The IBD Prehabilitation Program, pioneered at Cedars-Sinai, has significantly enhanced surgical outcomes and reduced complications for patients with the digestive disease.

Gil Melmed, MD, director of Inflammatory Bowel Disease Clinical Research, led the development of the multidisciplinary program and is eager to study its effectiveness in healthcare systems serving patient populations where English is not the primary language.

“We don’t know if the positive outcomes from the program are specific to our local environment and patient population or if they also have wider application,” Melmed said. “This generous grant from the Helmsley Charitable Trust enables us to expand the IBD prehabilitation protocols to a completely different environment and to patient populations in an international setting.”

Cedars-Sinai will partner with Sheba Medical Center through its ARC innovation center, along with two additional Israeli hospitals, to establish prehabilitation programs for IBD patients in need of surgery.

The 10-week program involves comprehensive care starting a month before surgery. Patients receive tailored dietary, mental health and physical therapy interventions both before and after their procedures.

“We have found that people participating in the program experienced a significant reduction in complications after surgery, as well as a reduction in 30-day readmissions and repeated surgery. They also required less opioid medication for pain,” said Melmed, who is also the associate director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai.

An estimated 3 million people in the U.S. have inflammatory bowel disease, according to the Centers for Disease Control and Prevention. Worldwide, the Crohn’s & Colitis Foundation estimates that about 10 million people are living with IBD. The disorder produces chronic and often destructive inflammation in the digestive tract. The two most common forms of IBD are Crohn’s disease and ulcerative colitis, with Crohn’s disease patients generally requiring abdominal surgery at least once in their lifetime.

“As part of the grant, we will develop patient materials in multiple languages, including English, Spanish, Arabic and Hebrew. If successful, we hope to expand to other countries to share this approach to meaningful improvement in health outcomes for people who require surgery to manage their disease,” Melmed said.

In 2022, the Helmsley Charitable Trust awarded Cedars-Sinai $1.25 million for initial development of the IBD prehabilitation program aimed at optimizing care and improving surgical outcomes and the overall health of patients undergoing major abdominal surgery.

Read more from Cedars-Sinai Stories and Insights: Is It IBS or IBD?

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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The results of the representative study are published in the journal Gastroenterology.

“This new study is among the largest population-based evaluations of IBS epidemiology. The results reveal that the condition is more prevalent than previously thought and varies by race and ethnicity,” said the study’s corresponding author, Brennan Spiegel, MD, MSHS, director of Health Services Research and the Dorothy and George Gourrich Chair in Digital Health Ethics at Cedars-Sinai.

In May and June of 2020, investigators conducted online surveys of adults age 18 and older. A large cross section of people living in the U.S. were asked to complete the Rome IV IBS questionnaire and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) survey to assess the presence and severity of their gastrointestinal symptoms.

“We wanted to update our understanding of how common IBS is in the U.S. and to get a sense of the associated burden of the illness. Because diagnosis is symptom-based, we used the Rome IV validated IBS questionnaire to survey respondents about their abdominal pain and changes in bowel habits. We also used the PROMIS survey to see what other symptoms they were experiencing,” said gastroenterologist and co-first author of the study Christopher Almario, MD, MSHPM, who is also an assistant professor of Medicine at Cedars-Sinai.

In addition to the significant size of the study cohort, investigators point out there have been few large-scale studies looking at racial and ethnic differences in IBS.

“Our findings showed that non-Hispanic Black people, Hispanics and non-Hispanic Asian people all were less likely to have IBS when compared to non-Hispanic white people,” said Almario.

“But some of the non-white participants who did have IBS experienced more severe symptoms. For example, Hispanics and non-Hispanic Black people with a form of IBS where diarrhea is common had more severe belly pain than their non-Hispanic white counterparts,” said Almario.

Since the prevalence of IBS appears to be on the rise, Almario suggests physicians may be seeing more patients with associated symptoms in their clinics.

“In addition to abdominal pain and changes in bowel habits, patients with IBS may experience bloating, excess gas and heartburn. It is important for healthcare providers to take a thorough patient history in order to identify and manage these treatable symptoms,” said Almario.

According to the study authors, the COVID-19 pandemic may have played a role in the increased prevalence of IBS, and they are performing additional data analysis to examine the potential connection.

“It is possible that both direct infection with the virus that causes COVID-19 and the psychological stress associated with living through a pandemic contributed to the rise in IBS prevalence through a number of mechanisms worthy of further investigation,” said Spiegel.

DOI: https://doi.org/10.1053/j.gastro.2023.08.010

Funding: Support for this study was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai.

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Read more on the Cedars-Sinai Blog: When to See a Doctor for Constipation

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