Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn's Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn's Disease (iCREST-CD).

BACKGROUND AND AIMS: Perianal lesion is a refractory phenotype of Crohn's disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. METHODS: Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD]. RESULTS: Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged <40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age <40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions. CONCLUSIONS: At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities. CLINICAL TRIALS REGISTRY: University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].

Nutrition and diet in inflammatory bowel disease.

PURPOSE OF REVIEW: This study was to review the current evidence for dietary risk factors for developing inflammatory bowel disease (IBD), and therapeutic benefit of dietary and enteral interventions in IBD. RECENT FINDINGS: A Westernized diet rich in protein, fats and refined carbohydrates and low in fibre, fruits and vegetables may increase risk of developing IBD. Nevertheless, there are methodological limitations in case-control studies, which can affect the accuracy of the outcomes. Currently, various dietary interventions and supplements have been attempted to control the disease activity of IBD, but none of them showed striking efficacy. Exclusive enteral nutrition (EEN) is recommended as the first-line therapy in paediatric patients with active Crohn's disease. EEN is recommended in adults with good adherence to enteral formula and with intolerance to corticosteroids. Partial enteral nutrition is not recommended as primary therapy for the maintenance of remission, but it is used when undernutrition cannot be treated sufficiently with diets. SUMMARY: Dietary risk factors for IBD, and the efficacies of dietary and enteral interventions need to be confirmed by large, well designed studies.

Leucine-Rich Alpha-2 Glycoprotein Is a Reliable Serum Biomarker for Evaluating Clinical and Endoscopic Disease Activity in Inflammatory Bowel Disease.

BACKGROUND: Leucine-rich alpha-2 glycoprotein (LRG) is a novel serum biomarker for inflammation in inflammatory bowel disease (IBD). This prospective study aimed to compare the value of LRG with C-reactive protein (CRP) and fecal calprotectin for evaluating clinical and endoscopic disease activity in patients with IBD. METHODS: At entry, clinical and endoscopic disease activity was assessed in 267 patients with IBD (ulcerative colitis [UC] 203; Crohn's disease [CD] 64), and the levels of LRG, CRP and fecal calprotectin were measured. The accuracy of the biomarkers for the detection of clinical and endoscopic disease activity was determined by the area under the receiver operating characteristic curve. RESULTS: Leucine-rich alpha-2 glycoprotein showed a significant relationship with the clinical and endoscopic severity in both UC and CD (both diseases, P < .0001). In the clinical assessment of UC, the accuracy of LRG was significantly higher than that of CRP (0.73 vs 0.63; P < .001). In the endoscopic assessment of UC, the accuracy of LRG was significantly higher than that of CRP (P = .01), but it was significantly lower than that of fecal calprotectin (P = .009; LRG, 0.80; CRP, 0.72; fecal calprotectin, 0.91). In the clinical and endoscopic assessment of CD, the accuracy was not significantly different between the biomarkers (clinical activity: LRG, 0.71; CRP, 0.64; fecal calprotectin, 0.66; in endoscopic activity: LRG, 0.79; CRP, 0.78; fecal calprotectin, 0.81). CONCLUSIONS: Leucine-rich alpha-2 glycoprotein is a reliable serum biomarker for the assessment of clinical and endoscopic disease activity in patients with IBD. It can be an alternative to CRP for the assessment of UC.

Leucine-rich alpha-2 glycoprotein is a reliable serum biomarker for the assessment of clinical and endoscopic disease activity in patients with IBD. It can be an alternative to C-reactive protein for the assessment of ulcerative colitis.

Characteristics of adult patients newly diagnosed with Crohn's disease: interim analysis of the nation-wide inception cohort registry study of patients with Crohn's disease in Japan (iCREST-CD).

BACKGROUND: The Inception Cohort Registry Study of Patients with Crohn's Disease aimed to clarify clinical characteristics and disease course of newly diagnosed Crohn's disease patients in Japan throughout a 4-year period. Results from an interim analysis of the largest nation-wide registry study that covers approximately 1% of Crohn's disease patient population in Japan are reported. METHODS: This prospective, observational registry study was conducted at 19 tertiary centers in Japan. Patients newly diagnosed with Crohn's disease after June 2016 (age ≥ 16 years at informed consent) were enrolled between December 17, 2018 and June 30, 2020. Patient demographics, diagnostic procedures and categories, disease location and lesion behavior (Montreal classification) at the time of diagnosis were recorded. RESULTS: Of 673 patients enrolled, 672 (99.9%) were analyzed (458: men, 214: women), male-to-female ratio: 2.1, median age at diagnosis 25 (range 13-86) years; peak age of disease diagnosis: 20-24 years. Most common disease location was L3 (ileocolonic; 60.1%). Non-stricturing, non-penetrating (B1) disease was most common behavior (62.8%); 48.9% reported perianal lesions. Notably, age-wise analysis revealed disease phenotypes varied between patients aged < 40 and ≥ 40 years in terms of male-to-female ratio (2.5/1.3)/disease location (L3: 66.3%/37.0%)/disease behavior (B1: 66.4%/50.0%)/perianal lesion: (55.7%/20.5%) at Crohn's disease diagnosis, respectively. CONCLUSIONS: Interim analysis of this nation-wide Inception Cohort Registry Study of Patients with Crohn's Disease revealed the demographics and disease characteristics of newly diagnosed Crohn's disease patients in Japan and demonstrated that disease phenotype varied between patients aged < 40 and ≥ 40 years, serving as important information for management of individual patients.

Fecal Diversion in Complex Perianal Fistulizing Crohn's Disease.

Complex perianal Crohn's disease (CD) remains a challenging problem. Fecal stream is thought to be a trigger of disease progression in patients with CD. In patients with refractory perianal CD, diversion of fecal stream is sometimes required to alleviate clinical symptoms when medical and local surgical management are unsuccessful. Several studies evaluated the outcomes of fecal diversion for complex perianal CD. After fecal diversion, the majority of patients achieved early clinical response, but the prospect of restoring bowel continuity was low (approximately 20%). Nearly half of the patients eventually required proctectomy. A number of studies attempted to identify predictive factors for the outcomes of fecal diversion. Only rectal involvement was associated with unsuccessful restoration of bowel continuity. Biologic therapy did not seem to improve the efficacy of fecal diversion, although the evidence level was low because of insufficient data or methodological limitations. Based on these results, fecal diversion may be useful in alleviating clinical symptoms related to severe perianal CD and avoiding immediate proctectomy. The impact of biologic therapy on the outcomes of fecal diversion should be further investigated.

Coronary Microvascular Dysfunction Restored After Surgery in Inflammatory Bowel Disease: A Prospective Observational Study.

Background We aimed to investigate the presence and severity of coronary microvascular dysfunction (CMD) in inflammatory bowel disease (IBD) including Crohn disease and ulcerative colitis and to elucidate the influence of surgical resection of the diseased intestines on CMD by assessing coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography. Methods and Results Thirty-seven patients with IBD (aged 44±15 years; 22 patients with Crohn disease and 15 patients with ulcerative colitis) and 30 controls (aged 46±12 years) were enrolled. For CFVR measurement, coronary flow velocity was recorded at rest and during hyperemia by ADP infusion using transthoracic Doppler echocardiography, and CFVR <2.5 defined CMD. CFVR measurement was repeated before and within 1 year after surgery. CFVR was similarly and significantly lower in patients with Crohn disease and those with ulcerative colitis than controls (Crohn disease: 2.92±1.03 [P<0.05 versus controls], ulcerative colitis: 2.99±0.65 [P<0.05 versus controls], and controls: 3.84±0.75). Multiple linear regression analysis showed that the presence of IBD and baseline hs-CRP (high-sensitivity C-reactive protein) were independently associated with low CFVR among all study participants (ß=-0.403 [P=0.001] and -0.237 [P=0.037], respectively). Hyperemic coronary flow velocity significantly improved after surgery only in patients with IBD who had CMD. CFVR significantly improved in patients with IBD who had both CMD and non-CMD, and the extent of CFVR improvements were greater in patients with CMD than non-CMD. Multiple linear regression analysis showed that the reduction of hs-CRP was independently associated with improvement of hyperemic coronary flow velocity and CFVR among all patients with IBD (ß=-0.481 [P=0.003] and ß=-0.334 [P=0.043], respectively). Conclusions IBD is associated with CMD, which improved after surgical resection of diseased intestines.

Impact of Preoperative Nutritional Status on the Incidence Rate of Surgical Complications in Patients With Inflammatory Bowel Disease With Vs Without Preoperative Biologic Therapy: A Case-Control Study.

OBJECTIVES: A case-control study was undertaken to assess the impact of preoperative nutrition on surgical outcomes in patients with inflammatory bowel disease with vs without preoperative biologic therapy. METHODS: Seventy patients who had received biologic therapy within 8 weeks before undergoing resection for active ulcerative colitis (n = 34) or Crohn's disease (n = 36) were included (BIO group). The control group comprised 70 patients without exposure to biologics, selected based on 5 matching criteria: inflammatory bowel disease subtype (ulcerative colitis/Crohn's disease), age (≤ or >40 years), disease severity (moderate/severe), surgical approach (open/laparoscopic), and main surgical procedure. Poor nutrition was defined as the presence of at least one of the following criteria: weight loss >10%-15% within 6 months, body mass index <18.5 kg/m, Subjective Global Assessment Grade C, or serum albumin <30 g/L. RESULTS: The proportion of patients with preoperative poor nutrition was 43% in the BIO and 33% in the control groups (P = 0.22). The incidence of postoperative infectious complications (anastomotic leak, intra-abdominal abscess, enterocutaneous fistula, or wound infection) was 16% in the BIO and 14% in the control groups (P = 0.81). In the BIO group, poor nutrition significantly increased the risk of infectious complications (27% vs 8% without poor nutrition, P = 0.03). In addition, in the control group, the incidence of infectious complications was higher in patients with poor nutrition, but not significantly (22% vs 11%, P = 0.21). DISCUSSION: Poor nutrition increases the risk of infectious complications after surgery. The detrimental effects of poor nutrition on postsurgical infection may be enhanced in patients who have received biologic therapy preoperatively.

Correction: A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Correction: A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

Faecal calprotectin level for assessing endoscopic activity and predicting future clinical course in patients with moderately active ulcerative colitis undergoing granulomonocytapheresis: a prospective cohort study.

BACKGROUND: Calprotectin is a stable neutrophil protein, which can be measured in faecal samples. The faecal level of calprotectin increases during disease activity in ulcerative colitis (UC). Nonetheless, the relevance of faecal calprotectin (FC) measurement during granulomonocytapheresis (GMA) for UC has not yet been fully evaluated. This prospective study was to investigate the value of FC for assessing disease activity and predicting clinical course in UC patients undergoing GMA therapy. METHODS: One hundred and eighty-four patients with moderately active UC with endoscopic activity (Mayo endoscopic subscore [MES] = 2 or 3) received Adacolumn GMA therapy (10 apheresis sessions over consecutive 5 weeks). Patients who achieved clinical remission were subsequently given maintenance medications for 12 months. FC levels were measured at entry and after treatment. RESULTS: After GMA, 80 of the 184 patients (43%) achieved clinical remission, and 51 (28%) achieved mucosal healing (MH; MES = 0 or 1). The median FC level significantly decreased in patients who achieved MH (P = 0.02), but not in those without MH. Thirty-four patients (43%) relapsed during the 12-month follow-up. The median FC level at the end of GMA therapy was significantly higher in patients who subsequently relapsed than in those who maintained remission (149.5 vs 45.5 µg/g, P < 0.001). A cut off value of 114 µg/g had a sensitivity of 76% and a specificity of 85% to predict future relapse. CONCLUSIONS: Our findings indicate that FC is a relevant biomarker, which is convenient to measure for assessing endoscopic activity and predicting relapse in patients who achieve remission following a course of GMA therapy.

A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

OBJECTIVES: Adsorptive granulomonocytapheresis (GMA) with the Adacolumn has been introduced as a non-pharmacologic treatment for ulcerative colitis (UC). However, a subset of patients who might respond well to GMA needs to be targeted. This study was conducted at three IBD centers to determine factors affecting the efficacy of GMA in patients with moderately-to-severely active UC. METHODS: From January 2008 to December 2017, a total of 894 active episodes (first attack or relapse) in 593 patients were treated with GMA. Clinical remission was defined as normal stool frequency and no rectal bleeding. Multiple clinical and laboratory parameters at entry were considered for efficacy assessment. RESULTS: Clinical remission was achieved during 422 (47%) of the 894 treatment cases. In the multivariate analysis, predictors for favorable response to GMA were age ≤60 years, UC duration <1 year, Mayo endoscopic subscore 2 (vs. 3), steroid naïve UC, and biologic naïve UC. Clinical remission rate was 70% in patients with four of the five factors, 52% in patients with three factors, 46% in patients with two factors, 39% in patients with one factor, and 18% in patients with none of these factors. Overall, the clinical remission rate was significantly higher in patients with a greater number of the five predictors (P < 0.0001). CONCLUSIONS: GMA appeared to be effective in steroid naïve and biologic naïve patients with short duration of UC. Elderly patients (>60 years) and those with severe endoscopic activity did not respond well to GMA. Additional, well designed, prospective, controlled trials should strengthen our findings.

Colitis with wall thickening and edematous changes during oral administration of the powdered form of Qing-dai in patients with ulcerative colitis: a report of two cases.

Orally administered Qing-dai, called indigo naturalis in Latin, is reportedly useful for the treatment of ulcerative colitis. We herein describe two patients with ulcerative colitis who developed colitis with wall thickening and edematous changes during oral administration of the powdered form of Qing-dai. In Case 1, a 35-year-old man developed colitis similar to ischemic colitis with bloody stool that recurred each time he ingested Qing-dai. He had no signs of recurrence upon withdrawal of Qing-dai. In Case 2, a 43-year-old woman underwent ileocecal resection for treatment of an intussusception 2 months after beginning oral administration of Qing-dai. Edema and congestion but no ulceration were present in the mucosa of the resected specimen. Both patients exhibited abdominal pain with bloody diarrhea, and abdominal computed tomography showed marked wall edema affecting an extensive portion of the large bowel.

Endoscopic score vs. fecal biomarkers for predicting relapse in patients with ulcerative colitis after clinical remission and mucosal healing.

Objectives: Achieving endoscopic remission or decreasing the level of fecal biomarkers as an ideal therapeutic goal in ulcerative colitis has not been determined. This prospective study was to compare the clinical relevance of endoscopic score with fecal biomarkers for predicting relapse after clinical remission and mucosal healing (MH). Methods: One hundred and sixty-four patients who achieved clinical remission and MH (Mayo endoscopic subscore (MES) 0 or 1) were included. At entry, fecal samples were collected for the measurement of calprotectin, lactoferrin, and hemoglobin. Thereafter patients received masalamine maintenance therapy, and were followed for 12 months. Results: During the 12-month study, 46 patients (28%) relapsed. The relapse rate was not significantly higher in 27/80 patients (34%) with MES 1 than in 19/84 patients (23%) with MES 0 (P = 0.16). The median fecal calprotectin, lactoferrin, and hemoglobin were significantly higher in patients with relapse than those in remission (calprotectin, 182 vs. 94 µg/g; lactoferrin, 185.5 vs. 111 µg/g; hemoglobin, 168 vs. 104 ng/mL; all P < 0.0001). A cutoff value of 115 µg/g calprotectin had 83% sensitivity and 81% specificity to predict relapse, whereas lactoferrin, 145 µg/g had 70% sensitivity and 79% specificity, and hemoglobin, 135 ng/mL showed 74% sensitivity and 73% specificity. The accuracy was significantly lower for hemoglobin as compared with calprotectin and lactoferrin. Conclusions: Fecal calprotectin, lactoferrin, and to a lesser degree fecal hemoglobin appeared to be objective biomarkers for predicting future relapse after achieving clinical remission and MH. The predictive value of these biomarkers was higher than with MES.

Comparison of Safety and Efficacy of Tacrolimus versus Infliximab for Active Ulcerative Colitis.

BACKGROUND: This narrative review was to determine which medication, tacrolimus (TAC) or infliximab (IFX), is safer and more effective in the management of active UC. Our literature search identified 5 studies directly comparing the outcomes of TAC versus IFX for active UC. A review of the 5 studies was undertaken. SUMMARY: The incidence of serious adverse events was not significantly different between the TAC and IFX groups. The short-term clinical remission and response rates and the colectomy-free rates were similar between the groups. TAC was usually withdrawn at week 12 and, therefore, the long-term efficacy of TAC could not be properly evaluated. The majority of patients in the IFX group maintained clinical remission in the long-term. The efficacy of IFX as second-line salvage therapy after failure of TAC appeared to be favourable, but the efficacy of TAC after failure of IFX was questionable. Key Messages: Both TAC and IFX appeared to be equally safe and effective in the short-term for patients with active UC. For the moment, treatment choice, TAC or IFX, should be guided by physician and centre experience. Randomised controlled trials are urgently warranted to rigorously compare the efficacy of TAC versus IFX for active UC.

Faecal biomarkers for screening small bowel inflammation in patients with Crohn's disease: a prospective study.

BACKGROUND: The value of faecal biomarkers for screening small bowel inflammation in patients with Crohn's disease (CD) remains to be elucidated. This prospective study was to evaluate the utility of faecal biomarkers for detecting small intestinal inflammation. METHODS: A total of 122 consecutive patients with a diagnosis of CD in the small intestine were screened for eligibility. Computed tomography enterography (CTE) was undertaken to evaluate small bowel inflammation followed by colonoscopy to confirm no large bowel involvement. Seventy eligible patients with inflammation confined to the small intestine were included. Faecal samples were collected for assaying calprotectin, lactoferrin and haemoglobin. For assessing the degree of small bowel inflammation, a semi-quantitative scoring system (CTE0, normal; CTE1, mild; CTE2, moderate; CTE3, severe) was applied. RESULTS: The median calprotectin, lactoferrin and haemoglobin levels were significantly higher in patients with small bowel inflammation, CTE scores 1-3 (n = 42) versus 0 (n = 28): calprotectin, 330 versus 40 ng/ml, p < 0.0001; lactoferrin, 14 versus 3 ng/ml, p < 0.0001; haemoglobin, 29.5 versus 6.5 ng/ml, p = 0.005. There was a strong positive relationship between the faecal biomarkers and CTE score: calprotectin, p < 0.0001; lactoferrin, p < 0.0001; haemoglobin, p = 0.0004. A cutoff value of 140 ng/ml for calprotectin had a sensitivity of 69% and a specificity of 82% with an area under the receiver operating characteristic curve (AUC) of 0.82 to detect small bowel inflammation (CTE scores 1-3), while lactoferrin 6 ng/ml had a sensitivity of 69% and a specificity of 79% with an AUC of 0.83, and haemoglobin 9 ng/ml showed a sensitivity of 71% and a specificity of 39% with an AUC of 0.70. CONCLUSIONS: Faecal calprotectin, lactoferrin, and to a lesser degree haemoglobin are relevant biomarkers for screening small bowel inflammation in CD patients without large bowel involvement. Further well-designed large-scale studies in this clinical setting should strengthen our findings.

Monitoring and detection of disease recurrence after resection for Crohn's disease: the role of non-invasive fecal biomarkers.

INTRODUCTION: Ileocolonoscopy is the gold standard for the diagnosis and assessment of postoperative recurrence in Crohn's disease (CD). Nevertheless, endoscopy is time-consuming and invasive. A minimally invasive and simple screening test would improve patient adherence to examination and provide greater clinical benefit. A number of fecal biomarkers have been evaluated for their utility for the diagnosis and monitoring of inflammatory bowel disease as alternative tests to endoscopy. Area covered: In this review, we focused on the utility of fecal biomarkers in the management of postoperative CD. Our major endeavor was to present an evidence-based assessment of the results of clinical trials on the available data. A literature search was conducted using the Medline. Expert commentary: Calprotectin and lactoferrin, both neutrophil-derived proteins, are the two most frequently used fecal biomarkers in clinical trials and practice. Several studies evaluated the role of these fecal biomarkers in patients with postoperative CD. These studies suggest that fecal calprotectin, and to a lesser degree lactoferrin, are useful in assessing endoscopic severity and in predicting future clinical recurrence after resection for CD. However, large scale, well-designed studies are necessary to rigorously evaluate the role of fecal biomarkers in postoperative CD.

Efficacy of granulocyte and monocyte apheresis for antibiotic-refractory pouchitis after proctocolectomy for ulcerative colitis: an open-label, prospective, multicentre study.

BACKGROUND: Granulocyte and monocyte apheresis (GMA) has shown therapeutic efficacy in active ulcerative colitis (UC). We thought that in patients with pouchitis after proctocolectomy for UC, GMA might produce immunological effects in the intestinal mucosa, and improve clinical symptoms. This prospective study was to evaluate the efficacy of GMA for antibiotic-refractory pouchitis after proctocolectomy for UC. METHODS: A total of 13 patients with pouchitis disease activity index (PDAI) > 7 unresponsive to 2 weeks of antibiotic therapy were included. All patients received 10 GMA sessions at 2 sessions/week over 5 consecutive weeks. The primary endpoints were response (a decrease of ⩾3 points in the PDAI) and remission (PDAI < 4). Secondary endpoints included reduction of white blood cells (WBCs), C-reactive protein (CRP), faecal markers (calprotectin and lactoferrin), reduction of the PDAI endoscopic subscore, and GMA safety. RESULTS: The median PDAI score was significantly decreased from 11 (range, 9-15) at entry to 9 (range, 6-13) after the GMA therapy (p = 0.02). A total of six patients (46%) responded to the treatment, but none achieved remission. The median endoscopic subscore (maximum: 6) was 5 (range, 4-6) at entry and 5 (range, 1-6) after the treatment (p = 0.10). None of the laboratory markers (WBCs, CRP, faecal calprotectin and lactoferrin) significantly changed during the treatment. Transient adverse events (AEs) were observed in two patients (15%), dyspnoea in one and headache in one. The AEs were not serious, and all patients completed the 10 GMA sessions. CONCLUSIONS: GMA has a good safety profile, but its efficacy appears to be limited in the management of chronic refractory pouchitis. However, a large controlled study should be conducted to evaluate the efficacy of GMA therapy in patients with pouchitis at an earlier clinical stage, before the disease has become refractory to conventional medical therapy.

Enteral nutrition and dietary interventions.

Currently, various dietary interventions or supplements, including probiotics and prebiotics, are available for patients with Crohn's disease. Among these interventions or supplements, there is nothing showing significant efficacy. Although the evidence level is not high, the available data suggest that enteral nutrition is effective in both active and quiescent Crohn's disease. However, the therapeutic efficacy of dietary and nutritional interventions needs to be supported by well-designed trials in large cohorts of patients. Further, a significant limitation of enteral nutrition is inadequate patient compliance due to poor palatability of an elemental diet. One major challenge is to establish practical strategies for increasing patient adherence for long-term enteral nutrition.