for both the IBD group and the 51 healthy control subjects to ensure fat composition for the two groups were similar.

“We found that higher visceral adiposity was associated with higher levels of pro-inflammatory cytokines, suggesting that fat tissue promotes inflammation, the opposite of what we want, and increases resistance to biologic drug therapy. More research is needed because we don’t know whether lowering visceral fat or giving higher doses of the medications would improve drug efficacy,” said Melmed.

Yarur, the study’s principal investigator, agrees, adding that a different kind of medication may be more effective in patients with a high intra-abdominal visceral fat. 

“We need to investigate drugs with different mechanisms of action, especially other small molecules, to see if our findings hold. As the prevalence of obesity and metabolic syndrome increases in our population, we need to find interventions that would improve the body composition of these IBD patients who are not currently helped by these biologic treatments,” said Yarur.

DOI: https://doi.org/10.1053/j.gastro.2023.06.036

Funding: The pilot study for this investigation was funded by a grant from the Digestive Disease Center at the Medical College of Wisconsin.

Conflicts of Interest:  Andres Yarur is a consultant, and member of the advisory board, for Takeda, which manufactures vedolizumab, and for Celltrion Healthcare, which produces one biosimilar of infliximab. Gil Melmed is also a consultant to Takeda and Janssen Immunology, the makers of infliximab and ustekinumab.

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Read more on Discoveries Magazine: Ancestry Matters: Genetic Risk Factors for IBD

IBD is an autoimmune disorder primarily causing ulcerative colitis or Crohn’s disease. The immune system attacks healthy tissue in the gastrointestinal track, and can lead to severe diarrhea, malnutrition, dangerous blood clots, pancreatitis, and extensive and painful scarring.

“Almost all treatments for IBD target inflammation that occurs in this disease,” said Kathrin Michelsen, PhD, research assistant professor of Medicine and Biomedical Sciences in the F. Widjaja Foundation Inflammatory Bowel Disease Institute in the Department of Medicine at Cedars-Sinai, and senior author of the study. “We want to learn how to repair what we refer to as a ‘leaky gut,’ the damaged intestinal lining that also occurs in people with IBD.”

Scientists hypothesize that people with leaky guts are vulnerable to getting harmful substances, such as some types of bacteria, in their bloodstream.

This study by Michelsen and colleagues follows up on previous studies that investigated the function of a gene called tumor necrosis factor superfamily member 15, or TNFSF15. This is one of the first genes found to be associated with IBD.

TNFSF15 produces a protein called TL1A that is involved in intestinal inflammation. The investigators sought to know more about how the interactions between this protein and the intestinal lining might cause IBD symptoms. They focused on the TL1A receptor, a protein called death receptor 3, or DR3. Receptors are proteins that bind to molecules and aid in the communication between cells. DR3 binds to the surface of TL1A, for example.

To perform their study, the investigators observed laboratory mice carrying the TNFSF15 gene and mice not carrying it. They examined cells taken from the intestines of the mice and cultured them in a petri dish to see whether the cells expressed the gene. They also studied whether the collection of cells lining the intestines, known as the epithelial barrier, were damaged and how the cells could heal and grow again. 

Epithelial barrier cells are connected by proteins that keep the lining of the intestines tight. This prevents bacteria from getting into the lamina propria, the connective tissues that also line the intestines and that form part of the immune system. People with IBD typically have inflammation in the lamina propria, which is supposed to serve as a protective physical barrier in the body.  

The investigators discovered that mice that did not produce DR3 had less tightly bound epithelial cells. Their intestines were permeable enough to allow in bacteria that caused inflammation in the lamina propria.

The investigators also discovered that although laboratory mice that had inflammation in their intestines showed increased levels of TL1A, their epithelial cells did not show increased DR3 expression.

“These findings suggest that therapeutic approaches targeting TL1A rather than DR3 could reduce inflammation while preserving the repair mechanisms that DR3 is essential for in epithelial cells,” said Yosuke Shimodaira, PhD, first author of the study and a former investigator at Cedars-Sinai.

DR3, for example, contributes to the regeneration of the epithelial barrier, which is necessary for healing cell damage in the intestines caused by IBD.

“There are currently clinical trials that are studying drugs that target TL1A,” Michelsen said. “It's really important to elucidate all the potential mechanisms that could impact potential therapeutic efficiency and efficacy in those clinical trials.”

The investigators are continuing to study the effects of other genes associated with IBD.

Funding: The study was funded by the National Institutes of Health (award number DK056328) and the F. Widjaja Foundation.

Read more on the Cedars-Sinai Blog: Living a Life That Isn't Defined By IBD