Obesity is a complex disease that results from increased energy intake and decreased energy expenditure. The gastrointestinal system plays a key role in the pathogenesis of obesity and facilitates caloric imbalance. Changes in gastrointestinal hormones and the inhibition of mechanisms that curtail caloric intake result in weight gain. It is not clear if the gastrointestinal role in obesity is a cause or an effect of this disease. Obesity is often associated with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Obesity is also associated with gastrointestinal disorders, which are more frequent and present earlier than T2DM and CVD. Diseases such as gastroesophageal reflux disease (GERD), cholelithiasis, or nonalcoholic steatohepatitis are directly related to body weight and abdominal adiposity. Our objective is to assess the role of each gastrointestinal organ in obesity and the gastrointestinal morbidity resulting in those organs from the effects of obesity.
Obesity, defined as the excess of adipose tissue that results in a health risk, is usually associated with diabetes mellitus (T2DM) and cardiovascular disease (CVD). Gastrointestinal disorders resulting from obesity are more frequent and present earlier than T2DM and CVD. Hence, gastrointestinal morbidity in the obese person should be an alarm signal indicating that the excess adiposity should be addressed more aggressively. Diseases such as gastroesophageal reflux disease (GERD), cholelithiasis, and nonalcoholic steatohepatitis are directly related to body weight and abdominal adiposity; they present earlier in the natural history of obesity. Raising awareness of these early conditions as complications of obesity and developing successful, low-cost, safe interventions to reverse obesity could prevent the progression to T2DM and CVD.
The objective of this paper is to review each gastrointestinal organ in order to assess their potential role in obesity and the gastrointestinal morbidity associated with obesity.
The role of gastrointestinal organs in the pathophysiology of obesity
Regulation of food intake is an essential factor in developing and maintaining obesity. Gastrointestinal functions are, therefore, integral to obesity, as the stomach is the reservoir that determines the entry of calories into the body, contributes to sensations of satiation or postprandial fullness, and signals the need to cease consumption of calories. Changes in gastric functions, such as more rapid gastric emptying or greater gastric accommodation, could lead to the ingestion of more calories, contributing to weight gain and obesity. Gastrointestinal hormones have an essential role in regulating appetite and satiety in coordination with the brain–gut axis. Emerging evidence suggests that the microbiome within the gastrointestinal tract may have a role in obesity.
The control of food intake has three stages: appetite, satiation, and satiety. Appetite describes the desire for food; satiation is the sense of feeling full during a meal, which induces meal termination; in contrast, satiety is the degree of fullness or satiation before the consumption of the next meal. Gastric function influences all three stages in the control of food intake and merges the signals from mechanical receptors of the stomach and gastrointestinal hormones released in response to the contact of nutrients with taste receptors and enteroendocrine signaling in the gut, as well as the autonomic and enteric nervous systems. Thus, alterations in gastric function or in any of these mechanisms may alter the response to food intake and lead to caloric overconsumption.
The initial studies of gastric function and sensation are almost a century old and involved distending a balloon in the stomach and noting the feeling of fullness.[2-4] More recent studies use noninvasive measurement of gastric volumes to assess the association between abnormal gastric function and obesity or induction of postprandial symptoms. Delgado-Aros and colleagues showed that, across a broad spectrum of body mass index (BMI), there was an association between higher BMI, higher fasting gastric volume, and decreased satiation. The decreased satiation was manifested as reduced symptoms of fullness and a higher maximum tolerated volume of a nutrient drink ingested at a constant rate in a laboratory setting.[5, 6] Figure 1 shows the higher maximum tolerated volume in obese compared to normal or underweight participants; an increase of 50 mL in the fasting gastric volume was associated with 114 ± 32 kcal (479 ± 134 kJ) more ingested at maximum satiation. These findings suggest that individuals with a higher BMI require more food to reach satiation (and, by inference, to signal termination of meal ingestion), and, over time, this results in higher caloric intake and weight gain. However, other data support the importance of behavioral adaptation; thus, other studies show obese individuals have more severe symptoms of fullness, bloating, nausea, and pain when reaching maximal satiation than individuals without obesity, and yet they continue to ingest calories.[1, 5, 7-9] This observation suggests that obese individuals can overcome the stop signal associated with satiation, and these data are consistent with a behavioral adaptation to satiation. Further studies are needed to differentiate the roles of the stomach, the brain centers, and the brain–gut axis in satiation and calorie overconsumption.
Appetite and satiety
There are multiple mechanisms that decrease satiety and increase appetite in obesity. These include gastric motor and sensory functions; production of the appetite-promoting acyl ghrelin by the P/D1 cells of the stomach fundus;[12, 13] a blunted response of the afferent vagus nerve to ingestion of a meal; and impaired release of other gastrointestinal hormones such as CCK, obestatin, GLP-1, or PYY, which usually inhibit gastric emptying and contribute to reduced appetite.[14-16]
These pathophysiological changes in obesity are well characterized in animal models; however, in humans these findings have not always been consistent, as illustrated in the case of gastric emptying that may be slow, normal, or fast in different studies.[17, 18] Nonetheless, the most prevalent gastric dysfunction in obese subjects (when compared to lean controls) is rapid gastric empting of solids.[19-25] High-fat diets retard gastric emptying. However, the alteration in gastric emptying in obesity does not appear to be related to the choice of macronutrient. Different types of high but equicaloric diets (high-fat, high-protein, or high-carbohydrate diets or balanced nutrient content) do not differentially affect gastric emptying or gastric volume in humans.
Several signaling molecules and pathways involved in the control of food intake and obesity are associated with changes in gastric function (Table 1).[27-31] The potential role of these signaling mechanisms in the development of obesity is also illustrated by the effects of genetic variations in the control of the ligand or its receptor, the effect of obesity on the signaling mechanism, and the potential therapeutic effects of pharmacological doses of the gut hormone or peptide (Table 1).
Table 1. Signaling molecules and pathways involved in the control of food intake and obesity and their effects on gastrointestinal functions and food intake
GLP-1R SNPs associated with altered β cell responsivity to GLP-1
Decreased in obese T2DM
Induces weight loss and glycemic improvement
Decreases FI and induces weight loss
Delayed GE; mediator of ileal brake
SNPs associated with obesity
Decreased in obesity in some studies
Induces weight loss
Decreased in obesity
At present, the lipase inhibitor orlistat and most of the medications (e.g., sibutramine, GLP-1 agonists, pancreatic polypeptide, fenfluramine–phentermine,[34, 35] and peptide YY) used to induce weight loss produce effects on the gut, such as fat malabsorption and a delay in gastric emptying.[36, 37] It is still unclear whether obesity medications affect gastric capacitance or satiation, with the exception of sibutramine, which caused significant retardation in gastric emptying of solids, reduced maximum tolerated volume (increased satiation), and increased postprandial peptide YY, but did not affect gastric capacity, compared with placebo.
Gut hormones and calorie consumption
The small intestine is the site of digestion and absorption of most nutrients; alterations in the normal physiology of the small intestine allow an overconsumption of calories. Examples of these alterations are (1) individuals with mutated small intestinal hormones (e.g., genetic polymorphisms of the PYY gene) tend to become obese; (2) obese individuals have lower concentrations of small intestinal hormones, such as CCK, GLP-1,[16, 40] OXM, and FGF-19 (Table 1); and (3) obese individuals with insulin resistance may have an increase in small intestinal enterocyte mass compared to obese individuals without insulin resistance.[43, 44]
Energy balance is a complex mechanism in which the gastrointestinal and central nervous systems are tightly connected (reviewed in detail in Ref.  and elsewhere). Orexigenic gastrointestinal hormones such as ghrelin activate the neuropeptide Y/agouti-related peptide (NPY/AGRP) appetite pathway in the arcuate nucleus of the hypothalamus, and anorexigenic gastrointestinal hormones such as GLP-1 or PYY3-36 inhibit the NPY/AGRP pathway and stimulate the proopiomelanocortin/cocaine/amphetamine-related transcript (POMC/CART) pathway in the arcuate nucleus of the hypothalamus to induce satiation and satiety and stop food intake. The arcuate nucleus sends signals to the paraventricular nucleus and the lateral hypothalamic area. In the brain stem, orexigenic and anorexigenic gut hormones modulate the nucleus of the tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMNV) and convey signals to the hypothalamus and higher brain areas. The effects on the hypothalamus and brainstem trigger higher brain–area responses, modulating behavior (e.g., initiating or stopping eating) and enhancing nutrient-related reward.
Emerging evidence suggests interaction of the human gut microbiome with metabolic and gastrointestinal systems.[46-48] Gut bacteria are essential in deconjugation, dehydrogenation, and dehydroxylation of primary bile acids in the distal small intestine and colon. The microbiota contribute to breaking down otherwise indigestible carbohydrates and increasing short-chain fatty acid absorption in the colon, providing additional energy and increasing fat storage in adipose tissue.[46, 47] The microbiota in obese subjects appear to be different from those of lean subjects.
Gastrointestinal morbidity in obesity
Obesity is a state of low-grade chronic inflammation that affects the whole body including the gastrointestinal organs. Compared to what is seen in people of lean body weight, the overweight or obese phenotype is associated with increased tissue inflammatory cytokines, activated immune responses, and altered cell signaling of metabolic pathways.[51, 52] In general, low-grade chronic inflammation and changes in metabolic hormones and the distribution of the adipose tissue in the abdominal cavity in obesity participate in the development of gastrointestinal morbidity.
Many esophageal disorders are related to obesity
The excess of body weight, especially an increase in the abdominal girth, produces higher intra-abdominal pressure and higher gastric acid production, reduces lower esophageal sphincter pressure, reduces the intra-abdominal length of the lower esophageal sphincter, and induces esophageal motor dysfunction.[53, 54] Independent of abdominal waist circumference, obesity is also associated with increased acid exposure.[54, 55] The mechanism of obesity-related hyperacidity may be based on increased estrogen levels compared to age and gender-adjusted normal-weight individuals. Increased estrogen levels are strongly associated with increased acid exposure and GERD, and this association is stronger in women than in men.[56-58] These pathophysiological changes can produce regurgitation, esophagitis, and GERD, which can progress to Barrett's esophagus and esophageal adenocarcinoma.
Gastroesophageal reflux disease
GERD is a chronic disorder characterized by the symptoms of heartburn and regurgitation that occur when gastric acid or bile reflux from the stomach to the esophagus. The gastric refluxate produces inflammation of the lining of the esophagus. The prevalence of GERD has increased significantly in the last 15 years, in parallel with the increased prevalence of obesity. Two meta-analyses have shown a positive association between body weight (BMI) and GERD.[59, 60] The association of BMI and GERD is stronger in obese women than in obese men; this difference has been attributed to increased estrogen levels in women. The association of BMI and GERD is stronger in Caucasians than in other ethnicities. The strong association between obesity and GERD is reinforced by improvement of GERD symptoms after weight loss. The American College of Gastroenterology, therefore, recommends weight loss to patients with GERD who are overweight/obese or recently gained weight.
Erosive esophagitis is the inflammation of the mucosa of the esophagus secondary to GERD. The risk factors for developing erosive esophagitis are male gender, older age, chronic alcohol intake, chronic smoking, increased BMI, and long history of GERD. Several meta-analyses have demonstrated the association of a higher BMI, increased waist circumference, and/or increased waist-to-hip ratio with erosive esophagitis and its severity.[60, 65, 66] Patients with central adiposity have a 1.87-fold higher risk of developing erosive esophagitis compared to normal-weight controls, and this effect of central adiposity (orange shape) is independent of body weight (OR 1.87; 95% CI: 1.51–2.31). In contrast, the increase in hip circumference or gluteofemoral (pear-shaped) obesity is inversely related to erosive esophagitis and Barrett's esophagus. These findings show that gluteofemoral obesity has a protective role in developing erosive esophageal disease in addition to being protective for progression to T2DM and CVD.
Barrett's esophagus describes metaplasia in which the normal squamous cell epithelium of the distal esophagus is replaced by a specialized columnar epithelium. Barrett's esophagus is usually a consequence of chronic GERD and predisposes to adenocarcinoma of the esophagus.[69-71] As with GERD and erosive esophagitis, multiple studies have shown an association between obesity, abdominal circumference, and metabolic syndrome and Barrett's esophagus.[68, 70, 72] Subsequent meta-analyses have shown that BMI and abdominal adiposity (measured by waist circumference) may be indirect risk factors for Barrett's esophagus owing to the relationship with GERD. The association of Barrett's esophagus with abdominal adiposity is even stronger when adjusted for BMI or GERD, suggesting that abdominal adiposity is an independent risk factor for developing Barrett's esophagus. The mechanism for the independent association of abdominal adiposity with Barrett's esophagus may be explained by higher levels of leptin, decreased levels of low molecular weight adiponectin, and increased cytokines that mediate chronic inflammation.[74-76] Although these mechanisms are not specific for abdominal obesity, further studies are needed to understand the independent association of abdominal adiposity with Barrett's esophagus.
Esophageal adenocarcinoma incidence rates are rising dramatically, likely owing to the increased prevalence of Barrett's esophagus, erosive esophagitis, and GERD. These conditions are all associated with obesity and abdominal adiposity. In subjects with Barrett's esophagus, obesity is directly associated with progression to adenocarcinoma, suggesting that obesity may at least modify the risk of developing adenocarcinoma. Higher levels of leptin and lower levels of adiponectin have been proposed as markers of progression to adenocarcinoma. In a meta-analysis of 2488 cases of esophageal adenocarcinoma, there was a strong association with obesity (males: OR 2.4, 95% CI: 1.9–3.2) and (females: OR 2.1, 95% CI: 1.4–3.2). In another meta-analysis, there was significantly higher risk of esophageal adenocarcinoma with increased central adiposity (OR, 2.51; 95% CI: 1.56–4.04) when compared to normal body habitus.
Many molecular pathways link obesity, metabolic syndrome, and cancer. First, increased insulin and insulinlike growth factor (IGF) might provide a mechanistic link between obesity and esophageal adenocarcinoma.[79, 80] Second, IGF-1 and IGF-2 increase angiogenesis and cell proliferation and decrease apoptosis. Third, elevated cytokines secondary to obesity-induced chronic inflammation induce vascular endothelial growth factor (VEGF), decrease adiponectin, and increase leptin. Leptin stimulates cell proliferation by activating epidermal growth factor receptor (EGFR) and inhibits apoptosis in esophageal cells. Histopathological studies of esophageal adenocarcinoma from obese patients have shown upregulated expression of leptin and adiponectin receptors in the esophageal tumor.
Obesity increases the prevalence of esophageal motility disorders. In one study, esophageal transit time was significantly prolonged in obese subjects compared to lean subjects. The increased esophageal transit time is considered to be a consequence of increased gastric and gastroesophageal junction resistance. In two cohorts of 111 and 116 obese patients who underwent esophageal manometric studies before surgery, 61% of patients had typically nonspecific manometric abnormalities of esophageal peristalsis and a wide range of lower esophageal sphincter (LES) dysfunction, including isolated hypertensive LES pressure (>35 mmHg, 3–14%), isolated hypotensive LES pressure (<12 mmHg, 3%), diffuse esophageal spasm (1–7%), and achalasia (1%).[85, 86] However, the specificity and significance of these findings are unclear in the absence of lean control studies.
While obesity alters the gastric physiology and its neural–hormonal–enteric regulation, it is unclear whether gastric function abnormalities are the causes or the consequences of obesity. Obesity is associated with symptoms that may arise in the stomach, such as upper abdominal pain, nausea, vomiting, retching, and gastritis.[87, 88]
Erosive gastritis, similar to erosive esophagitis, is an endoscopic and histological diagnosis defined as inflammation in the mucosa of the stomach. Gastritis can be acute or chronic and can lead to ulceration and bleeding. Obesity is a risk factor for erosive gastritis and gastric and duodenal ulcer.[89, 90] Yamamoto and colleagues suggested that there is an association of low adiponectin with erosive gastritis, independent of BMI or Helicobacter pylori infection. Adiponectin is reduced in abdominal obesity and metabolic syndrome and is the mediator of comorbidities related to obesity.
Obesity is considered a proinflammatory and procarcinogenic state and is becoming one of the most important modifiable risk factors for cancer, including gastric cancer. The association of gastric cancer and obesity was summarized in a meta-analysis that showed that excess BMI was associated with an increased risk of gastric cancer. A subsequent larger meta-analysis found that obesity was associated mainly with an increased risk of gastric cardia cancer. It is not clear if the association is related to other confounders such as an association of obesity with H. pylori infection. There are data supporting the concept that obesity accelerates H. pylori–mediated gastric carcinogenesis.
The small intestine is the site of digestion and absorption of most nutrients. As with the stomach, the small intestine adapts to caloric overconsumption; in addition, alterations in the normal physiology of the small intestine allow an overconsumption of calories.
The prevalence of diarrhea is higher in obese patients compared to normal-weight controls. A population-based survey study in Rochester, Minnesota of 2,660 people showed that the prevalence of diarrhea in obese individuals was 30% compared to 17% in normal-weight controls (OR 2.7, 95% CI: 1.1–6.8). Similar studies have been replicated in Australia and New Zealand.[98, 99] The higher prevalence of diarrhea could be attributed to changes in bile acids, resulting in bile acid diarrhea, to increased colonic transit, and/or to increased permeability (Figure 2).[102, 103] Obesity is also associated with increased levels of fecal calprotectin, a marker of intestinal inflammation. Medications used by obese individuals, such as metformin for T2DM or polycystic ovary syndrome, may also cause diarrhea.
Celiac disease is an immune disease triggered by gluten and mainly affects the small intestine. The typical presentation is weight loss, diarrhea, and malabsorption. Paradoxically, the recognition and prevalence of celiac disease in the obese population are increasing. In patients with newly diagnosed celiac disease, the prevalence of obesity varies from 39% to 44%.[106, 107] Obese patients with celiac disease are more likely to gain more weight on a gluten-free diet.[106, 108] Similar finding are reported in children with celiac disease.
Inflammatory bowel disease
Inflammatory bowel diseases (IBD)—Crohn's disease or ulcerative colitis—are autoimmune disorders that mainly target the small bowel and colon. In a case–control study, there was a U-shaped association between BMI and Crohn's disease. Patients who are underweight or overweight are more likely to have Crohn's disease. These findings were not reproduced in a recent European cohort, which showed no association between obesity and IBD in adults. On the contrary, in children, the prevalence of obesity in IBD is similar to that in the general population, but obese children with IBD have a more severe disease than those of normal weight.
Colon and rectum
The association between obesity and constipation is controversial. Delgado-Aros et al. showed that the prevalence of constipation is higher in obese people in a community-based epidemiological study; these findings were not reproduced in other large cohort studies. In children, constipation, but not constipation-predominant irritable bowel syndrome, is more common in obese individuals.[113, 114]
Diverticulosis and diverticulitis become more common in the colon with aging. Obesity is associated with a higher risk of developing diverticulosis, and obese individuals exhibit more diverticular bleeding and recurrent diverticulitis than normal-weight individuals.
There are three main types of polyps in the colon: adenomas and serrated and hyperplastic polyps. Adenomas and serrated polyps predispose to colon cancer. Several studies have documented the increased prevalence of adenomatous polyps with higher BMI (OR 2.1, 95% CI: 1.4–2.3) or obesity (OR 2.16, 95% CI: 1.13–4.14). This association was stronger in women (OR 4.42; 95% CI: 1.53–12.78) than in men (OR 1.26, 95% CI: 0.52–3.07). The study also found that weight gain is another risk factor for adenomas (OR 2.30, 95% CI: 1.25–4.22). The association between higher BMI and colonic adenomatous polyps has been validated in other cohorts and populations.[119-123] Similarly, obesity is associated with an increased risk of adenoma recurrence. Obesity is also associated with a higher risk of sessile serrated polyps of the colon (OR 2.57, 95% CI: 1.75–4.90), with even stronger association if the serrated polyp is larger than 1 cm (OR 3.96, 95% CI: 1.27–12.36).
Colorectal cancer is the fourth most common cancer in the United States. The incidence of colon cancer is similar in men and women and increases with age; 90% of cases of colorectal cancer occur after age 50. Multiple meta-analyses in over 70,000 cases of colon cancer show obesity as a risk factor.[126-129] For every increase in BMI of 5 kg/m, the risk of colon cancer increases by 18%. The association of obesity and colorectal cancer is stronger in men than in women (RR 1.24, 95% CI: 1.20–1.28 for men, and RR 1.09, 95% CI: 1.04–1.12 for women). The risk of colorectal cancer increases with a higher waist circumference (RR 1.33, 95% CI: 1.19–1.49 for men, and RR 1.16, 95% CI: 1.09–1.23 for women). The relationship between obesity, abdominal adiposity, and colon cancer is likely to be multifactorial, owing to changes in leptin, adiponectin, the microbiome, secondary bile acids, and insulin resistance, and has been extensively reviewed elsewhere.
Anal canal and pelvic floor
Female patients have a higher likelihood of experiencing constipation secondary to pelvic floor disorders (83% in one large series of 390 female patients) and, particularly, constipation associated with descending perineum syndrome, which is usually associated with multiparity and is almost exclusively observed in females. However, it is unclear whether BMI is an independent risk factor in constipation associated with these pelvic floor disorders.
Fecal incontinence, defined as the inability to control bowel movements, producing undesired leakage of stool from the rectum, has been associated with a higher BMI, but the association has been weak or not statistically significant. Studies report a range of results from no association to up to 69% of obese subjects having fecal incontinence.[87, 133]
It has been proposed that, in the Western world, obesity and nonalcoholic fatty liver disease (NAFLD) will be leading risk factors for cirrhosis in the next decade, especially because of the recent advances in the treatment of viral hepatitis and the increasing epidemic of obesity. Additionally, NAFLD is strongly associated with metabolic syndrome, CVD, and T2DM, as the liver is an essential organ in the regulation of digestion, energy distribution, and fat storage, and the latter may lead to lipotoxicity, which may be the mechanism for development of metabolic syndrome, insulin resistance, and diabetes.
Nonalcoholic fatty liver disease
Nonalcoholic fatty liver disease is the accumulation of fat in the liver in the absence of other possible causes such as alcohol. Obesity contributes to the accumulation of lipid in the liver by increasing uptake of free fatty acids into the liver, impairing fatty acid β-oxidation, or increasing the incidence of de novo lipogenesis. NAFLD is subclassified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The main difference between NAFL and NASH is the degree of hepatic inflammation, which may be indistinguishable from alcoholic steatohepatitis. The worldwide prevalence of NAFLD is 20% (range 6–35%) and in the United States the prevalence range is 10–46%. The prevalence of NAFLD in obese adults is as high as 90–95%, and in diabetics it is up to 70%. Obese persons have up to 4.6-fold higher risk (95% CI: 2.5–110) of developing hepatic steatosis compared to lean controls. Around 20% of patients with NAFLD will progress to NASH, and 20% of those with NASH will end up having cirrhosis. NAFLD is currently the third most common cause of hepatocellular carcinoma (HCC) in the United States, after viral hepatitis and alcoholic cirrhosis. It is intriguing that one-third of the cases of HCC occurred in the absence of NAFLD-associated cirrhosis.[138, 139] There was a strong association between obesity (adjusted HR, 4.1; 95% CI: 1.4–11.4) or being overweight (adjusted HR, 1.93; 95% CI: 0.7–5.3) and cirrhosis-related death or hospitalization.
Treatment of NAFLD is based initially on weight loss and physical activity: Loss of at least 3–5% of body weight appears necessary to improve steatosis, but a greater weight loss (up to 10%) may be needed to improve necroinflammation.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Obesity, possibly due to associated low-grade chronic inflammation, has been associated with the risk of all cancers, including HCC. Case–control and cohort studies concluded that the relative risk (RR) of HCC was 1.17 (95% CI: 1.02–1.34) for overweight and 1.89 (95% CI: 1.51–2.36) for obese patients. Furthermore, abdominal obesity was associated with a 3.51-fold increase in RR for HCC (95% CI: 2.09–5.87), and general obesity was an independently significant risk factor. The effect of obesity on HCC is likely due, in part, to NAFLD and low-grade inflammation. Additionally, obese patients with HCC have a poor prognosis when compared to a nonobese group.
Obesity has been well recognized for its strong association with gallstone diseases.[150, 151] Obese subjects have a higher incidence of cholelithiasis, cholecystitis, and cholesterolosis when compared to lean controls. A meta-analysis showed that the risk for gallbladder disease in men was 1.63 (95% CI: 1.42–1.88) for overweight and 2.51 (95% CI: 2.16–2.91) for obesity; in women, the RR was 1.44 (95% CI: 1.05–1.98) for overweight and 2.32 (95% CI: 1.17–4.57) for obesity. Abdominal circumference is a risk factor for gallstone diseases, independent of BMI.[154, 155] These associations have been attributed to abdominal adiposity, hyperinsulinemia, insulin resistance, hyperleptinemia, hyperlipidemia, and gallbladder dysmotility.[150, 156-158]
Obesity and fat infiltration of the pancreas play significant roles in the endocrine pancreatic dysfunction that leads to the development of type 2 diabetes mellitus (further details are not pertinent to this review). Obesity has also been associated with pancreatitis and pancreatic cancer.
Acute pancreatitis is defined as inflammation of the pancreas and can be mild to fulminant, with mortality up to 20% in severe necrotizing pancreatitis.[160, 161] In a meta-analysis, obese subjects had an increased risk of developing severe acute pancreatitis (RR, 2.20, 95% CI: 1.82–2.66), higher risk of local (RR, 2.68, 95% CI: 2.09–3.43) and systemic complications (RR, 2.14, 95% CI: 1.42–3.21), and higher risk of in-hospital mortality (RR, 2.59, 95% CI: 1.66–4.03) when compared to lean subjects. These associations have been attributed to low-grade chronic inflammation and low levels of adiponectin.[144, 162, 163]
Pancreatic cancer is the ninth most common cause of cancer worldwide. Multiple meta-analyses have reported an association between BMI, as well as abdominal obesity, and the occurrence of adenocarcinoma of the pancreas. A recent meta-analysis showed a 10% increased risk in women and 13% increased risk in men for every 5 units increase in BMI (95% CI: 1.04–1.22). Additionally, for every extra 10 cm of waist circumference, there was an 11% increased risk of pancreatic cancer (RR, 1.11, 95% CI: 1.05–1.18).
Table 2 summarizes the quantified risks of gastrointestinal disorders in obesity. The increased prevalence of gastrointestinal morbidity in the general population may be related to the increased prevalence of obesity in Western countries. Thus, it is important to recognize the role of higher BMI and, particularly, increased abdominal adiposity in the development of gastrointestinal morbidity, which are sometimes neglected because of the effects of obesity on diabetes mellitus and cardiovascular disease that deservedly demand the physician's attention.
Table 2. Quantified risk ratios of gastrointestinal disorders in obesity
In conclusion, gastrointestinal disorders are directly caused by obesity, although understanding the association between obesity and gastrointestinal morbidity is limited by the lack of studies analyzing the effects of weight loss as potential therapy or risk reduction in gastrointestinal morbidity; for example, it is unclear whether there is resolution of GERD or chronic diarrhea after significant nonsurgical weight loss in obese patients. Furthermore, the gastrointestinal system plays an essential role in the development of obesity through its modulation of appetite, satiation, and satiety. The role of the gastrointestinal tract is emphasized by the observation that the most effective treatment for obesity is bariatric surgery, which alters the gastrointestinal anatomy and causes metabolic adaptations to energy intake.
M. Camilleri is supported by NIH Grant RO1-DK67071.