Sleep Quality Improvement a ‘Tremendous Opportunity’ in Treating GI Conditions

Sleep dysfunction is so prevalent it has been described as an epidemic, affecting nearly a third of adults in the U.S. by some estimates. In addition to neurocognitive effects like impaired attention and slower response time, other health impacts of insufficient sleep are becoming increasingly recognized. Notably, the upregulation of proinflammatory cytokines and altered visceral and somatic perception caused by sleep disruption have important implications for a variety of gastrointestinal conditions, experts told Healio Gastroenterology and Liver Disease.

Unfortunately, the importance of assessing sleep quality is not widely appreciated in clinical practice, but providers would be wise to consider interventions for chronic sleep disorders for their patients with GI conditions, according to David A. Johnson, MD, MACG, FASGE, FACP, of Eastern Virginia Medical School, who has been researching the impacts of sleep on GI disorders and on general health for more than two decades.

“We’ve had a tremendous misperception of sleep as just a placeholder between two periods of daylight, work and activity, but that’s clearly not the case,” Johnson said in an interview. “The effect of sleep on the promotion of GI and general health is profound, and intervention for sleep fragmentation or disruption is a tremendous opportunity to augment our approach to health and disease management.”

In his new book, Sleep Effect on Gastrointestinal Health and Disease: Translational Opportunities for Promoting Health and Optimizing Disease Management, Johnson and colleagues outline the physiology of sleep and GI health, and the clinical effects of sleep dysfunction in a variety of GI conditions, including gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disease and even colorectal cancer. In this and much of his work on the subject, he describes a “dynamic bidirectional relationship” between sleep and the GI system, which affects “a complex balance of circadian rhythms, neurohormonal transmitters and the intestinal microbiome.”

Sleep-gut Axis

The intricate relationship between sleep and the gut can result in a “vicious cycle” that makes it difficult to discern if poor sleep exacerbates GI symptoms, or if GI disease disrupts sleep and circadian function, Johnson said.

“Both the gut and the brain function on an independent basis, but in a very intertwined, dynamic manner,” he said. “The relationship between the gut and brain is clearly recognized, but I don’t think to date we’ve given the gut-brain axis and its implications on sleep the service and attention that it really deserves, especially considering our increasing understanding of circadian rhythms, which are apparent not only in the brain, but in virtually all of the organ systems.”

These endogenous molecular oscillations occur in 24-hour patterns that are notably inexact and can be influenced by environmental factors like light exposure and even diet, which can ultimately affect sleep quality. Thus, differentiating between disruptions in circadian rhythms vs. sleep itself as the driver of GI symptoms is important for guiding treatment, Johnson said. Exacerbated GI disease caused by disturbances in circadian rhythms may be improved by pharmacotherapy like melatonin, while behavioral modifications may be better suited for disease that is exacerbated by disrupted sleep.

“When I take a sleep history I try to figure out where the sleep problem is,” he said. “There are patients who can’t get to sleep, and that’s a sleep initiation problem, while others can get to sleep and just don’t feel well the next day, and that’s a sleep transition problem. Trying to separate those things helps me direct them toward the best treatment approach.”

Sarah K. Ballou, PhD, a GI psychologist at Beth Israel Deaconess Medical Center, said circadian rhythms could play an especially important role in sleep dysfunction in functional GI disorders.

“There’s definitely a difference between circadian dysfunction and poor sleep quality,” she said in an interview. “Our GI tract follows its own circadian clock, so digestive functions are different at night than they would be during the daytime.”

For example, many people develop circadian-induced GI symptoms when experiencing jet-lag, she said. Similarly, studies have shown this phenomenon to be common among shift-workers who work odd hours.

“It’s been shown that nurses who work night or rotating shifts have a higher prevalence of IBS compared to those who work during the day and sleep at night,” Ballou said.

Sleep in Functional GI Conditions

One such study conducted by William D. Chey, MD, and colleagues from University of Michigan showed that nurses who worked rotating shifts (n = 75) showed a significantly higher prevalence of IBS vs. those who worked regular day shifts (n = 214; 48% vs. 31%; P < .01). Similarly, rotating shift nurses showed a higher prevalence of abdominal pain vs. both day shift (81% vs. 54%; P < .0001) and night shift workers (61%; P = .003). The authors concluded that circadian rhythm disturbances may explain these findings.

This type of research is important for understanding the role that circadian disruption plays in GI symptoms, as most sleep quality studies evaluate individuals with more typical sleep schedules, Ballou said. However, she noted that published data and her own clinical experience suggest that poor sleep is the primary driver of IBS symptoms, and not the other way around.

“What I hear from many patients I see in the clinic is that when they have problems sleeping, their IBS symptoms are worse the next day,” she said. “And there have been published studies that support this.”

For example, a small study of 24 women with IBS published in the Journal of Clinical Sleep Medicine showed that poorer self-reported sleep quality predicted increased next-day abdominal pain, anxiety and fatigue (P < 0.05), and more objective actigraphy measures showed poor sleep predicted worse next-day anxiety and fatigue. Temporally reversed analysis, however, showed none of the symptoms predicted subsequent sleep quality.

However, Ballou noted that some data paint a different picture.

“It certainly seems like if a patient has poor sleep one night, they will have worse symptoms the next day, but there’s also research showing that patients with functional GI disorders might have a higher rate of nighttime GI symptoms than we previously thought,” she said.

A recent study published in Alimentary Pharmacology and Therapeutics comparing 24 patients with IBS and 26 healthy controls based on self-reports and actigraphy showed that IBS patients had more waking episodes during sleep (12.1 vs 9.3; P < 0.001), and these predicted worse abdominal pain (P 0.01), GI distress (P < 0.001) and quality of life measures (P < 0.001).

“Originally, we thought that if a patient has symptoms at night, that was a red flag that maybe there was something else going on besides IBS,” Ballou said. “But it seems that patients with IBS also do wake up in the middle of the night with abdominal pain, or to have a bowel movement, which of course could impair their sleep, so it definitely can be a bi-directional relationship.”

Additionally, there are conflicting data on sleep quality when comparing objective measures of sleep between patients with IBS and healthy controls, which could suggest that hypersensitivity may play a role in sleep dysfunction associated with functional GI disorders.

“Rather than objectively shorter sleep times or objectively more middle of the night awakenings, it could be some aspect of hypervigilance or hyperawareness to sleep that’s causing dysfunction in functional GI disorders,” she said. “That’s something important to think about when we’re considering why these patients are having worse sleep.”

Johnson agreed, noting that changes in sensory perception are associated with poor sleep in functional GI disorders. Importantly, stress, anxiety and depression in these patients have been linked to both increased symptoms and sleep disruption, he said.

“One of the key parameters for patients with depression is that they don’t sleep well, and that they feel really tired the next day,” he said. “When you look at disease states like IBS and you have sleep dysfunction, we clearly know you change sensory perception. Sensory thresholds are all lowered when you have poor sleep.”

Sleep and the Gut Microbiome

Further complicating the gut-sleep connection is the emerging role of the microbiome in these interactions. According to a review article by Johnson and colleagues, recent but limited data suggest that sleep and circadian disruption may be linked to intestinal dysbiosis, a known driver of inflammation, which stems from microbial processes like intestinal permeability, endotoxemia and innate immune activation.

“There’s clearly mounting evidence that the microbiome is intricately related,” Johnson said. “The interplay is very complex and appears to be bi-directional as well.”

In a translational study, Johnson and colleagues showed that sleep fragmentation significantly alters the gut microbiome in mice.

“The gut microbiome essentially undulates as you go through a 24-hour cycle, influenced by a variety of effects including food intake, excretion and exercise,” Johnson said. “It’s important to recognize that you start and finish in the same place, provided there is normal sleep, according to the mice data. When we fragmented sleep in the mice, we showed the gut microbiome inverted, so the pendulum-like pattern basically flipped and became dysbiotic. This suggests there is a tremendous disruption of the gut microbiome just based on the sleep effect.”

Other mouse models Johnson highlighted in his review article have shown that inflammation persists even after normal sleep is restored, possibly due to a “proinflammatory cascade” sustained by interactions between the dysbiotic microbiome, the circadian rhythm and environmental factors. More provocative, Johnson added, is that sleep fragmentation appears to induce intestinal membrane permeability in mice. “Leaky gut,” as it is commonly known, is a “formative challenge” in many GI conditions in humans, including IBD, cirrhosis, bacterial peritonitis and hepatic encephalopathy, he said.

“When the barrier that keeps all the gut bacteria where it should be becomes leaky, it can cause microbial translocation, and when we looked at the effects on mesenteric lymph nodes, we found that all 60 DNA gene arrays went down,” Johnson said. “So, you have this incredible downregulation of the genes that promote gut integrity as it relates to the sleep effect. Then we looked at same gene arrays in the cortex of the brain and found that, lo and behold, all 60 are disrupted, so clearly there is an effect back at the brain level that may disrupt sleep. When you start to look at how complex it becomes, sleep becomes intertwined in almost every disease state there is.”

Although the understanding of how sleep dysfunction interacts with the gut microbiome and the pathophysiology of GI diseases is in its early stages, Johnson and colleagues argued that clinicians need to recognize the importance of this connection now and should therefore always “obtain a detailed sleep history and promote proper sleep hygiene in patients with chronic inflammatory conditions to minimize proinflammatory drivers.”

However, for proper assessment of sleep quality in clinical practice, not all approaches are created equal, Johnson said.

Proper Sleep Assessment

While there are several approaches to screening for sleep dysfunction in clinical practice, the primary issue is first convincing clinicians to prioritize screening despite its barriers, according to Ballou.

“It makes sense that it’s not being asked about in clinics, because follow-up visits are so short and there’s just so much to cover, especially with patients who have functional GI disorders,” she said. “So, it’s completely understandable that asking about sleep quality is falling off the list of things to cover. If physicians would like to start screening routinely for sleep problems, this is something they could have a medical assistant or nurse to ask about during vital signs. Just as many hospitals are now asking about depression, they can ask about sleep and that way they can be better prepared to help guide patients toward appropriate treatment.”

Clinicians who want to implement sleep assessment into their practice should keep it simple, as more standardized methods used in research settings are impractical, Johnson said. For example, he said that validated questionnaires like the Pittsburgh Sleep Quality Index that rely on perceived sleep quality are useful in research but may be too time-consuming for use in clinical practice. Similarly, physiologic lab studies for sleep quality are not feasible for daily clinical practice and are even problematic in research settings because they do not evaluate sleep under normal conditions.

“This results in what we call the ‘first night effect,’” he said. “They put you in a room, in a bed that’s not yours, wire you up like you’re going to Mars and then they say have a normal night’s sleep, which is obviously unlikely to reflect the kind of sleep you’re normally getting at home. Although they’re very helpful in providing significant physiologic implications in conditions like sleep apnea, it’s not practical in the general population to evaluate sleep abnormalities.”

However, smartphone technology may provide a feasible strategy for acquiring objective sleep assessment in clinical practice, he noted.

“There are a variety of applications that patients can use, that work with smartphones or wrist devices that can measure restlessness based on body motion,” he said. “Some have found that helpful — personally, I have not found it helpful in day-to-day assessments, but it’s an option.”

Therefore, integrating simple questions about sleep quality is the best option for clinical practice, according to Johnson. His book suggests these basic questions should address sleep duration, sleep quality, the sleep-wake schedule, frequency and duration of naps, substance use, and medical conditions that can interfere with sleep. However, even this approach carries limitations, Johnson said.

“I use a very simple series of questions, but when you ask if a patient has sleep problems, two out of three will say no,” he said. “The problem with that is sleep is potentially amnestic, so even though a patient may have had a cognitive awakening, gotten up and even talked to someone, the next day they may not remember because of the normal amnestic effect of sleep. Also, sensory arousal that, for example, induces secondary peristalsis in response to an acid reflux event is another non-cognitive mechanism that can disrupt sleep, which a patient may not recall.”

To get around these issues, focusing questions on next-day function as a marker of sleep quality is essential, Johnson said.

“I ask how the patient sleeps at night and I’ll ask the bed partner of the individual how they sleep at night, but the key questions assess next-day function,” he said. “A key parameter when I take a good sleep history is how the patient feels when they wake up. Do they feel refreshed and ready to start the day, or do they feel tired and have to pull themselves out of bed? Irritability, loss of focus and attention, and fatigue in the early afternoon are all subtle parameters that you have not had a restful sleep.”

Proper assessment of sleep dysfunction is particularly important in patients with GERD, as the condition is highly prevalent, affecting more than a quarter of North Americans. Further, GERD patients commonly experience nocturnal symptoms that disrupt sleep, and as such, it is perhaps the most well-studied GI condition regarding its relationship with sleep, according to Johnson.

Nocturnal GERD

Nocturnal symptoms are common among GERD patients. A survey of 1,000 adults with frequent heartburn symptoms showed that almost 80% of responders reported nighttime symptoms, and among them, 75% had secondary sleep dysfunction. More recent large population-based studies have also linked GERD risk to insomnia (OR = 3.2; 95% CI, 2.7–3.7), sleeplessness (OR = 3.3; 95% CI, 2.9–3.8) and problems falling asleep (OR = 3.1; 95% CI, 2.5–3.8).

“Perhaps most importantly, compared with typical GERD, there is ample evidence dating back over 2 decades to suggest that nocturnal GERD is associated with a more severe disease process such as erosive esophagitis,” Johnson and colleagues wrote. “The reason for this more severe reflux process is complex and multifactorial with evidence suggesting that there are a number of changes related to esophageal clearance mechanisms that act synergistically to contribute to disease pathogenesis. Heartburn, salivation, swallowing, and esophageal peristalsis are the 4 primary mechanisms that protect the esophageal mucosa; however, these protective mechanisms are all altered at night with physiological changes in GI motility.”

Fortunately, PPI therapy appears to be effective for improving nocturnal symptoms, sleep, and next-day function in patients with GERD, according to data from three randomized controlled trials.

The most recent of these compared the effects of 20 mg esomeprazole (n = 137) vs. placebo (n = 125) in patients with nocturnal GERD for 4 weeks, including symptom improvement and next-day function.

Significantly more patients in the PPI group achieved nighttime heartburn relief (34.3% vs. 10.4%; P < .0001), better sleep quality and, notably, improved work productivity.

“There was about a 5 and a half hour per week improvement in work productivity for the intervention group,” Johnson said.

While the data clearly show that PPIs are a good option for improving sleep dysfunction in patients with GERD, Johnson emphasized that timing of dosing is important in these patients. Although many believe they should take a PPI at night to treat nocturnal symptoms, it is much more effective if taken in the morning.

“The mistake most people make for nighttime heartburn is think they should take their medication at night, but the randomized trials have clearly shown the advantages of taking these in the morning before breakfast,” he said. “The prime assault time when patients have the majority of reflux is during the day, even if they have nighttime heartburn, so you really want to control the acid through the course of that major exposure, and that will in effect reduce nocturnal symptoms.”

The importance of effective PPI therapy for improving nocturnal GERD is perhaps most interestingly illustrated by a study of driving ability as a parameter of next-day function in GERD patients, Johnson said.

“There clearly is a cognitive effect in next day function, but there’s also a psychomotor effect because of poor sleep,” he said. “We performed an open label study to evaluate this in patients with nighttime heartburn and reflux by using a driving simulator.”

A comparison of driving performance among 15 patients with frequent GERD both on and off esomeprazole showed they had poorer performance before taking the PPI (P = .004) compared with a retest after 4 weeks of therapy. Sleepiness and symptoms also decreased with PPI use.

Johnson and colleagues further compared the GERD patients to three matched cohorts without GERD, including healthy individuals aged younger than 60 years, healthy elderly patients (mean age, 78 years), and patients aged younger than 60 years with obstructive sleep apnea.

“We found that the patients with nighttime reflux drove statistically worse than the other control groups, and just a little bit better than those with sleep apnea,” Johnson said. “These findings are significant because sleep is a significant reported cause for motor vehicle accidents and fatalities.”

Such data highlight the importance of screening for nocturnal GERD symptoms and considering PPI therapy in these patients.

While there is a unique pharmacotherapeutic approach for nocturnal GERD patients, patients with functional GI conditions like IBS who have sleep dysfunction are more likely to benefit from the same interventions as any patient reporting poor sleep, according to Ballou.

Interventions for FGIDs

While sleep medications are a feasible approach for sleep dysfunction in functional GI disorders, behavioral interventions are the recommended first-line approach, especially cognitive behavioral therapy (CBT) for insomnia, Ballou said.

“There’s definitely the avenue of medication to help patients sleep, although a lot of patients might not want to add another medication to their list of meds, or they might be concerned about developing tolerance or side effects,” she said. “For these patients, cognitive behavioral therapies are very effective and recommended as first-line treatment. Physicians who are hearing that their patients aren’t sleeping well should give their patients information on CBT for insomnia, and many psychologists in private practice are trained in this, so it’s fairly accessible.”

CBT for insomnia is usually done in just a few sessions, most commonly between four and six, Ballou said. The intervention involves making specific behavioral changes to help patients achieve better sleep.

“Some of the treatment will address, for instance, what patients do when they wake up in the middle of the night and they’re frustrated or worried that they can’t fall back asleep,” she said. “Helping them handle those thoughts is key.”

CBT for insomnia also incorporates many different behavioral components, like sleep restriction therapy, which reduces time spent in bed to encourage using that time more efficiently, and sleep hygiene education, which promotes healthy practices around sleep like not watching TV in bed, keeping the bedroom at the right temperature, making sure the bed is comfortable, avoiding caffeine after noon, and similar strategies. This is the gold standard because it incorporates so many complementary behavioral strategies, Ballou said.

However, melatonin is a well-studied pharmaceutical intervention across many conditions and may also be a promising option for patients with functional GI disorders as well.

“Melatonin is interesting because the data on melatonin for improving sleep quality is mixed,” Ballou said. “Some people feel it’s mostly the placebo effect and other studies show it’s superior to placebo.”

For example, a randomized controlled trial of 40 IBS patients with and without sleep problems showed that 3 mg melatonin for 2 weeks improved abdominal pain (P < .001) and increased rectal pain thresholds (P < .001) better than placebo, but there were no differences in bloating, stool type or frequency, anxiety or depression, or sleep quality. Another randomized controlled trial of 80 women with IBS showed that 6 months of melatonin therapy improved visceral pain and abdominal bloating (P < .01) and constipation (P < .05), but the benefits seen in patients with IBS-D were not significant compared with placebo.

“Melatonin works on your circadian rhythm, so if the circadian rhythm is healthy and you’re taking melatonin at a time when your circadian rhythm would usually have you fall asleep, in theory it wouldn’t do a whole lot,” Ballou said. “There’s also evidence that melatonin works directly on the gut. Researchers have given melatonin to patients with IBS with and without sleep problems and they found their IBS symptoms got a bit better.”

Data suggesting that melatonin may work directly on the GI tract shows the drug may be particularly promising in patients with IBD, for which the connection between sleep and inflammation is especially important given the risk for disease flare and neoplasia, according to Johnson.

Sleep in IBD

Another translational study by Johnson and colleagues showed that giving melatonin before sleep fragmentation essentially blocked the induction of drug-induced colitis in mice.

“Why that is we’re not absolutely sure, but melatonin has about a 400-fold concentration in the GI tract compared with levels in the pineal gland where it’s secreted in the brain,” he said. “So, melatonin has an intrinsic regulation effect in the normative gut physiology, and whether augmentative melatonin may be helpful in some of these patients, in particular some of the IBD patients or leaky gut patients, really deserves better study.”

Until better data on this intervention become available, clinicians should promote the use of behavioral therapies in addition to standard of care interventions for improving sleep and quality of life in patients with IBD, according to Stephen B. Hanauer, MD, of Northwestern University.

“Sleep disruption is common in IBD patients,” he told Healio Gastroenterology and Liver Disease. “Indeed, a discriminating feature between IBS and IBD is the need to awaken from sleep due to pain or bowel movements.”

Illustrating the prevalence of the problem, a survey study of 199 patients with IBD showed that compared with healthy controls they experienced more difficulty falling asleep, more frequent sleep fragmentation, higher use of sleeping pills, less daytime energy, increased tiredness, and poorer overall sleep quality. Those with worse symptoms were also more likely to report poorer sleep quality, and more likely to report worse symptoms the next day after a night of poor sleep, especially those with Crohn’s disease.

“Clearly, when inflammation is controlled, there will be less nocturnal bowel activity or pain,” Hanauer said. However, he believes there is insufficient evidence to conclude that improving sleep will improve the inflammatory component of IBD symptoms. Despite this, sleep can still be viewed as a component of health maintenance in IBD, and he therefore recommends using behavioral approaches in addition to usual care.

“We frequently utilize cognitive behavioral approaches in conjunction with effective pharmacologic or surgical therapies to improve overall quality of life in patients; including improving sleep hygiene,” he said. “However, we strongly urge avoidance of benzodiazepine hypnotics due to their addictive potential, but I do prescribe low doses of tricyclic therapies for patients with sleep issues, as well.”

While improving sleep plays an important role in the complex management of IBD, Hanauer said that in this condition, most clinicians believe it is a consequence rather than a cause of disease activity.

According to Johnson, however, some data suggests that, again, the relationship between sleep, inflammation and IBD activity may be bi-directional.

“Patients with active IBD will typically have nocturnal stooling, and they may be on steroids, have abdominal pain, or be on some type of pain reliever, all of which can disrupt sleep,” he said. “So, the patient may already be waking up many times at night, and thus have all these chemokines and cytokines upregulated, which are also upregulated just based on sleep fragmentation, so you may have a perpetuation of the disease just based on the sleep fragmentation alone.”

As in IBS, symptoms in an IBD patient could be amplified based on sensory thresholds being lowered due to poor sleep but sleep also has a profound effect on upregulation of the neurohormonal pathways, which is related to upregulation of inflammatory cytokines and chemokines, Johnson noted.

“Most notably as it relates to IBD, sleep disruption is associated with upregulation of TNF alpha, interleukins, and C-reactive protein,” he said. “There’s also a significant upregulation in toll like receptor pathways, which have also been shown to be upregulated in IBD related colon cancers. So, as you start to talk about cancer upregulation, particularly in IBD, it becomes potentially a significant consequence.”

Given this knowledge, proactively promoting healthy sleep in IBD patients, especially those in remission, is important for prevention of the associated risks of sleep dysfunction.

“In IBD patients who are in remission, sleep disruption is associated with the risk for relapse, with odds ratios that are increased by about 2 to 3 times over 6 months of follow-up,” Johnson said. “So, promoting sleep in a proactive way, even in the IBD patient in remission, makes sense.”

Sleep hygiene in IBD patients shows promise for potentially improving the relatively low rates of efficacy for biologic medications, he added.

“IBD treatments are really exceptionally promising, but we still don’t really hit the mark like I think we should, as biologics show a 40% induction rate of disease remission, which is way beyond what we’ve seen in the past, but we’re still woefully short of what I would call clinical success in a majority of patients,” he said. “Why is that? We’re targeting just the disease with the drug, and we’re missing opportunities like promoting diet, lifestyle, and importantly, sleep health in these patients.”

While Ballou has primarily focused her research on improving sleep in patients with IBS, she hopes to extend this to IBD.

“Right now, I’m doing a study evaluating behavioral treatments for sleep in patients with IBS,” she said. “There are published data about poor sleep in IBS and data about sleep and fatigue in IBD, and there are some data to suggest poor sleep one night can affect symptoms the next day, but we don’t have any data to show what will happen if we help these patients to sleep better.”

As the relationships between sleep and GI health continue to emerge, sleep as a target for intervention is becoming increasingly logical, according to Johnson. As he concludes in the introduction of his new book on the subject, “clearly, it is time for us all to open our eyes and realize the value of closing them.” – by Adam Leitenberger

• References:
• American Gastroenterological Association. “AGA Seeks Regulatory Relief for GIs.” 2018. Accessed March 30, 2018. http://www.gastro.org/news_items/aga-seeks-regulatory-relief-for-gis.
• Buchanan DT, et al. J Clin Sleep Med. 2014;doi:10.5664/jcsm.4038.
• Johnson D, et al. Aliment Pharmacol Ther. 2010;doi:10.1111/j.1365-2036.2010.04339.
• Johnson DA, et al. Gastroenterol Hepatol Open Access. 2017;doi:10.15406/ghoa.2017.06.00180.
• Johnson DA, et al. Sleep Effect on Gastrointestinal Health and Disease: Translational Opportunities for Promoting Health and Optimizing Disease Management. 2018. Nova Biomedical.
• Nojkov B, et al. Am J Gastroenterol. 2010;doi:10.1038/ajg.2010.48.
• Parekh PJ, et al. Am J Gastroenterol. 2014;doi:10.1038/ajg.2014.247.
• Parekh PJ, et al. J Clin Gastroenterol. 2018;doi:10.1097/MCG.0000000000000965.
• Patel A, et al. Aliment Pharmacol Ther. 2016;doi:10.1111/apt.13677.
• Rubin D, Patel S. Clinical Session IIA. Presented at: Advances in IBD; Nov. 9-11, 2017; Orlando, Fla.

• For more information:
• Sarah K. Ballou, PhD, can be reached at sballou@bidmc.harvard.edu.
• Stephen B. Hanauer, MD, can be reached at shanauer@northwestern.edu.
• David A. Johnson, MD, can be reached at dajevms@aol.com.

Disclosures: Ballou, Hanauer and Johnson report no relevant financial disclosures.