Obesity is a leading cause of illness and death worldwide.^{[1] and [2]} It is one of the greatest public health challenges of this century, with more than 1.6 billion adults classified as being overweight and 400 million as obese.³ From 1980 to 2002, rates of obesity more than doubled in the United States, reaching 32% in the adult population, thus achieving the highest rates of obesity in the developed world.⁴ Although overall obesity rates began to plateau in the 2000s, severe obesity in adults and children has continued to increase.⁵ The most dramatic increases have occurred in class III obesity (body mass index [BMI] ≥40), with an increase from 0.78% in 1990 to 2.2% in 2000.⁵

As the rates of obesity have escalated, it is more than just waistbands that have expanded. Obesity is a risk factor for some of the most prevalent diseases in North America, including coronary artery disease, stroke, diabetes mellitus, hypertension, and osteoarthritis.⁶ Moreover, common digestive disorders, such as gastroesophageal reflux, esophagitis, nonalcoholic fatty liver, gallstones, and certain cancers, arise with greater frequency in obese individuals compared with normal-weight individuals (Table 1).⁷

Obesity-related health care costs have also ballooned. Americans who are obese now make up a quarter of the population and are responsible for a 40 billion-dollar rise in annual medical spending.⁸ On average, an obese person spends more than 1400 dollars for his or her medical care annually, almost 42% more than is spent by a nonobese person.⁸ Although there are no current recommendations for testing in the absence of symptoms or preexisting laboratory abnormalities, weight loss is a recommended strategy to prevent the symptoms that are related to obesity-related gastrointestinal disorders and to decrease the risk of progression of diseases.⁷

Gastrointestinal symptoms related to obesity and obesity treatments

Generally defined as a BMI of 30 kg/m² or more (less accurate in body builders and pregnant women), obesity has been linked to a wide range of gastrointestinal symptoms.^{[9], [10], [11] and [12]} Disruption of mechanisms that regulate appetite and satiety is fundamental to the development of obesity.⁹ Acid regurgitation, heartburn, and diarrhea are some symptoms that are reported with increased frequency in obese subjects compared with normal-weight subjects (Table 2).¹³ Pharmacologic and surgical treatments of obesity, by altering gastrointestinal function through mechanisms that regulate hunger, food intake, or absorption of nutrients, influence the energy consumed and meal termination.^{[14], [15], [16] and [17]}

Gut hormones and regulation of appetite and satiety

There are 3 primary mechanisms that control appetite: 1) the hypothalamus serves as the center for the integration of feeding and associated neuroendocrine and gastrointestinal activities; 2) the gastrointestinal tract provides a rich source of hunger and satiety factors that modulate meal intake and termination^{[9] and [18]}; and 3) adipose-derived leptin is involved in the long-term regulation of energy intake and expenditure.^{[19], [20] and [21]}

The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones exert exocrine actions, regulate the secretion of insulin, and central nervous system circuits that control food intake, and influence gut motility.²² They interact with the brain via the gut-brain axis through which they modulate peptide neurotransmitter release via hypothalamic and brainstem centers (Fig. 1). Apart from ghrelin, most gut peptides known to influence appetite, including insulin,²³ glucagon-like peptide 1 (GLP-1),²⁴ peptide YY (PYY),²⁵ oxyntomodulin (OXM),²⁶ cholecystokinin (CCK),^{[27] and [28]} and pancreatic polypeptide (PP),²⁹ do so by inducing satiety and some also by affecting intestinal motility.

Ghrelin, a hormone that is synthesized primarily in the epithelial P/D1 cells of the gastric fundus,^{[18], [30] and [31]} is an agonist of the growth hormone receptor and a member of the motilin-related family of regulatory peptides. Ghrelin stimulates appetite and induces a positive energy balance, thus leading to body-weight gain in addition to its ability to stimulate growth hormone secretion and to accelerate gastric motility.¹⁸ Ghrelin modulates the synthesis and secretion of several neuropeptides in the hypothalamus that stimulate feeding and regulate related hypothalamic functions.¹⁸ Unique among gut hormones, plasma ghrelin levels gradually increase with fasting and decrease immediately after a meal, supporting a role in meal initiation.^{[18], [32] and [33]} Plasma ghrelin levels also increase with diet-induced weight loss,^{[34] and [35]} which suggests that ghrelin may act to counter diet-induced weight loss by invigorating hunger and increasing energy intake.

Insulin is secreted by the Islets of Langerhans in the pancreas to promote storage of energy; its circulation is increased in response to food intake and in states of obesity.³⁶ Insulin receptors are expressed in the CNS³⁷ and injections of insulin into the brain of insulin-deficient animals can markedly reduce eating behavior.³⁸ Adipocyte-derived leptin an important anorexigenic hormone that like insulin, is involved in long-term energy homeostasis. Leptin is secreted in response to a positive energy balance, and circulated to the hypothalamus and other regions of the brain inducing negative feedback responses.^{[39] and [40]} The actions of ghrelin and leptin are complimentary, yet they are antagonistic in that they modulate appetite, gastric motility, and body weight by counterregulating the same hypothalamic signals, neuropeptide Y (NPY) and agouti-related peptide (AgRP). NPY and AgRP are two extremely potent orexigenic peptides of the arcuate nucleus (AR) within the hypothalamus that together act to reduce energy expenditure.^{[18], [41], [42] and [43]} In addition to the inhibition of orexigenic neurons within the AR, leptin also stimulates the activity of proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), two anorexigenic hypothalamic neurons that contribute to increased thermogenesis and energy expenditure.^{[44], [45] and [46]} Within the AR these anatomically distinct neuronal populations provide overlapping projections to other key parts of the hypothalamus implicated in the control of feeding. As a therapeutic agent, leptin held great promise. However, exogenous administration of supraphysiologic doses of leptin failed to produce any notable diminution in appetite or weight loss.⁴⁷ To date, obesity-related resistance to the action of leptin has limited its therapeutic effectiveness.⁴⁸

GLP-1, which is coreleased postprandially with PPY and OXM from L cells of the small intestine in proportion to the amount of energy consumed, acts as a powerful incretin, enhancing meal-related insulin secretion.⁴⁹ Clinically, long-acting GLP-1 receptor agonists (such as exendin-4) facilitate glucose control by several different mechanisms, promote a subtle yet prolonged satiety effect, and improve glycemic control when used as adjunctive therapy in patients with type 2 diabetes receiving metformin.⁵⁰ GLP-1 has been shown to delay gastric emptying and intestinal transit time.⁴⁹ Gastrointestinal inhibitory peptide (GIP), another incretin peptide, is secreted from K cells in the duodenum and proximal jejunum in the presence of glucose and fat within minutes of food ingestion.²² Although GIP promotes energy storage through direct action on adipose tissue, it is not known to have an effect on food intake.²²

PYY3-36, the major form of PYY, reduces acute food intake in normal-weight humans¹⁶ by modulating appetite circuits in the hypothalamus. PYY has high affinity for the Y2 family of receptors of the hypothalamus, and it inhibits orexiant NPY neurons, activates anorexiant POMC neurons and α-MSH hormone, and may contribute to its anorectic effect through actions on the vagus and brainstem.^{[16], [25] and [51]} The physiologic effects of PYY3-36 include delayed gastric emptying and reduced gastric secretion, and PYY has been implicated as a major constituent of the ileal brake.^{[3] and [52]}

Digestion of lipids results in the release of PP, the amount secreted being proportional to the calorie content of the meal.⁵³ PP is considered a long-term appetite suppressant with peripheral administration in obese mice, resulting in reduced food intake and slowed weight gain.⁵³ The mechanism that mediates PP satiety effect remains unknown, although it is known to stimulate the Y2 receptors in the hypothalamus and may directly activate neurons in regions of the AR.²² The actions of OXM are to diminish gastric secretion and reduce food intake when administered centrally to rodents or peripherally to rodents or humans.^{[26] and [54]} OXM increases energy expenditure by more than 25% and reduces food intake, body weight, and adiposity in rodents.⁵⁵ A discrete receptor for OXM has not been identified, yet OXM does bind to the GLP-1 receptor and has been shown to cause similar patterns of central neuronal activation after peripheral administration.⁵⁶

The anorexiant effect of CCK was recognized more than 30 years ago.⁵⁷ CCK is synthesized by L cells of the small intestine and secreted in the proximal duodenum. CCK-1 receptors are primarily expressed by vagal afferent neurons, the targets by which CCK is thought to produce the sensation of satiety.⁵⁸ The half-life of CCK is just 1 to 2 minutes, suggesting it may serve as a short-term regulator of appetite. Animal studies have shown administration of CCK to reduce food intake but increase meal frequency without affecting the body weight.⁵⁹ Biologic functions of CCK include delayed gastric emptying, stimulation of pancreatic enzyme secretion, and gallbladder contraction.^{[60] and [61]}

Circulating levels of these gut hormones and those of the central nervous system can be affected by increased or decreased adiposity, pharmacotherapy, and gastrointestinal bypass surgery.

Effect of obesity treatments on gastrointestinal symptoms

Of the two Food and Drug Administration–approved medications for the long-term treatment of obesity, sibutramine acts as anorexiant, whereas orlistat impairs the digestion and absorption of dietary fat.¹⁴ Anorexiants increase satiation (level of fullness or meal-related satisfaction), which regulates the amount of food consumed or the level of satiety (absence of hunger) and determines the frequency of eating.⁶² Sibutramine is a centrally acting serotonin and noradrenaline reuptake inhibitor that inhibits appetite and induces thermogenesis, thus contributing to reduced energy intake with enhanced energy expenditure.⁶³ Predictably, fat malabsorption that occurs with the use of orlistat results in oily and frequent bowel movements, fecal urgency, and flatulence. With continued use, deficiencies in the fat-soluble vitamins A, D, E, and K may occur.⁶⁴

All surgeries that restrict gastric luminal capacity cause satiety when solid food is ingested, leading to reduced calorie intake and loss of weight.⁶⁵ Nausea, bloating, and vomiting are common after bypass surgery owing to restricted anatomy and altered motility.⁶⁵ These symptoms may subside with increased fluid intake, reduced food volume, chewing food well, and slow eating, although testing to exclude dehydration or a complication of surgery may be warranted if symptoms persist. Small intestine bacterial overgrowth is a frequent late complication of gastric bypass, as established by elevated serum folate levels and detection of abnormal glucose-hydrogen breath testing.^{[66], [67] and [68]} Symptoms of bacterial overgrowth may include abdominal bloating, nausea, abdominal cramping and discomfort, steatorrhea, flatulence, anemia, and weight loss.

Gastric bypass can result in dumping syndrome when high-density carbohydrates are consumed.⁶⁹ Early dumping symptoms comprise both gastrointestinal (nausea, vomiting, abdominal pain, diarrhea and bloating) and vasomotor symptoms, whereas late dumping symptoms are the results of reactive hypoglycemia.⁷⁰ Rapid gastric emptying that delivers a significant proportion of nutrients quickly to the small intestine as well as large, difficult-to-digest particles contributes to the pathogenesis of this syndrome. The result is a fluid shift from the intravascular component to the intestinal lumen, which results in cardiovascular symptoms, release of several gastrointestinal and pancreatic hormones, and late postprandial hypoglycemia.⁷⁰ Nutrient diversion into the distal small intestine causes iron and B12 deficiency anemia and thiamine deficiency⁷¹ and may also worsen lactose intolerance. After gastric bypass, patients may experience constipation caused by decreased food or water intake, or in some patients, iron supplementation, narcotics, or antidepressants.⁷² They may also experience diarrhea that can be related to dietary fat. Reduced fat intake or supplementation of a small amount of pancreatic enzymes may reduce symptoms. With rapid weight loss, there is an increased risk for developing gallstones. About 1 in 10 people with gastric bypass will experience problems from gallstones and will need their gallbladders to be removed.⁷³ In the postbariatric setting, additional gastrointestinal symptom–related problems may include intestinal obstruction, migration of mechanical devices (vertical banded gastroplasty), fistula formation, disruption of suture lines, and chronic nutritional deficiencies (malabsorption) associated with a range of gastrointestinal complaints.^{[69] and [74]}

Effect of bariatric surgery on gut hormones

Gastric bypass is a surgical technique that combines gastric restriction with bypass of the stomach to variable lengths of the small intestine that leads to significant, sustained weight loss in patients with severe obesity.^{[75] and [76]} Small gastric pouch size is a key determinant in the early satiation and persistently suppressed appetite that occurs after this type of surgery.^{[77] and [78]} Malabsorption does not appear to play as large a role in weight loss after a short-limb intestinal bypass compared with that played after long-limb bypass.⁷⁶ Yet, as bypass surgery seems to be more beneficial in achieving sustained weight loss than purely restrictive gastric surgery, it was hypothesized that interference in other factors affecting energy balance may add to the effectiveness of this type of surgery.^{[78] and [79]} Roux-en-Y gastric bypass has been shown to cause a decline in plasma ghrelin levels in most subjects^{[32], [34], [41] and [80]} and a distinct increase in GLP-1 and PYY plasma levels compared with gastric banding and control patients,⁷⁸ possibly contributing to the significant and lasting weight-reducing effects of the procedure.^{[78] and [80]} In patients experiencing poor weight loss after gastric bypass procedures, the postprandial PYY and GLP-1 responses were attenuated compared with patients with good postoperative weight loss.⁸¹ Inhibiting the satiety gut hormone responses with octreotide after successful RYGB resulted in the return of appetite and increase in food intake.^{[81] and [82]} It seems that bariatric surgery provides a stimulus to the distal small intestine mucosal endocrine L cells, resulting in an increase in PYY, GLP-1, and many of the enteroglucagon family of gut peptides.^{[81] and [82]}

Laparoscopic adjustable gastric banding surgery involves the creation of a small gastric pouch by securing a modifiable restrictive gastric band just below the gastroesophageal junction.⁸³ The band can be adjusted to achieve desired weight and nutritional outcomes. In a randomized controlled trial that compared optimal with lesser gastric band restriction, optimal restriction was associated with greater fasting and postprandial satiety levels (P<.01), whereas plasma ghrelin, leptin, and insulin levels did not change between optimal and reduced restriction and were not significantly different from normal levels.⁸³

Overall, gut hormones that are affected by bypassing the stomach and proximal small intestine and by enhanced nutrient delivery to the distal intestine may play a major role in mediating weight loss after gastric bypass.^{[84] and [85]}

Gastrointestinal symptoms associated with increased BMI

Several studies have demonstrated an association between obesity and gastrointestinal symptoms.^{[9], [10], [86] and [87]} In a population-based study, acid regurgitation, heartburn, food staying in the stomach, vomiting, nausea, upper abdominal pain, bloating, and diarrhea occurred more often in obese patients with binge-eating disorders (see Table 2).¹³ In this study, an increase in body weight of more than 4.5 kg during a 10-year period was associated with the onset of new gastrointestinal symptoms.¹³ BMI is an independent risk factor for the presence of self-reported heartburn, regurgitation, and bloating in a United States community-based population.⁹

In a meta-analysis, Nguyen and El-Serag⁸⁸ showed that a high BMI was associated with an increased risk of heartburn, regurgitation, and water brash compared with a normal BMI. Overweight and obesity have been shown to be the strong independent risk factors of gastroesophageal reflux disease (GERD) symptoms and erosive esophagitis,⁸⁹ with the suggestion of a dose-response relationship.

Gastrointestinal diseases related to obesity

Obesity has been shown to be a risk factor for many gastrointestinal disorders (see Table 1).⁷

Obesity and the Esophagus

An increase in the prevalence of obesity and GERD in Western populations during the past 50 years suggests that an association exists between these 2 conditions, with most epidemiologic studies supporting this conclusion.⁹⁰ Clinical trials that examined the relationship of increased BMI and GERD-related disorders found that a high BMI was associated with a 1.5- to 2.5-fold increase in the risk of GERD and its complications, including symptoms of heartburn and regurgitation, erosive esophagitis, and esophageal adenocarcinoma.^{[91] and [92]} In a recent meta-analysis, increased BMI was strongly associated with esophageal adenocarcinoma in men (relative risk of 1.52, P<.0001) and in women (1.51, P<.0001).⁹³ Abdominal diameter but not BMI is associated with a 2-fold increased risk of developing Barrett esophagus (BE).^{[94], [95] and [96]} Obesity is only an indirect risk factor for developing BE, with BMI status having no predictive value with respect to the progression of symptoms to BE.⁹⁷ Truncal obesity poses a higher risk for developing BE in male Caucasians than peripheral obesity.^{[88] and [94]} Anatomic and physiologic obesity-related changes, including reduced lower esophageal sphincter pressure, presence of a hiatal hernia, increased intragastric pressure, and esophageal motility disorders, may account for some of the findings.⁹⁰

Obesity and the Gallbladder

In the general population, immutable risk factors for developing gallstones are female gender, increased age, and genetic traits. Obesity, the metabolic syndrome, and rapid weight loss are the modifiable risk factors of gallstone formation.⁹⁸ After bariatric surgery, traditional risk factors are not predictive of symptomatic gallstone formation. Weight loss of more than 25% of original weight postoperatively was the only predictive factor for the development of gallstones and selection of patients for subsequent cholecystectomy.⁹⁹ A meta-analysis of prospective observational studies showed that a 5-kg/m² increase in BMI was strongly associated with gallbladder cancer in women (1.59, P = .04) but not in men (1.09, P = .12).⁹³

Obesity and the Liver

The prevalence of nonalcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma has been independently associated with obesity,⁸⁸ with the correlation between fatty liver and obesity being particularly strong.¹⁰⁰ In the general population, the prevalence of NAFLD ranges from 3% to 24% but increases to 58% to 74% in obese subjects.⁸⁸ Obesity is frequently accompanied by the metabolic syndrome, a persistent inflammatory state that promotes fatty acid accumulation as it promotes insulin resistance.¹⁰¹ As the severity of the metabolic syndrome worsens, the risk of developing liver damage, such as nonalcoholic steatohepatitis (NASH), increases. Severe NASH is an uncommon complication of NAFLD, but it was reported in some obese patients after jejunoileal bypass surgery, characterized by sudden onset of fever, jaundice, and tender hepatomegaly and associated with a flu-like prodrome.^{[102] and [103]} The progressive liver disease that developed in conjunction with this surgical technique led to the abandonment of the procedure as a means of weight loss.¹⁰² NASH is an uncommon complication of modern bypass surgery.¹⁰⁴ Autopsy series have shown a 6-fold increase in the relative risk of developing cirrhosis in obesity.¹⁰⁵ The risk of developing hepatocellular carcinoma is also increased.^{[88] and [106]} A meta-analysis of overweight and obesity relative to liver cancer showed in summary results that the risk was 17 and 89% higher, respectively, compared with those of normal weight.¹⁰⁶ The relative risk of hepatic cancer was considerably higher in men (2.42) compared with that in women (1.67).

Obesity and the Colon

Increased adiposity seems to be a risk factor for developing adenocarcinoma of the colon and adenomatous polyps. A large meta-analysis by Ansary Moghaddam and colleagues¹⁰⁷ showed a relative risk of colorectal cancer of 1.19 (95% confidence interval [CI], 1.11–1.29) when comparing obese individuals with normal-weight individuals and a relative risk of 1.45 (95% CI, 1.31–1.61) when comparing those with a high central adiposity measure with those with a low measure. The risk of developing colon cancer in women was lower (1.08; 95% CI, 0.98–1.18) than that in men (1.41; 95% CI, 1.30–1.54). The BMI-related risk of colon cancer was higher and less evident in young women than in older women. There was a dose-response relationship between colorectal cancer and BMI, in which for every 2-kg/m² increase in BMI, the risk of colorectal cancer increased by 7% and for a 2-cm increase in waist circumference, the risk increased by 4%.⁸⁸ In a separate study, obesity was found to be a risk factor for advanced adenomatous polyps. For every 1-unit increase in BMI more than 30, there was a corresponding 1% increase in the frequency of advanced adenomas.¹⁰⁸

Summary

There is a clear relationship between obesity and many gastrointestinal symptoms. Appetite and satiety are symptoms that are highly regulated through a neuroendocrine, gut-brain-adipose axis. Diet, pharmacologic, and surgical approaches to lose weight are influenced by this complex, redundant neuroendocrine regulatory system. Obesity increases the risk of many digestive disorders, including many cancers. Some unresolved issues relate to what appropriate measure of adiposity is used in terms of disease risk, the mechanisms that underlie gender differences, and the effect of weight loss on specific disease-related risks. Knowledge of these issues will provide the basis to develop health strategies to prevent obesity-related diseases.