Abstract: The worldwide prevalence of obesity has reached staggering proportions, and the inflammatory bowel disease (IBD) population has not been immune to this trend, with obesity rates estimated to be between 15% and 40%. With the concurrent rise in incidence of IBD itself, there are biologically plausible mechanisms that suggest a potential role of obesity in the pathogenesis of IBD, although epidemiologic data on this issue are conflicting. Similarly, studies exploring the impact that obesity may have on the natural history of disease have produced inconsistent results. Some studies suggest higher and others lower rates of surgery in obese Crohn’s disease patients, other studies suggest a higher risk of surgery in obese ulcerative colitis patients, and yet other studies reveal no difference in outcomes regarding hospitalization or surgery for either group. Regardless of its impact on the pathogenesis or natural history of IBD, the rising prevalence of obesity in this population results in a need to better understand the effect it has on IBD management. Although pharmacologic data suggest that obesity may influence the absorption, distribution, and clearance of the available therapeutic agents, the actual clinical consequen-ces that these differences have on disease management are less clear. Finally, it is possible that weight loss interventions for obesity could have an impact on the clinical course of IBD.
Along with the rising prevalence of obesity in the US population, a similar trend has been occurring in the inflammatory bowel disease (IBD) population,1-6 a cohort that has historically been thought to experience malnourishment. With this rise in both obesity and IBD comes a surge of research gaps. For example, it is not yet clear if obesity plays a role in the pathogenesis of IBD. Whether obesity might impact the natural history of IBD also remains to be fully determined, and whether medical and surgical therapies for IBD are impacted by obesity is poorly understood. Finally, it is not known if weight loss strategies are safe and effective in the IBD population. This article summarizes the available literature on the intersection between obesity and IBD and identifies knowledge gaps in this relatively unexplored topic.
Prevalence of Obesity in Inflammatory Bowel Disease Patients
The prevalence of obesity worldwide has risen to epidemic proportions and is one of the leading public health issues of the 21st century. Escalating obesity rates in the IBD population have been documented to parallel those in the general population. Data from cross-sectional and single-center cohorts suggest that the prevalence of obesity (body mass index [BMI], ≥30) in IBD patients is between 15% and 40%,1 a proportion that increases further when overweight (BMI, 25 to <30) patients are also considered (Table).1-6 In a population-based cohort of IBD patients from Olmsted County, Minnesota, the prevalence of overweight and obese patients rose from 24% and 12%, respectively, in 1990 to 1994 to 34% and 20%, respectively, in 2005 to 2010.7 This trend was corroborated in an analysis of 10,282 clinical trial participants with Crohn’s disease (CD), where it was noted that the mean BMI at the time of enrollment increased from 20.8 in 1991 to 27.0 in 2008.8 These trends are not unique to the adult population, with rates of overweight and obese patients having similar increases in children.9,10
Obesity and the Pathogenesis of Inflammatory Bowel Disease
With a coinciding upward trajectory of incident IBD cases across the globe,11-15 particularly in geographic regions where IBD was previously uncommon, environmental triggers have been thought likely to contribute to the pathogenesis of this disease. Support of an environmentally based hypothesis includes studies that suggest an increased risk of de novo IBD in immigrants who move from low- to high-prevalence countries.16 Understanding the role of environmental exposures in the development of IBD has recently been identified as 1 of the 5 areas of research gaps in a Challenges in IBD research document sponsored by the Crohn’s & Colitis Foundation.17 Several environmental factors associated with modernization have been implicated in this rising prevalence, including improved hygiene,18 increased antibiotic use,19,20 alterations in the intestinal microbiome,21,22 and dietary changes associated with an industrialized lifestyle.23,24 Obesity may be another important risk factor to consider, and it is also perhaps impacted by many of the aforementioned elements, although its role in the development of IBD has been arguably understudied despite its expanding presence worldwide.
The plausibility of obesity playing a pathogenic role in the development of IBD is centered around the idea that adipose tissue is not a biologically inert organ; rather, it is responsible for producing a repository of pro- and anti-inflammatory cytokines (including tumor necrosis factor–alpha [TNF-α] and interleukin-6), many of which are central to the development of IBD.25-28 Moreover, it has been suggested that creeping fat itself is a distinct form of adiposity with unique biochemical properties, producing a different cytokine milieu compared to that of subcutaneous fat or even mesenteric fat in obese non-IBD patients.29,30 Additional postulated mechanisms include alterations in the intestinal microbiota21 as well as disrupted intestinal permeability resulting from zonulin production, a mediator of intercellular tight junctions, by visceral adipocytes.31
The few available epidemiologic studies on this topic are conflicting, and additional investigation is needed to clarify any role that obesity may play in the pathogenesis of IBD.32-34 A cohort of over 300,000 individuals from the Copenhagen School Health Records Register was studied to assess the relationship between BMI in the ages of 7 to 13 years and adult-onset IBD. For each incremental increase in BMI by 1 at all examined ages, there was an increased risk of CD before age 30 years (hazard ratio [HR], 1.2) and a decreased risk of ulcerative colitis (UC) diagnosis, irrespective of age (HR, 0.9).34 In contrast, a large cohort study examining over 300,000 adults from the European Prospective Investigation Into Cancer and Nutrition study found no association between BMI and incident CD or UC.32 A notable difference between these 2 studies is that the former utilizes childhood BMI as a predictor while the latter focuses on obesity in adulthood, bringing into question whether exposure to obesity earlier in life is where the impact truly takes place. In summary, although biologic plausibility may be present to suggest a causative role of obesity in IBD patients, this remains speculative at best, and additional study is required.
Influence of Obesity on Inflammatory Bowel Disease Phenotype
Whether obesity influences the disease phenotype of IBD is unclear, as the few available studies exploring this issue have produced conflicting results (Table). A population-based cohort of 488 IBD patients demonstrated a nonsignificant trend (P=.06) for obese CD patients having higher rates of isolated colonic disease, but did not note any appreciable differences in disease behavior or presence of perianal disease in CD patients, nor differences in disease extent for patients with UC.35 Although another retrospective review suggested that obese patients may have higher rates of anoperineal disease,36 the remaining available studies have largely suggested no differences in disease distribution or behavior for CD or UC patients.2,5
Impact of Obesity on the Natural History and Outcomes of Inflammatory Bowel Disease
Obesity has also been implicated as a potential detrimental risk factor in IBD-related outcomes, largely extra-polated from data associating obesity with worse clinical outcomes in other chronic inflammatory conditions, such as rheumatoid arthritis and psoriasis.26,37 Studies exploring the prognostic impact of obesity on IBD outcomes are limited and produce conflicting results (Table).
In a retrospective review of 581 IBD patients, obese individuals were less likely to be hospitalized (42.1% vs 66.0%; P<.0001) or undergo surgery (41.1% vs 61.1%; P=.005), compared to their normal- and underweight counterparts.2 The reverse was demonstrated in a review of CD patients, which suggested a higher risk of developing active disease (odds ratio [OR], 1.50; 95% CI, 1.07-2.11) or requiring hospitalization (OR, 2.35; 95% CI, 1.56-3.52) for obese patients.38 A single-center review of 148 CD patients revealed that those with a BMI of greater than 25 had a shorter time to first surgery compared to those with a BMI of less than 18.5 (24 vs 252 months; P=.043); however, the actual number of surgeries over time did not differ.5 A retrospective review of 221 CD patients followed for a median of 14.2 years found a 5% decreased risk of surgery with each incremental increase in BMI by 1 (HR, 0.95; 95% CI, 0.91-0.99), although there was no difference in the risk of future corticosteroid use or hospitalization.39 A prospective case-control study found no association between BMI and future risk of surgery or corticosteroid use.4
In regard to UC, the data are similarly sparse and inconsistent. A population-based cohort of 267 UC patients demonstrated that with each incremental increase in BMI by 1, patients were at a 6% increased risk of future surgery (P=.01) and a 3.4% higher risk of hospitalization (P=.052).39 Although a retrospective analysis of 1494 IBD patients did not demonstrate any association between obesity and rates of corticosteroid use, hospitalization, or surgery,3 other studies have reported either higher rates of surgery in overweight UC patients38 or, conversely, a protective effect with a lower proportion of years with active disease in obese patients.6
Overall, due to the relative paucity of data, small patient cohorts, limited follow-up, and conflicting results, the effects that obesity may have on IBD-related outcomes are not well understood.
Impact of Obesity on the Management of Inflammatory Bowel Disease Patients
Medical Management
How obesity actually impacts the medical management of IBD remains unclear. It seems logical to surmise that obesity may impact the absorption, distribution, and clearance of the current armamentarium of drugs, and a few pharmacokinetic studies have indeed produced data to suggest such an effect.40,41 Two commonly implicated factors by which obesity may impact response to biologic therapy in particular include the mode of drug administration (subcutaneous vs intravenous) and the issue of weight-based vs fixed-dose regimens.
Differences have been described in the pharmacokinetic profiles of subcutaneously vs intravenously administered medications,42 leading to the suggestion that obesity could potentially influence subcutaneous therapies more than intravenous ones. Bhalme and colleagues performed a retrospective review of CD patients treated with either infliximab or adalimumab, and found that patients who had a BMI of at least 30 experienced a shorter time to dose escalation due to loss of response while on adalimumab, but not infliximab.43 Another postulated explanation for the reported difference seen in adalimumab- vs infliximab-treated patients has included the former’s fixed-dosing schedule, resulting in obese patients being less likely to receive weight-appropriate therapy. However, a retrospective analysis of 1494 IBD patients compared the actual milligram per kilogram dose of medication that patients were receiving based on their BMI category. The analysis found that as BMI increased, the actual weight-based dose that patients received significantly decreased, which was true for both intravenously and subcutaneously delivered anti–TNF-α agents.3 For instance, the mean weight-based doses of infliximab and adalimumab were 3.96 mg/kg and 0.31 mg/kg, respectively, in patients with class III obesity, compared to 7.89 mg/kg and 0.62 mg/kg, respectively, in normal-weight patients (P<.0001).3 Findings were similar for oral immunomodulators.
Conflicting findings have suggested that obesity does not seem to play a role in the receipt of weight-appropriate therapy,44 implying that obesity may have some intrinsic effect on treatment response, independent of drug levels or mode of exposure. Among the numerous mechanisms that have been postulated to play a role in altered pharmacokinetics are larger volumes of distribution and enhanced proteolysis, as well as obese patients simply having a more expansive repository of adipose tissue, producing a larger burden of TNF-α. A recent pooled meta-analysis reported that obese UC patients experienced higher odds of anti–TNF-α treatment failure (OR, 1.41; 95% CI, 1.01-1.98; P=.045), regardless of whether they received fixed-dose or weight-based treatment regimens.45 Kurnool and colleagues performed a review of 160 UC patients treated with biologic agents, including both weight-based regimens (infliximab) as well as fixed-dose regimens (adalimumab, certolizumab pegol [Cimzia, UCB], vedolizumab [Entyvio, Takeda], and golimumab [Simponi, Janssen]).46 The authors found that each incremental increase in BMI of 1 was associated with a 4% increased risk of treatment failure (adjusted HR, 1.04; 95% CI, 1.00-1.08) for all patients, regardless of the type of biologic utilized.46 Similar findings from Harper and colleagues demonstrated a 30% increased risk of UC flare (HR, 1.30; 95% CI, 1.07-1.58) and a 6% increased risk of CD flare (HR, 1.06; 95% CI, 1.02-1.11) with each incremental increase in BMI by 1.47 Contrasting these findings is a pooled data analysis of 1205 infliximab-treated IBD patients from 4 landmark clinical trials (ACCENT-I, SONIC, ACT-1, and ACT-2), which did not identify any difference in clinical remission or response based on BMI.48 These findings were supported by a systematic review and meta-analysis demonstrating that obesity was a risk factor for anti–TNF-α therapy failure in several rheumatic diseases, but not IBD.49
Therefore, although there seem to be some data to suggest pharmacokinetic mechanisms by which obese patients may experience diminished response to therapy, the true clinical impact of these mechanisms on treatment outcomes is less clear and requires further study.
Surgical Management
Obesity has repeatedly been recognized as a risk factor for perioperative morbidity, largely driven by surgical site infections, but also by impaired wound healing, potentially increased thromboembolic complications, longer length of hospital stay, and need for short-term rehabilitation.50-53
For a myriad of reasons, obesity also creates technical challenges for IBD-related operations, particularly those requiring pelvic exposure. Not surprisingly, this greater complexity results in an increased risk of laparoscopic procedures that are converted to open procedures, as well as longer operative times.51 Two operative considerations of particular interest to the IBD population are related to issues with stoma creation and pouch construction. Obesity, particularly increased abdominal adiposity, not only makes creation of a stoma challenging, but also appears to increase the risk of postoperative complications such as stoma retraction, mucocutaneous separation, stomal prolapse, and para-stomal hernia.54 Additionally, obesity makes pouch construction cumbersome, if not impossible, in some cases due to foreshortening of the mesentery by mesenteric fat, which impedes the achievement of adequate pouch length and reach into the pelvis. A report cited obesity as a risk factor for increased pelvic sepsis,55 which is a major predictor for pouch failure requiring excision. However, more contemporary data suggest that this may not be the case.51 This dichotomy is likely related to the idea that earlier research more frequently reported on outcomes of single-stage operations, and with the more contemporary use of a diverting stoma in 2- or 3-stage operations, the risk of surgical complications has diminished. These findings suggest that pursuing 3-stage ileal pouch–anal anastomosis is the preferred strategy in obese patients, which may then also allow for an opportunity to achieve weight loss prior to eventual pouch construction and restoration of continuity. Moreover, patients need to be counseled appropriately on potential perioperative risks in the setting of obesity.
Although obesity appears to increase the risk of short-term perioperative complications as previously discussed, several studies have suggested that in high-volume centers, long-term pouch function in obese patients may be similar to that of their nonobese counterparts.50,51,55 Worth mentioning, however, is that these studies were largely done examining BMI at the time of restorative proctocolectomy. In a review of 846 IBD patients who underwent pouch surgery, those with postoperative weight gain were found to have increased risk for CD of the pouch (30.6% vs 18.5%; P=.001), mechanical or surgical pouch complications (18.4% vs 12.3%; P=.049), and postoperative pouch-related complications (21.1% vs 10.6%; P<.001).56 Furthermore, excessive postoperative weight gain (defined as 15% increase in index body weight) led to higher rates of pouch failure (HR, 1.69; 95% CI, 1.01-2.84; P=.048) even after adjustments were made for postoperative immunosuppressive therapy, CD of the pouch, postoperative pouch-associated hospitalization, and mechanical or surgical pouch complications. Therefore, although elevated BMI at the time of restorative proctocolectomy may negatively impact perioperative outcomes, avoidance of significant postoperative weight gain should also be advised to prevent increased risk of future pouch complications.
Impact of Obesity on Cost and Quality of Life in Inflammatory Bowel Disease Patients
Outside of simply impacting medical and/or surgical outcomes of IBD patients, several studies suggest that obesity also negatively impacts overall quality of life, as well as the financial burden placed on IBD patients. A large Internet-based study of more than 7000 participants with IBD demonstrated that those who were obese were significantly more likely to have higher rates of anxiety, depression, fatigue, and pain and reduced social function both at baseline as well as over a 12-month follow-up, even after adjusting for disease activity.57 Additionally, an analysis utilizing the Nationwide Readmissions Database 2013 demonstrated that obesity was associated with a significantly higher number of annual hospital days (8 vs 5 days; P<.01), more of which were preventable admissions, as well as a higher cost of hospitalization-related care (median, $17,277 vs $11,847; P<.01).58
The IBD population already has a higher prevalence of anxiety and depression as well as reduced quality of life, independent of obesity.59 Moreover, the cost burden of time away from work for flares, clinic visits, testing required for disease management, hospitalizations, and medical therapy is already substantial for these patients. It is, therefore, important to recognize that obesity may further exacerbate these issues, and could represent an opportunity to intervene via a modifiable risk factor to improve these metrics.
Impact of Obesity Treatment on Inflammatory Bowel Disease Outcomes
Regardless of the impact that obesity may have on IBD management, it is now a highly prevalent comorbidity among IBD patients, and what remains unclear is how to best manage it in this special population. Clinically available management options for obesity in the general population include lifestyle modifications, weight loss pharmacotherapy, novel endoscopic procedures, and bariatric surgery. Certainly, there is ample support to substantiate the benefits of weight loss for overall health and well-being, and even literature to suggest that weight loss may positively impact outcomes in other immune-mediated disorders, such as psoriasis.60 However, data pertaining to the application of lifestyle management or clinically available weight loss pharmacotherapy in the IBD population are lacking, and obesity has classically been considered a relative contraindication to bariatric surgery. With the recent recognition that obesity is on the rise within this special population, there has been increased inquiry into the safety and feasibility of weight loss procedures in this cohort of patients.
Although data are sparse, studies have demonstrated that bariatric surgery is likely both feasible and safe in IBD patients.61-63 Moreover, some researchers have even postulated that weight loss surgery may result in improved IBD outcomes.63-65 Drawing from conclusions citing improvement of other chronic inflammatory disorders, such as psoriasis66 and systemic lupus erythematosus,67 it has been presumed plausible that weight loss surgery may be advantageous in controlling disease activity in IBD patients. Multiple proposed explanations for this hypothesis exist, ranging from the reduction of excess visceral adiposity, which results in decreased generation of proinflammatory cytokines, to the reduction of the pharmacologic volume of distribution, which allows for a decrease in the required doses of IBD medications. The idea that weight loss may result in improved control of IBD is largely based off data from the aforementioned pharmacokinetic studies and clinical data reporting that higher BMI may be a predictor of earlier loss of response and need for dose escalation of anti–TNF-α therapy.47,68 Although clinical data remain limited, in a case-control study of 25 IBD patients who underwent bariatric surgery and matched IBD controls who had not undergone bariatric surgery, investigators found that the surgical patients experienced a numerically lower number of IBD-related complications (specifically rescue corticosteroid use and IBD-related surgery) at 48% vs 72% in the control group (OR, 0.44; 95% CI, 0.1-1.6; P=.27).65 However, although the surgical patients achieved a mean reduction in BMI of 12 following bariatric surgery, their postoperative BMI still remained higher than that of the control group.
On the other hand, there have been a few reports suggesting an increased risk of de novo IBD following bariatric surgery, proposing that such an operation in the context of a genetically predisposed individual may give rise to the development of IBD via changes in the microbiome, excess cytokine release by adipose tissue, or anatomic alternations resulting in variable toxin exposures to the intestinal tract.69,70 Braga Neto and colleagues performed a 2-center study describing what is currently the largest case series of 44 individuals who developed de novo IBD following bariatric surgery.69 This development most commonly occurred in patients undergoing Roux-en-Y gastric bypass, followed by gastric banding and stapling, over a median latency period of 7 years between the operation and IBD diagnosis. However, a recently published analysis of the Explorys database suggested that the prevalence of de novo IBD was lower in obese patients treated with bariatric surgery (7.72/1000 patients) or weight loss medications (7.22/1000 patients) compared to obese patients who were not treated with those interventions (11.66/1000 patients).71 Although these findings are certainly intriguing, to date there are only approximately 60 reported cases of de novo IBD following bariatric surgery, and true causality of this relationship is not known. Certainly, these findings should not preclude the performance of weight loss surgeries, but they may prompt the inclusion of new-onset IBD in the differential diagnosis for diarrhea and abdominal pain in patients following bariatric surgery.
In summary, although bariatric procedures seem to be safe and effective, larger and more rigorous studies are required to establish the role of these procedures in this special patient population. At the present time, although IBD may not necessarily be a contraindication to bariatric procedures, they should be performed judiciously and only in the appropriate context under the direction of a multidisciplinary care team given the complexities involved.
Future Directions
Obesity is clearly an increasingly prevalent comorbid condition in the IBD population, although as previously outlined, its clinical relevance in the pathogenesis, natural history, and treatment outcomes of IBD appears contradictory among the few available studies. There are several inherent limitations in the current literature that may contribute to this lack of clarity.
First of all, most accessible data come from retrospective studies measuring BMI at varying time frames throughout the disease course. Adiposity is a dynamic measurement and no doubt experiences a number of changes throughout an individual’s disease course. If obesity does impact IBD outcomes, it is not clear when this effect is most influential (eg, obesity at the time of IBD diagnosis, weight gain throughout the course of disease, or presence of increased adiposity even years prior to the onset of IBD). Both the retrospective nature of the studies as well as the variable time frames at which obesity is assessed in the studies make it difficult to implicate causality. In addition, many studies neglect addressing potential confounding factors such as smoking status, corticosteroid use, or disease activity, all of which may impact weight status at a singular point in time.
Of important note is also that the overwhelming majority of existing studies utilize BMI as a surrogate measure of obesity. It remains unknown whether BMI is an accurate reflection of adipose stores, namely visceral adipose tissue (VAT), particularly given that one of the main hypotheses supporting the role of obesity in IBD patients involves the unique metabolic and biochemical properties of VAT as compared to subcutaneous adipose tissue (SAT). There are a few studies suggesting that VAT, but not BMI, might carry prognostic value in predicting postoperative outcomes and disease recurrence in CD patients.72,73 A prospective study showed that the ratio of VAT to SAT was associated with stricturing CD behavior as well as future serial fecal calprotectin and quality-of-life measurements, although the same was not true for BMI.74 It is plausible, therefore, to consider that the inability of BMI to differentiate VAT from SAT may contribute to the conflicting results seen in the current literature.
For future studies, it would be beneficial to focus on prospective disease evaluation, improved control of confounding factors, and assessment of obesity utilizing measures that reflect VAT. Ideally, this involves cross-sectional imaging studies such as computed tomography, magnetic resonance imaging, or dual energy x-ray absorptiometry, all of which have been utilized in VAT assessment.
Conclusion
A growing body of evidence suggests that the IBD population is facing an obesity epidemic paralleling that of the general population. Interestingly, this is occurring alongside an increasing incidence of IBD, particularly in newly developed countries, bringing rise to questions regarding the role of obesity in the pathogenesis of IBD. Although there are pathophysiologically sound theories to support a potential role of obesity in the development of IBD, robust epidemiologic data are lacking. Similarly, studies on the impact of obesity on the natural history of disease and IBD-related complications are conflicting.
Despite the aforementioned inconsistencies, management of these patients may warrant special consideration, as there are pharmacokinetic data to imply that obesity may not only adversely impact the achievement of adequate therapeutic drug levels, but even response to therapy independent of drug levels via mechanisms, including greater TNF-α burden or increased proteolysis and clearance. Although it should be noted that clinical data to this effect are inconclusive, in patients who are obese, clinicians may consider preferential use of weight-based therapies (if there are no other compelling clinical indications for fixed-dose regimens) and more vigilant monitoring with therapeutic drug levels to ensure adequate therapy for this particular population.75 There are also special considerations to be made in the surgical management of these patients, particularly regarding stoma and pouch creation.
Particularly with patients who often identify their gastroenterologist as their primary care physician, it is increasingly important to remain cognizant of the fact that obesity should be addressed not only for the potential implications it may have on their IBD course, but also for the known adverse effects it may have on general health outcomes. Patients should be counseled and/or referred appropriately for weight management strategies, whether via lifestyle interventions, medications, or consideration of surgical or novel endobariatric procedures at experienced medical centers.
With the significant knowledge gap that exists regarding the impact of obesity on IBD management, additional study is needed to understand the implications of this ever-growing issue pervading this special population.
Disclosures
Dr Johnson has no relevant conflicts of interest to disclose. Dr Loftus has consulted for AbbVie, Allergan, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Takeda, and UCB. He has received research support from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, Takeda, and UCB.
References
1. Nic Suibhne T, Raftery TC, McMahon O, Walsh C, O’Morain C, O’Sullivan M. High prevalence of overweight and obesity in adults with Crohn’s disease: associations with disease and lifestyle factors. J Crohns Colitis. 2013;7(7):e241-e248.
2. Flores A, Burstein E, Cipher DJ, Feagins LA. Obesity in inflammatory bowel disease: a marker of less severe disease. Dig Dis Sci. 2015;60(8):2436-2445.
3. Seminerio JL, Koutroubakis IE, Ramos-Rivers C, et al. Impact of obesity on the management and clinical course of patients with inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(12):2857-2863.
4. Pringle PL, Stewart KO, Peloquin JM, et al. Body mass index, genetic susceptibility, and risk of complications among individuals with Crohn’s disease. Inflamm Bowel Dis. 2015;21(10):2304-2310.
5. Hass DJ, Brensinger CM, Lewis JD, Lichtenstein GR. The impact of increased body mass index on the clinical course of Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4(4):482-488.
6. Stabroth-Akil D, Leifeld L, Pfützer R, Morgenstern J, Kruis W. The effect of body weight on the severity and clinical course of ulcerative colitis. Int J Colorectal Dis. 2015;30(2):237-242.
7. Lynn AM, Harmsen WS, Tremaine WJ, Loftus EV. Trends in the prevalence of overweight and obesity at the time of inflammatory bowel disease diagnosis: a population-based study. Gastroenterology. 2018;154(6)(suppl):S614-S615.
8. Moran GW, Dubeau MF, Kaplan GG, Panaccione R, Ghosh S. The increasing weight of Crohn’s disease subjects in clinical trials: a hypothesis-generatings time-trend analysis. Inflamm Bowel Dis. 2013;19(13):2949-2956.
9. Long MD, Crandall WV, Leibowitz IH, et al; ImproveCareNow Collaborative for Pediatric IBD. Prevalence and epidemiology of overweight and obesity in children with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17(10):2162-2168.
10. Kugathasan S, Nebel J, Skelton JA, et al; Wisconsin Pediatric Inflammatory Bowel Disease Alliance; Pediatric Inflammatory Bowel Disease Collaborative Research Group. Body mass index in children with newly diagnosed inflammatory bowel disease: observations from two multicenter North American inception cohorts. J Pediatr. 2007;151(5):523-527.
11. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46-54.e42.
12. Shivashankar R, Tremaine WJ, Harmsen WS, Loftus EV Jr. Incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota from 1970 through 2010. Clin Gastroenterol Hepatol. 2017;15(6):857-863.
13. Ponder A, Long MD. A clinical review of recent findings in the epidemiology of inflammatory bowel disease. Clin Epidemiol. 2013;5:237-247.
14. Ng SC, Tang W, Ching JY, et al; Asia–Pacific Crohn’s and Colitis Epidemiologic Study (ACCESS) Study Group. Incidence and phenotype of inflammatory bowel disease based on results from the Asia–Pacific Crohn’s and Colitis Epidemiology Study. Gastroenterology. 2013;145(1):158-165.e2.
15. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390(10114):2769-2778.
16. Benchimol EI, Mack DR, Guttmann A, et al. Inflammatory bowel disease in immigrants to Canada and their children: a population-based cohort study. Am J Gastroenterol. 2015;110(4):553-563.
17. Ho SM, Lewis JD, Mayer EA, et al. Challenges in IBD research: environmental triggers. Inflamm Bowel Dis. 2019;25(suppl 2):S13-S23.
18. Cholapranee A, Ananthakrishnan AN. Environmental hygiene and risk of inflammatory bowel diseases: a systematic review and meta-analysis. Inflamm Bowel Dis. 2016;22(9):2191-2199.
19. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2011;106(12):2133-2142.
20. Aniwan S, Tremaine WJ, Raffals LE, Kane SV, Loftus EV Jr. Antibiotic use and new-onset inflammatory bowel disease in Olmsted County, Minnesota: a population-based case-control study. J Crohns Colitis. 2018;12(2):137-144.
21. Joossens M, Huys G, Cnockaert M, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut. 2011;60(5):631-637.
22. Sartor RB, Wu GD. Roles for intestinal bacteria, viruses, and fungi in pathogenesis of inflammatory bowel diseases and therapeutic approaches. Gastroenterology. 2017;152(2):327-339.e4.
23. Tjonneland A, Overvad K, Bergmann MM, et al; IBD in EPIC Study Investigators. Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study. Gut. 2009;58(12):1606-1611.
24. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology. 2013;145(5):970-977.
25. Wozniak SE, Gee LL, Wachtel MS, Frezza EE. Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009;54(9):1847-1856.
26. Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev. 2014;13(9):981-1000.
27. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005;111(11):1448-1454.
28. Weidinger C, Ziegler JF, Letizia M, Schmidt F, Siegmund B. Adipokines and their role in intestinal inflammation. Front Immunol. 2018;9:1974.
29. Fink C, Karagiannides I, Bakirtzi K, Pothoulakis C. Adipose tissue and inflammatory bowel disease pathogenesis. Inflamm Bowel Dis. 2012;18(8):1550-1557.
30. Karmiris K, Koutroubakis IE, Xidakis C, Polychronaki M, Voudouri T, Kouroumalis EA. Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. Inflamm Bowel Dis. 2006;12(2):100-105.
31. Moreno-Navarrete JM, Sabater M, Ortega F, Ricart W, Fernández-Real JM. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PLoS One. 2012;7(5):e37160.
32. Chan SS, Luben R, Olsen A, et al. Body mass index and the risk for Crohn’s disease and ulcerative colitis: data from a European Prospective Cohort Study (The IBD in EPIC Study). Am J Gastroenterol. 2013;108(4):575-582.
33. Harpsøe MC, Basit S, Andersson M, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol. 2014;43(3):843-855.
34. Jensen CB, Ängquist LH, Mendall MA, Sørensen TIA, Baker JL, Jess T. Childhood body mass index and risk of inflammatory bowel disease in adulthood: a population-based cohort study. Am J Gastroenterol. 2018;113(5):694-701.
35. Lynn AM, Harmsen WS, Aniwan S, et al. Prevalence of obesity and influence on phenotype within a population-based cohort of inflammatory bowel disease patients. Gastroenterology. 2018;154(6)(suppl):S608.
36. Blain A, Cattan S, Beaugerie L, Carbonnel F, Gendre JP, Cosnes J. Crohn’s disease clinical course and severity in obese patients. Clin Nutr. 2002;21(1):51-57.
37. Iannone F, Lopalco G, Rigante D, Orlando I, Cantarini L, Lapadula G. Impact of obesity on the clinical outcome of rheumatologic patients in biotherapy. Autoimmun Rev. 2016;15(5):447-450.
38. Steed H, Walsh S, Reynolds N. A brief report of the epidemiology of obesity in the inflammatory bowel disease population of Tayside, Scotland. Obes Facts. 2009;2(6):370-372.
39. Lynn AM, Harmsen WS, Tremaine WJ, Bazerbachi F, Abu Dayyeh BK, Loftus EV. Impact of obesity on future IBD-related complications in a population-based cohort of Crohn’s disease (CD) and ulcerative colitis (UC) patients. Gastroenterology. 2018;154(6)(suppl):S620-S621.
40. Sharma S, Eckert D, Hyams JS, et al. Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn’s disease: results from a randomized, multicenter, phase-3 study. Inflamm Bowel Dis. 2015;21(4):783-792.
41. Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014;20(12):2247-2259.
42. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49(2):71-87.
43. Bhalme M, Sharma A, Keld R, Willert R, Campbell S. Does weight-adjusted anti-tumour necrosis factor treatment favour obese patients with Crohn’s disease? Eur J Gastroenterol Hepatol. 2013;25(5):543-549.
44. Bond A, Asher R, Jackson R, et al. Comparative analysis of the influence of clinical factors including BMI on adalimumab and infliximab trough levels. Eur J Gastroenterol Hepatol. 2016;28(3):271-276.
45. Dai ZH, Xu XT, Ran ZH. Associations between obesity and the effectiveness of anti-tumor necrosis factor-α agents in inflammatory bowel disease patients: a literature review and meta-analysis [published online January 19, 2020]. Ann Pharmacother. doi:10.1177/1060028019900660.
46. Kurnool S, Nguyen NH, Proudfoot J, et al. High body mass index is associated with increased risk of treatment failure and surgery in biologic-treated patients with ulcerative colitis. Aliment Pharmacol Ther. 2018;47(11):1472-1479.
47. Harper JW, Sinanan MN, Zisman TL. Increased body mass index is associated with earlier time to loss of response to infliximab in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(10):2118-2124.
48. Singh S, Proudfoot J, Xu R, Sandborn WJ. Obesity and response to infliximab in patients with inflammatory bowel diseases: pooled analysis of individual participant data from clinical trials. Am J Gastroenterol. 2018;113(6):883-889.
49. Singh S, Facciorusso A, Singh AG, et al. Obesity and response to anti-tumor necrosis factor-α agents in patients with select immune-mediated inflammatory diseases: a systematic review and meta-analysis. PLoS One. 2018;13(5):e0195123.
50. Kiran RP, Remzi FH, Fazio VW, et al. Complications and functional results after ileoanal pouch formation in obese patients. J Gastrointest Surg. 2008;12(4):668-674.
51. McKenna NP, Mathis KL, Khasawneh MA, et al. Obese patients undergoing ileal pouch-anal anastomosis: short-and long-term surgical outcomes. Inflamm Bowel Dis. 2017;23(12):2142-2146.
52. Canedo JA, Pinto RA, McLemore EC, Rosen L, Wexner SD. Restorative proctectomy with ileal pouch-anal anastomosis in obese patients. Dis Colon Rectum. 2010;53(7):1030-1034.
53. Causey MW, Johnson EK, Miller S, Martin M, Maykel J, Steele SR. The impact of obesity on outcomes following major surgery for Crohn’s disease: an American College of Surgeons National Surgical Quality Improvement Program assessment. Dis Colon Rectum. 2011;54(12):1488-1495.
54. Beck SJ. Stoma issues in the obese patient. Clin Colon Rectal Surg. 2011;24(4):259-262.
55. Efron JE, Uriburu JP, Wexner SD, et al. Restorative proctocolectomy with ileal pouch anal anastomosis in obese patients. Obes Surg. 2001;11(3):246-251.
56. Wu XR, Zhu H, Kiran RP, Remzi FH, Shen B. Excessive weight gain is associated with an increased risk for pouch failure in patients with restorative proctocolectomy. Inflamm Bowel Dis. 2013;19(10):2173-2181.
57. Jain A, Nguyen NH, Proudfoot JA, et al. Impact of obesity on disease activity and Patient-Reported Outcomes Measurement Information System (PROMIS) in inflammatory bowel disease. Am J Gastroenterol. 2019;114(4):630-639.
58. Nguyen NH, Ohno-Machado L, Sandborn WJ, Singh S. Obesity is independently associated with higher annual burden and costs of hospitalization in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019;17(4):709-718.e7.
59. Neuendorf R, Harding A, Stello N, Hanes D, Wahbeh H. Depression and anxiety in patients with inflammatory bowel disease: a systematic review. J Psychosom Res. 2016;87:70-80.
60. Upala S, Sanguankeo A. Effect of lifestyle weight loss intervention on disease severity in patients with psoriasis: a systematic review and meta-analysis. Int J Obes (Lond). 2015;39(8):1197-1202.
61. Bazerbachi F, Sawas T, Vargas EJ, et al. Bariatric surgery is acceptably safe in obese inflammatory bowel disease patients: analysis of the Nationwide Inpatient Sample. Obes Surg. 2018;28(4):1007-1014.
62. Sharma P, McCarty TR, Njei B. Impact of bariatric surgery on outcomes of patients with inflammatory bowel disease: a Nationwide Inpatient Sample analysis, 2004-2014. Obes Surg. 2018;28(4):1015-1024.
63. Aminian A, Andalib A, Ver MR, Corcelles R, Schauer PR, Brethauer SA. Outcomes of bariatric surgery in patients with inflammatory bowel disease. Obes Surg. 2016;26(6):1186-1190.
64. Keidar A, Hazan D, Sadot E, Kashtan H, Wasserberg N. The role of bariatric surgery in morbidly obese patients with inflammatory bowel disease. Surg Obes Relat Dis. 2015;11(1):132-136.
65. Braga Neto MB, Gregory MH, Ramos GP, et al. Impact of bariatric surgery on the long-term disease course of inflammatory bowel disease. Inflamm Bowel Dis. 2020;26(7):1089-1097.
66. Romero-Talamás H, Aminian A, Corcelles R, Fernandez AP, Schauer PR, Brethauer S. Psoriasis improvement after bariatric surgery. Surg Obes Relat Dis. 2014;10(6):1155-1159.
67. Corcelles R, Daigle CR, Talamas HR, Batayyah E, Brethauer SA, Schauer PR. Bariatric surgery outcomes in patients with systemic lupus erythematosus. Surg Obes Relat Dis. 2015;11(3):684-688.
68. Bultman E, de Haar C, van Liere-Baron A, et al. Predictors of dose escalation of adalimumab in a prospective cohort of Crohn’s disease patients. Aliment Pharmacol Ther. 2012;35(3):335-341.
69. Braga Neto MB, Gregory M, Ramos GP, et al. De-novo inflammatory bowel disease after bariatric surgery: a large case series. J Crohns Colitis. 2018;12(4):452-457.
70. Cañete F, Mañosa M, Clos A, Cabré E, Domènech E. Review article: the relationship between obesity, bariatric surgery, and inflammatory bowel disease. Aliment Pharmacol Ther. 2018;48(8):807-816.
71. Kochhar GS, Desai A, Syed A, et al. Risk of de-novo inflammatory bowel disease among obese patients treated with bariatric surgery of weight loss medications. Aliment Pharmacol Ther. 2020;51(11):1067-1075.
72. Connelly TM, Juza RM, Sangster W, Sehgal R, Tappouni RF, Messaris E. Volumetric fat ratio and not body mass index is predictive of ileocolectomy outcomes in Crohn’s disease patients. Dig Surg. 2014;31(3):219-224.
73. Holt DQ, Moore GT, Strauss BJ, Hamilton AL, De Cruz P, Kamm MA. Visceral adiposity predicts post-operative Crohn’s disease recurrence. Aliment Pharmacol Ther. 2017;45(9):1255-1264.
74. Bryant RV, Schultz CG, Ooi S, et al. Visceral adipose tissue is associated with stricturing Crohn’s disease behavior, fecal calprotectin, and quality of life. Inflamm Bowel Dis. 2019;25(3):592-600.
75. Singh S, Picardo S, Seow CH. Management of inflammatory bowel diseases in special populations: obese, old, or obstetric. Clin Gastroenterol Hepatol. 2020;18(6):1367-1380.