Clip closure to prevent adverse events after EMR of proximal large nonpedunculated colorectal polyps: meta-analysis of individual patient data from randomized controlled trials.

BACKGROUND AND AIMS: After EMR, prophylactic clipping is often performed to prevent clinically significant post-EMR bleeding (CSPEB) and other adverse events (AEs). Prior evidence syntheses have lacked sufficient power to assess clipping in relevant subgroups or in nonbleeding AEs. We performed a meta-analysis of individual patient data (IPD) from randomized trials assessing the efficacy of clipping to prevent AEs after EMR of proximal large nonpedunculated colorectal polyps (LNPCPs) ≥20 mm. METHODS: We searched EMBASE, MEDLINE, Cochrane Central Registry of Controlled Trials, and PubMed from inception to May 19, 2021. Two reviewers screened citations in duplicate. Corresponding authors of eligible studies were invited to contribute IPD. A random-effects 1-stage model was specified for estimating pooled effects, adjusting for patient sex and age and for lesion location and size, whereas a fixed-effects model was used for traditional meta-analyses. RESULTS: From 3145 citations, 4 trials were included, representing 1248 patients with proximal LNPCPs. The overall rate of CSPEB was 3.5% and 9.0% in clipped and unclipped patients, respectively. IPD were available for 1150 patients, in which prophylactic clipping prevented CSPEB with an odds ratio (OR) of .31 (95% confidence interval [CI], .17-.54). Clipping was not associated with perforation or abdominal pain, with ORs of .78 (95% CI, .17-3.54) and .67 (95% CI, .20-2.22), respectively. CONCLUSIONS: Prophylactic clipping is efficacious in preventing CSPEB after EMR of proximal LNPCPs. Therefore, clip closure should be considered a standard component of EMR of LNPCPs in the proximal colon.

Timing of Resumption of Anticoagulation After Polypectomy and Frequency of Post-procedural Complications: A Post-hoc Analysis.

BACKGROUND: Optimal timing for anticoagulation resumption after polypectomy is unclear. We explored the association between timing of anticoagulation resumption and occurrence of delayed post-polypectomy bleeding (PPB) and thromboembolic (TE) events. METHODS: We performed a post-hoc analysis of patients in an earlier study whose anticoagulants were interrupted for polypectomy. We compared rates of clinically important delayed PPB and TE events in relationship to timing of anticoagulant resumption. Late resumption was defined as > 2 days after polypectomy. RESULTS: Among 437 patients, 351 had early and 86 late resumption. Compared to early resumers, late resumers had greater polypectomy complexity. PPB rate was higher (but not significantly) in the late versus early resumers (2.3% vs. 0.9%, 1.47% greater, 95% CI [- 2.58 to 5.52], p = 0.26). TE events were more frequent in late versus early resumers [0% vs. 1.2% at 30 days, 0% vs. 2.3%, 95% CI 0.3-8, (p = 0.04) at 90 days]. On multivariate analysis, timing of restarting anticoagulation was not a significant predictor of PPB (OR 0.97, 95% CI 0.61-1.44, p = 0.897). Significant predictors were number of polyps ≥ 1 cm (OR 4.14, 95% CI 1.27-13.66, p = 0.014) and use of fulguration (OR 11.43, 95% CI 1.35-80.80, p = 0.014). CONCLUSIONS: Physicians delayed anticoagulation resumption more commonly after complex polypectomies. The timing of restarting anticoagulation was not a significant risk factor for PPB and late resumers had significantly higher rates of TE events within 90 days. Considering the potentially catastrophic consequences of TE events and the generally benign outcome of PPBs, clinicians should be cautious about delaying resumption of anticoagulation after polypectomy.

Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis.

OBJECTIVE: Although perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn's disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD. DESIGN: Male and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1iΔIEC ) or Paneth cell-specific deletion of Phb1 (Phb1ΔPC ) and Phb1fl/fl control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1iΔIEC or Phb1ΔPC mice. RESULTS: Phb1iΔIEC mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells (Phb1ΔPC ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1iΔIEC or Phb1ΔPC mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo. CONCLUSION: Our results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn's disease patients exhibiting Paneth cell defects.

Efficacy of Prophylactic Hemoclips in Prevention of Delayed Post-Polypectomy Bleeding in Patients With Large Colonic Polyps.

BACKGROUND & AIMS: The efficacy of prophylactic placement of hemoclips to prevent delayed bleeding after removal of large colonic polyps has not been established. We conducted a randomized equivalence study to determine whether prophylactic placement of hemoclips affects incidence of delayed post-polypectomy bleeding (PPB). METHODS: During elective colonoscopy performed at 4 Veterans Affairs Medical Centers, 1098 patients who had polyps ≥1 cm removed were randomly assigned to groups that received prophylactic hemoclips (n = 547) or no hemoclips (n = 551), from September 2011 through September 2018. Data on PPB (rectal bleeding resulting in hemoglobin decreases ≥2 g/dL, hemodynamic instability, colonoscopy, angiography, or surgery) within 30 days of colonoscopy (called delayed PPB) were collected during telephone interviews or hospital visits 7 and 30 days after colonoscopy. The primary outcome was the incidence of important post-polypectomy bleeding. RESULTS: Twelve patients in the hemoclip group (2.3%) and 15 patients in the no hemoclip group (2.9%) had important delayed PPB. There were no deaths, and no patients in either group required angiography or surgery. In intention-to-treat analysis, two 1-sided test's lower and upper confidence interval limits were -2.07 and 1.01, indicating that the data approached but did not meet equivalence criteria. On multiple logistic regression analysis, significant predictors of PPB included use of warfarin with bridging, thienopyridines, polyp size, and polyp location, but hemoclip placement did not associate with important delayed PPB. CONCLUSIONS: In a randomized trial, we found that prophylactic placement of hemoclips after removal of large colon polyps does not affect the proportion of important delayed PPB events, compared with no hemoclip placement. These findings call into question the widespread, expensive practice of routinely placing prophylactic hemoclips after polypectomy. ClinicalTrials.gov ID: NCT01647581.

Valuing innovative endoscopic techniques: prophylactic clip closure after endoscopic resection of large colon polyps.

BACKGROUND AND AIMS: Clip closure of the mucosal defect after resecting large (≥20 mm) nonpedunculated colorectal polyps reduces postprocedure bleeding and is cost saving for payers. Clip costs are not reimbursed by payers, posing a major barrier to adoption of this technique in the community. We aimed to determine appropriate clip costs to support broader use of this procedure in practice. METHODS: We performed budget impact analysis using our recent decision analytic model, comparing prophylactic clip closure with no clip closure on national cost and outcomes data, to determine the maximum feasible clip price while maintaining cost savings in practice. Sensitivity analyses were performed on important clinical factors. RESULTS: In the original model, the baseline postprocedure bleeding risk was 6.8%, increasing cost of care by $614.11 averaged among all patients undergoing large polyp resection without clip closure. Prophylactic clip closure of only large right-sided polyps reduced postprocedure bleeding risk by 70.7% but resulted in cost saving only if the price of clips was $100 or less. Comparatively, prophylactic clip closure of large left-sided polyps had no clinical benefit and was not cost saving. Clip closure strategies focused only on extra-large polyps (≥40 mm), or patients taking antithrombotics regardless of polyp characteristics, were only minimally cost saving. Cost savings and maximum tolerated clip prices depended on medical comorbidity, which directly influences the costs of care to manage postprocedure bleeding. CONCLUSIONS: Prophylactic clip closure after endoscopic resection of large colon polyps, particularly those in the right colon segment, is cost saving but requires clip costs less than $100. Translating these findings into practice requires gastroenterology practices to obtain reimbursement from payers for improved clinical outcomes and to align commercial clip prices with this clinical indication.

Managing Patients with Inflammatory Bowel Disease Who Develop Prostate Cancer.

Prostate cancer is the most common cancer among men in the USA. Interestingly, recent studies suggest that patients with inflammatory bowel disease (IBD) are at increased risk of developing prostate cancer. Importantly, patients with IBD who develop prostate cancer require thoughtful care when using immunosuppressants to treat the IBD in the setting of malignancy. Further, consideration must be given to the proximity of the prostate to the gastrointestinal tract when treating with radiation where there is concern for the effects of inadvertent exposure of radiation to the diseased bowel. In general, management of immunosuppression after diagnosis of prostate cancer is contingent on the specific immunosuppressive agents, the duration of cancer remission and/or plans for cancer treatment, and the potential risks and benefits of stopping or altering the administration of those agents. Concerns that patients with IBD would have increased risk of disease exacerbation and gastrointestinal toxicity have previously limited the use of radiation. While currently no consensus has been reached regarding the safety of radiation therapy in patients with IBD, recent studies suggest that radiation therapy may be used safely in patients with IBD who develop prostate cancer, especially brachytherapy and intensity-modulated radiation therapy which may have less bowel toxicity compared to conventional methods of external beam radiation therapy. A multidisciplinary team approach including gastroenterologists, urologists, radiation oncologists, and medical oncologists should be undertaken to best treat patients with IBD and prostate cancer.

A Comparison of the Rate of Gastrointestinal Bleeding in Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants or Warfarin.

OBJECTIVES: Early reports suggested that the risk of gastrointestinal bleeding (GIB) was higher for patients on non-vitamin K antagonist oral anticoagulants (NOACs) than for those on warfarin. We compared the incidence of GIB in our patients on NOACs with those on warfarin. METHODS: We used our VA pharmacy database to identify patients taking NOACs (dabigatran, rivaroxaban, and apixaban) or warfarin between January 2011 and June 2015, and used the VistA system to identify those who were hospitalized for GIB. We included only patients with clinically significant GIB, defined as documented GI blood loss with a hemoglobin drop ≥2 g/dl, hemodynamic instability, and/or need for endoscopic evaluation, angiography, or surgery. RESULTS: We identified 803 patients on NOACs and 6,263 on warfarin. One hundred and fifty-eight patients on warfarin had GIB (2.5%), compared with only five patients (0.6%) on NOACs (odds ratio=4.13; 95% confidence interval: 1.69-10.09). Blood transfusion for GIB was significantly more common in patients on warfarin than on NOACs (64.6% vs. 20%, P=0.04). Within 90 days of GIB hospitalization, 12 patients (7.6%) in the warfarin group died, whereas there were no deaths in the NOAC group. CONCLUSIONS: In our patients, the incidence of GIB for those on warfarin was more than four times that for those on NOACs. Blood transfusions for GIB were more common in warfarin patients, and no NOAC patients died of GIB. In contrast to early reports, our findings suggest that the risk of GIB and subsequent complications is considerably lower for patients on NOACs than for patients on warfarin.

Increased Cell Adhesion Molecules, PECAM-1, ICAM-3, or VCAM-1, Predict Increased Risk for Flare in Patients With Quiescent Inflammatory Bowel Disease.

GOALS AND BACKGROUND: Predicting the risk of flare-ups for patients with inflammatory bowel disease (IBD) is difficult. Alterations in gut endothelial regulation of mucosal immune homeostasis might be early events leading to flares in IBD. Cell adhesion molecules (CAMs), in particular, are important in maintaining endothelial integrity and regulating the migration of leukocytes into the gut. STUDY: We evaluated the mRNA expression of various tight junction proteins, with an emphasis on CAMs, in 40 patients with IBD in clinical remission. Patients were retrospectively assessed at 6, 12, and 24 months after baseline colonoscopy, and at the end of all available follow-up (maximum 65 mo), for flare events to determine whether baseline mRNA expression was associated with subsequent flares. RESULTS: At all follow-up points, the baseline expression of platelet endothelial cell adhesion molecule-1 (PECAM-1), ICAM-3, and VCAM-1 was significantly higher in patients who flared than in those who did not (2.4-fold elevation, P=0.012 for PECAM-1; 1.9-fold increased, P=0.03 for ICAM-3; and 1.4-fold increased, P=0.02 for VCAM-1). PECAM-1 and ICAM-3 expression was significantly increased in patients who flared as early as 6 months after baseline colonoscopy. In contrast, there were no significant differences between patients with and without flares in baseline expression of other CAMs (ESAM, ICAM-1, ICAM-2, E-selectin, P-selectin, and MadCAM1). CONCLUSIONS: Increased expression of PECAM-1, ICAM-3, and VCAM-1 in colonic biopsies from patients with IBD in clinical remission is associated with subsequent flares. This suggests that increases in the expression of these proteins may be early events that lead to flares in patients with IBD.

Clinical Implications of Histologic Abnormalities in Ileocolonic Biopsies of Patients With Crohn's Disease in Remission.

BACKGROUND: For patients with Crohn's disease (CD) who have colonoscopy during periods of clinical remission, the utility of taking ileocolonic biopsy specimens to assess disease activity is disputed. GOALS: We explored the clinical implications of histologic disease activity in such patients. STUDY: We reviewed medical records of CD patients who underwent elective colonoscopy while in clinical remission at our VA Medical Center from 2000 to 2013, and who had at least 6 months of follow-up. We correlated endoscopic and histologic disease activity with the subsequent development of flares. RESULTS: We identified 62 CD patients who had a total of 103 colonoscopies during clinical remission; 55 colonoscopies revealed complete endoscopic healing and 48 showed active disease. Flares within 6, 12, and 24 months of colonoscopy were not more common in patients with endoscopic activity than those with complete endoscopic healing. In contrast, patients with any of 5 histologic features of active inflammation (erosions, cryptitis, crypt abscess, increased neutrophils, or increased eosinophils in the lamina propria) had more flares than patients without those changes (P<0.05). Among the individual histologic features, an increase in eosinophils or neutrophils in the lamina propria and cryptitis were associated with higher flare rates (P<0.05). CONCLUSIONS: For CD patients who have a colonoscopy while in clinical remission, biopsy seems to provide important prognostic information beyond that provided by endoscopic assessment of disease activity alone. In particular, increased eosinophils or neutrophils in the lamina propria and cryptitis are strongly associated with an increased risk of clinical flares within 1 to 2 years.

Obesity in Inflammatory Bowel Disease: A Marker of Less Severe Disease.

BACKGROUND: Both obesity and inflammatory bowel disease (IBD) are highly prevalent in Western societies. IBD, including Crohn's disease (CD) and ulcerative colitis (UC), has been historically associated with cachexia and malnutrition. It is uncertain how obesity, a chronic pro-inflammatory state, may impact the course of IBD. AIM: The aim of this study was to report the prevalence of obesity in patients with IBD in a metropolitan US population and to assess the impact of obesity on disease phenotypes, treatment, and surgical outcomes in IBD patients. METHODS: We reviewed the medical records of patients identified from the IBD registries of the Dallas Veterans Affairs Medical Center and Parkland Health and Hospital Systems who were seen from January 1, 2000, to December 31, 2012. RESULTS: Of 581 identified IBD patients, 32.7 % were obese (BMI ≥ 30) and 67.6 % were non-obese (BMI < 30). There were 297 (51.1 %) patients with CD and 284 (48.9 %) patients with UC. The rate of obesity was 30.3 % among CD patients and 35.2 % among UC patients. Overall, obese patients were significantly less likely to receive anti-TNF treatment, undergo surgery, or experience a hospitalization for their IBD than their non-obese counterparts (55.8 vs. 72.1 %, p = .0001). CONCLUSION: Obesity is highly prevalent in our IBD patients, paralleling the obesity rates in the US population. Clinical outcomes were significantly different in obese versus non-obese patients with IBD. Despite the plausible mechanisms whereby obesity might exacerbate IBD, we have found that obesity (as defined by BMI) is a marker of a less severe disease course in IBD.

The prophylactic placement of hemoclips to prevent delayed post-polypectomy bleeding: an unnecessary practice? A case control study.

BACKGROUND: With the recent, widespread availability of endoscopic hemoclips, it has become common clinical practice to apply hemoclips to some non-bleeding polypectomy sites "prophylactically" to prevent delayed post-polypectomy bleeding (PPB). Few published data support this practice, however. AIM: The aim of this study was to compare rates of delayed PPB in matched patients who had polypectomies performed with and without the prophylactic placement of hemoclips. METHODS: We reviewed medical records of patients who had elective colonoscopy at our VA Medical Center between July 2008 and December 2009. We identified patients who had hemoclips applied prophylactically (cases) and compared their rate of delayed PPB within 30 days to that of patients who had polypectomy without hemoclipping (controls). Controls were matched 1:1 to cases based on age and on factors known to contribute to the risk of PPB including polyp size, morphology, technique of polyp removal, number of polyps removed, and use of anticoagulants. RESULTS: We identified 184 patients (cases) who underwent prophylactic hemoclipping and 184 well-matched controls. An average of 3.8 polyps per patient were removed in the case group compared to 3.3 polyps per patient in controls (p = 0.6). Delayed PPB occurred in three patients in the prophylactic hemoclip group and in one patient in the control group (1.6 vs. 0.5 %, p = 0.62). CONCLUSIONS: We found no significant difference in the rate of delayed PPB between patients who had prophylactic hemoclipping of polypectomy sites and a well-matched control group of patients who had polypectomy without prophylactic hemoclipping. These data call into question the expensive practice of prophylactic hemoclipping.

Low rate of postpolypectomy bleeding among patients who continue thienopyridine therapy during colonoscopy.

BACKGROUND & AIMS: It is not clear whether the cardiovascular risk of discontinuing treatment with antiplatelet agents, specifically the thienopyridines, before elective colonoscopy outweighs the risks of postpolypectomy bleeding (PPB). We studied the rate of PPB in patients who continue thienopyridine therapy during colonoscopy. METHODS: We performed a prospective study of 516 patients not taking warfarin who received polypectomies during elective colonoscopies; 219 were receiving thienopyridines, and 297 were not (controls). The occurrence of immediate PPB and delayed PPB was recorded. Delayed PPB was categorized as clinically important if it resulted in repeat colonoscopy, hospitalization, or blood transfusion. RESULTS: Patients receiving thienopyridines were older and had significantly more comorbid diseases than controls; the mean number of polyps removed per patient was significantly higher (3.9 vs 2.9) in the thienopyridine group. Immediate PPB developed in 16 patients in the thienopyridine group (7.3%) and in 14 in the control group (4.7%, P = .25). Among patients who completed a 30-day follow-up analysis (96% of patients enrolled), clinically important, delayed bleeding occurred in 2.4% of patients receiving thienopyridines and in none of the controls (P = .01). All PPB events in both groups were resolved without surgery, angiography, or death. CONCLUSIONS: Although a significantly higher percentage of patients who continue thienopyridine therapy during colonoscopy and polypectomy develop clinically important delayed PPB than patients who discontinue therapy, the rate of PPB events is low (2.4%), and all are resolved without sequelae. The risk for catastrophic cardiovascular risks among patients who discontinue thienopyridine therapy before elective colonoscopies could therefore exceed the risks of PPB. ClinicalTrials.gov, Number NCT01647568.

Prone positioning of obese patients for colonoscopy results in shortened cecal intubation times: a randomized trial.

BACKGROUND: Obesity is a risk factor for colorectal cancer, and colonoscopy can be technically challenging in obese patients. It has been proposed (with little supporting data) that prone positioning of obese patients might facilitate a difficult colonoscopy. AIM: The aim of this study was to determine if starting colonoscopy in the prone position for obese patients decreases cecal intubation times. METHODS: This was a prospective, randomized study conducted at the North Texas VA Medical Center. Patients with a body mass index of ≥30 kg/m(2) undergoing elective colonoscopy were randomized 1:1 to either initial prone positioning or standard, left-lateral positioning. The outcome measurements were cecal intubation time, frequency of repositioning, sedative medications used, reports of pain, complications, and procedure tolerability. RESULTS: Fifty patients were randomized to have colonoscopy starting in the standard, left-lateral decubitus position, and 51 to the prone position. The average cecal intubation time for the standard group was 550 vs. 424 s in the prone group (p = 0.03). Patient repositioning was used in 28 % of patients in the standard group versus 8 % in the prone group (p = 0.009). There was no difference in subjective reports of pain between groups (p = 0.95) or in average pain scores (p = 0.79). Follow-up interviews were conducted in 93 % of patients, all of whom said that they would be willing to have repeat colonoscopy in the same position. CONCLUSIONS: Performance of colonoscopy in the prone position for obese patients results in significantly shorter cecal intubation times and decreased need for patient repositioning. Prone positioning is well accepted and does not significantly increase procedure-related discomfort.

Acss2/HIF-2 signaling facilitates colon cancer growth and metastasis.

The microenvironment of solid tumors is characterized by oxygen and glucose deprivation. Acss2/HIF-2 signaling coordinates essential genetic regulators including acetate-dependent acetyl CoA synthetase 2 (Acss2), Creb binding protein (Cbp), Sirtuin 1 (Sirt1), and Hypoxia Inducible Factor 2α (HIF-2α). We previously shown in mice that exogenous acetate augments growth and metastasis of flank tumors derived from fibrosarcoma-derived HT1080 cells in an Acss2/HIF-2 dependent manner. Colonic epithelial cells are exposed to the highest acetate levels in the body. We reasoned that colon cancer cells, like fibrosarcoma cells, may respond to acetate in a pro-growth manner. In this study, we examine the role of Acss2/HIF-2 signaling in colon cancer. We find that Acss2/HIF-2 signaling is activated by oxygen or glucose deprivation in two human colon cancer-derived cell lines, HCT116 and HT29, and is crucial for colony formation, migration, and invasion in cell culture studies. Flank tumors derived from HCT116 and HT29 cells exhibit augmented growth in mice when supplemented with exogenous acetate in an Acss2/HIF-2 dependent manner. Finally, Acss2 in human colon cancer samples is most frequently localized in the nucleus, consistent with it having a signaling role. Targeted inhibition of Acss2/HIF-2 signaling may have synergistic effects for some colon cancer patients.

Human intestinal organoids from Cronkhite-Canada syndrome patients reveal link between serotonin and proliferation.

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.

Diet in the Pathogenesis and Management of Crohn's Disease.

Crohn's disease (CD) is chronic immune-related disease of the gastrointestinal tract hypothesized to be caused by an interplay of genetic predisposition and environmental exposures. With the global incidence increasing, more patients are exploring dietary exposures to explain and treat CD. However, most patients report minimal nutritional education from their provider, and providers report few nutritional resources to help them educate patients. This highlights the previous deficit of literature describing the role and influence of diet in CD. To address this need, this article reviews available literature on the possible roles of diet in the pathogenesis, exacerbation, and treatment of CD.