Inflammation is a type of defence mechanism that the body exhibits in response to damage to part or all of its tissues. Depending on the severity of the insult and consequent damage to cells, the inflammatory response involves recruitment of varying proportions of neutrophils, eosinophils, basophils, lymphocytes (both T and B cells), natural killer cells and cells of the monocyte macrophage lineage. Inflammation normally seeks to eliminate the cause of the insult and repair the damage caused. However, if the damage persists, persistent recruitment of inflammatory cells to the injured area will lead to further damage leading to chronic inflammation.  The gastrointestinal (GI) tract is a hollow muscular tube running from the mouth to the anus. It is about 7 to 9 meters long in adult. The enormous mucosal surface, which is the innermost layer of the gastrointestinal tract, is constantly exposed to a plethora of antigenic, mitogenic, mutagenic, and toxic stimuli thus clearly making the gastrointestinal tract vulnerable to such inflammatory responses. 
Gastrointestinal inflammatory diseases
Inflammation can affect any part of the gastrointestinal tract.
Inflammatory Bowel Disease
The inflammatory bowel diseases (IBD) are chronic inflammatory diseases affecting the gastrointestinal tract. IBD encompasses two forms of intestinal inflammation, namely ulcerative colitis and Crohn’s disease. Crohn’s Disease may affect all parts of the gastrointestinal tract, but more commonly it involves the distal part of the small intestine and the colon. On the other hand, ulcerative colitis results in colonic inflammation which can affect only the rectum, or can progress proximally to involve the colon, either partly or entirely . Currently, the etiology of IBD is unknown, but recent investigations have identified contribution of genetic, environmental as well as immunological factors underlying the disease . Susceptibility to disease is thereby determined by genes encoding immune responses which are triggered by environmental stimuli . Figure 1.1 shows a combination of genetic and environmental culprits triggering activation of intestinal immune and non-immune systems which culminate in inflammation and tissue damage. 
Figure 1.1: Etiology and pathogenesis of IBD.
Current medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use is associated with severe side effects and complications, such as an increased rate of malignancies or infectious diseases. 
Gastritis (Inflammation of stomach lining)
Gastritis represents a group of disorders characterized by gastric epithelial cell injury and regeneration together with the induction of inflammatory changes in the gastric mucosa . Inflammation of the gastric mucosa occurs as a result of an imbalance between mucosal defensive and aggressive factors. It is now well – established that H. pylori infection is the cause of the most common form of chronic gastritis . Studies have established that H.pylori directly contributes to abundant inflammatory response and cause injury to gastric epithelial cells through elaboration of cytotoxic factors and it may also make gastric epithelial cells more susceptible to carcinogenic conversion . There is also evidence that drugs and alcohol may cause gastritis. Iron therapy has also been implicated as a cause of gastritis. Iron-pill gastritis involves mucosal erosion which is accompanied by acute and chronic inflammation and marked regenerative epithelial changes . Autoimmune and hypersensitivity reactions may also be culprits in gastritis. 
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Esophagitis (Inflammation of the oesophagus)
Eosinophilic esophagitis is a chronic inflammatory condition whereby presence of dense eosinophilic inflammation of esophageal mucosa contributes to esophageal dysfunction. Eosinophilic esophagitis is a newly acknowledged disease whose incidence and prevalence is rapidly increasing in developed and developing countries . The disease is a major cause of gastrointestinal morbidity among children and adults. It is thought to be immune mediated, whereby food or environmental antigens trigger a T-helper (Th)-2 inflammatory response. 
Chronic pancreatitis is well-known as a persistent inflammatory disorder of the pancreas, characterized by destruction of the pancreatic parenchyma, maldigestion, chronic pain and diabetes mellitus. Susceptibility to chronic pancreatitis is inherited in a complex manner, involving mutations in several genes conferring various degrees of risk.  Although the exact etiology of acute and chronic pancreatitis is unknown, studies have revealed that they are most frequently caused by a high consumption of alcohol and tobacco . Other common causes include gallstones, hypertriglyceridemia, hyperparathyroidism, trauma, pancreatic tumors, and intra-abdominal and non-abdominal surgery. Drugs constitute a relatively infrequent cause of acute pancreatitis and account for 1.4 to 2% of the cases in the general population. 
Gastroenteritis refers to inflammation of the gastrointestinal tract, involving the stomach and intestines. Acute gastroenteritis is a common disease occurring worldwide, which affects all age groups and leading to an estimated three million deaths annually. In many patients the causal agent cannot be identified, but research has implicated bacteria and parasites as well as viruses such as rotavirus, adenovirus, and caliciviruses as major culprits in causing gastroenteritis. 
Symptoms of gastrointestinal inflammatory diseases
Table 1.1: Symptoms of GI inflammation
Gastrointestinal Inflammatory Disease
Inflammatory Bowel Diseases
Blood in stools
Fistulas (usually around the rectal area, may cause draining of pus, mucus, or stools)
Weight loss 
Vomiting (possibly with blood)
Abdominal pain and bloating
Loss of appetite
Blood in the stools. 
Dysphagia (difficulty swallowing)
chest pain or abdominal pain 
Mild yellowing of skin (jaundice)
Fatty stools 
Nausea and vomiting
Joint stiffness or muscle pain
Poor feeding and weight loss 
Biomarkers of Gastrointestinal inflammation
Inflammatory activities occurring within the gastrointestinal tract can be assessed using a variety of techniques. Presently, the most reliable means to assess intestinal inflammation is endoscopy with mucosal biopsy. However, this technique is expensive, invasive, time-consuming and is not popular with patients . Moreover, this technique requires a skilled operator and an uncomfortable preparatory regimen. Other techniques constitute measurement of conventional non-invasive acute-phase inflammatory markers in plasma and faeces. 
Blood inflammatory biomarkers
Serological biomarkers are principally produced when the intestine is exposed to the normal commensal bacteria and their increased levels might be indicative of an impaired or wrongly regulated inflammatory response. Erythrocyte sedimentation rate (ESR), white blood cell count (WBC) and C-reactive protein (CRP) are well-established indicators of inflammatory conditions within the intestine. 
C-reactive protein (CRP)
CRP is one of the vital acute phase proteins in humans, which is normally produced in low quantities by hepatocytes (<1â€…mg/L). However, in the event of an acute phase stimulus like inflammation, hepatocytes amplify production of CRP and may reach peak concentrations of 350-400â€…mg/L. In vivo, CRP is involved in opsonisation of infectious agents and damaged cells.  C- Reactive protein is an objective marker of inflammation and, in gastrointestinal diseases such as Crohn’s disease and acute pancreatitis, its levels correlate well with clinical disease activity. 
Table 1.2: Advantages and disadvantages of C-Reactive Protein
Rapid response to inflammatory stimulus
Unaffected by age and gender
Quantitation is precise and reproducible 
CRP has a short half life (19â€…hours) in comparison with other acute phase proteins and its level will increase early after the onset of the inflammation and also rapidly decline after inflammation has been resolved. 
Less clinical information available.
Relatively more expensive than ESR. 
Erythrocyte sedimentation rate (ESR)
ESR refers to the rate at which erythrocytes migrate through the plasma. 
Table 1.3: Advantages and disadvantages of erythrocyte sedimentation rate
Erythrocyte sedimentation rate
Much clinical information available 
Affected by age, gender and red blood cell morphology 
ESR is affected by conditions such as anaemia, polycytemia, as well as thalassemia. 
Reflects levels of many plasma proteins 
Responds slowly to inflammatory stimulus.  In comparison with CRP, ESR levels peak much slowly, and may also take many days to decline, even if the inflammatory condition has subsided. 
Faecal biomarkers in gastrointestinal inflammation
Increased translocation of granulocytes into the intestinal mucosa during inflammatory conditions results in excretion of elevated amounts of proteins from these cells in faeces. Inflammatory mediators detectable in faeces have been recognised as candidate biomarkers in intestinal inflammation as they are non-invasive, simple, sensitive and specific parameters useful to assess gastrointestinal inflammation. 
Detection of Indium-111-labeled leucocytes in faeces is regarded as the gold standard stool marker of gastrointestinal inflammation. 
Table 1.4: Advantages and disadvantages of Indium-111-labeled leucocytes
111indium labelled neutrophils
Specific, quantitative, and sensitive measure of intestinal inflammation. 
It requires special sterile labelling facilities.
It is costly, in terms of patient’s hospitalization, analysis and disposal of isotopic material. (about £300/patient)
It involves exposing patients to ionizing radiation.
There are practical problems with obtaining complete faecal collections over four days. 
The complexity of this technique, as well as its high cost and the exposure of patients to ionizing irradiation have limited its use thus prompting research to be oriented towards more simple and cost-effective alternatives to the indium-111 technique. In this regard, faecal calprotectin has been proposed as an excellent candidate. 
Calprotectin was first described by Magne Fagerhol and collaborators in 1980. Calprotectin is a small calcium- and zinc-binding protein which originates from neutrophil granulocytes. It is estimated that the amount of calprotectin in each granulocyte is equivalent to the amount of haemoglobin in an erythrocyte (about 20 pg of calprotectin per granulocyte). Besides having an antimicrobial function, calprotectin plays a role in inhibition of several metalloproteinases and induction of apoptosis in both malignant and non-malignant cell cultures. It is also assumed that calprotectin plays a key role in regulating the intestinal microbiota. Since the intestinal mucosa is under constant exposure to a plethora of microbes and their harmful products the concentration of calprotectin is much higher in normal intestinal environments as compared to the amount of calprotectin in blood. In inflammatory conditions the concentration of calprotectin may rise to over 100 folds of its normal value . Detection of calprotectin in tissue samples, body fluids, and stools therefore provides a non-invasive means to assess the presence of intestinal inflammation. Health conditions which lead to abnormally elevated calprotectin levels include active rheumatoid arthritis, meningococcal sepsis and active inflammatory intestinal disease  as well as in other organic gastrointestinal diseases such as diverticular disease, infectious enterocolitis, nonsteroidal anti-inflammatory drug (NSAID) enteropathy, and cancer. 
Table 1.5: Advantages and disadvantages of Calprotectin
Faecal calprotectin has several characteristics of an ideal test: simple, non-invasive, reproducible and relatively low cost.
It is stable for 3 to 7 days at room temperature and when the faeces are at -20°C no change in calprotectin has been observed over time.
It resists enzymatic degradation both in vivo and in vitro, thus calprotectin levels can be measured in the stools easily.
Calprotectin is unaffected by medication and dietary supplements.
It can be conveniently assessed in small samples. 
Calprotectin is not a disease specific marker and thus easily detects inflammation throughout the whole gastrointestinal tract. Studies have reported increased levels of faecal calprotectin in IBD patients as well as in those with several other inflammatory conditions of the lower gastrointestinal tract. 
Calprotectin significantly correlated with four day faecal excretion of 111indium which is the gold standard stool biomarker of intestinal inflammation. 
Use or nonsteroidal antiinflammatory drugs (NSAIDs) can lead to elevations in calprotectin levels. Hence, NSAIDs treatment should be stopped before taking faecal samples for calprotectin determination.
The most evident criticism of the faecal tests is that they are not acceptable to patients and they are generally unpleasant to work with. 
Menstrual bleeding or other bleeding in the body above 100 ml might lead to elevated faecal calprotectin levels.
Faecal calprotectin is generally assumed to be evenly distributed; however some authors suggest that there may be significant intra-individual biological variations in calprotectin levels caused by other factors excluding disease.
Faecal calprotectin levels are raised in any condition that leads to neutrophil translocation to the gut, such as in infections and neoplasms. Thus, the sensitivity of faecal calprotectin is not as high as desired. 
Lactoferrin is an iron-containing glycoprotein secreted by the majority of mucosal membranes. It is the main component of secondary polymorphonuclear granules, which are the prime cells of an acute inflammatory response. In intestinal inflammation, leukocytes invade the mucosa, which results in an increase in the excretion of lactoferrin into the faeces.  Besides calprotectin, faecal lactoferrin is apparently the most widely employed as a biomarker of intestinal inflammation. 
Table 1.6: Advantages and disadvantages of lactoferrin
It can be detected using simple and relatively cheap techniques. The quantification of lactoferrin concentration in faeces is done using the relatively inexpensive and easy enzyme-linked immunosorbent assay (ELISA) technique.
It has excellent stability in faeces over a long period of time. 
Studies have shown that faecal lactoferrin is a highly sensitive and specific marker for detecting intestinal inflammation. 
It is a measure of mucosal inflammation which is detectable at a concentration which is inadequate to bring about an increase in levels of ESR and CRP. 
A study revealed that lactoferrin was the better neutrophil-derived faecal biomarker of inflammation as compared with elastase, lysozyme and myeloperoxidase, in terms of its better accuracy and cost-effectiveness. 
Faecal lactoferrin is highly precise in distinguishing organic from functional intestinal diseases. 
Some studies have suggested that lactoferrin is less accurate of lactoferrin than calprotectin for detection of intestinal inflammation. 
NSAIDs intake may increase lactoferrin levels, perhaps owing to the associated induced enteropathy.
Faecal tests are frequently criticised in that they are generally not acceptable to patients and nasty to work with. 
Factors affecting gastrointestinal inflammation
Drug use and gastrointestinal inflammation
A number of the frequently used drugs today may have deleterious effects on the gastrointestinal system and have been associated with gastrointestinal inflammatory diseases.
Drugs causing Colitis
The frequency of colitis which is induced by drugs is often under estimated. Studies have found that colitis may be induced due to antibiotics, NSAIDs, laxatives, vasoconstrictive agents, oestroprogestatives . Pseudomembranous colitis is caused by antibiotics which facilitate an overgrowth of Clostridium difficile. Hemorrhagic colitis can be induced by antibiotics such as penicillin, amoxycillin and ampicillin. Ischemic colitis may be caused by drugs which induce mesenteric vasoconstriction . More recently, cases of colitis caused by non-steroidal anti-inflammatory drugs (NSAIDs) are increasingly being reported. However, the mechanism of NSAIDs-induced colitis is still not known.  Toxicity of NSAIDs to mucosal cells might cause increased intestinal permeability, which is a prerequisite for colitis. 
Drugs causing Inflammatory bowel diseases (IBD)
A number of drugs have been incriminated as causing or aggravating IBD. These include antibiotics, NSAIDs and oral contraceptives. 
Classes of drugs responsible for GI inflammation
NSAIDs: Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the mostly used pharmaceuticals worldwide, and are particularly useful in prevention and treatment of pain and inflammatory diseases. Prostaglandins, produced by arachidonic acid metabolism via the cyclooxygenase enzymes are largely involved in conferring protection to gastric mucosa. NSAIDs inhibit the production of both cyclooxygenase enzymes (COX-1 and COX-2), and thereby decrease the production of prostaglandins that leads to the antiinflammatory, antipyretic, and analgesic effects of NSAIDs. However, inhibition of prostaglandin production may be related to an increase in the formation of leukotrienes which attract inflammatory cells, causing local sites of inflammation.  The main pathogenic effect of NSAIDs on intestinal mucosa is the increase of mucosal permeability that results in subsequent development of small intestine inflammation.  Nearly three-quarters of patients on long-term treatment with NSAIDs have small-intestinal inflammation . The small intestinal inflammation which is induced by NSAIDs has been associated with blood loss and protein loss . NSAIDs intake has been associated with several gastrointestinal inflammatory diseases. Studies have suggested association of the use of indomethacin, piroxicam, ketoprofen, naproxen, rofecoxib and celecoxib with acute pancreatitis . In addition, some authors have put forward NSAIDs as a cause of diffuse chemical or reactive gastritis; however this has not been explicitly documented in studies involving pre- and post-treatment biopsies . Studies have also shown association between NSAID intake and appendicitis in the elderly . Studies have shown that over the long run, NSAIDs treatment leads to small bowel inflammation as depicted by increased translocation of indium 111-labeled leucocytes into the ileum. Recent studies have also associated mucosal inflammation with NSAIDs treatment as revealed by increased faecal calprotectin shedding. The severity of calprotectin shedding and leukocyte migration was however independent of the type or dose of NSAID taken. 
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Oral contraceptives: One of the adverse effects of oral contraceptives is that estrogens can lead to increased blood levels of triglyceride and hypertriglyceridemia is one of the well-established causes of pancreatitis. Thus common estrogen-containing treatments and conditions including birth control pills, hormone replacement therapy for menopause, tamoxifen treatment, clomiphene treatment for polycystic ovary syndrome and pregnancy may play a role in etiology of pancreatitis.  Studies have supported that estrogens are an uncommon but well-known risk factor of pancreatitis in women and men with pre-existing hyperlipidemia.  Oral contraceptive use also was associated with risk of Crohn’s Disease and ulcerative colitis. 
Statins: Statins, also known as the 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, are the most frequently prescribed lipid-lowering agents existing on the market. Several observational studies have associated statin therapy with pancreatitis . While the use of statin therapy was associated with reduced risk of pancreatitis in patients with normal or mildly elevated triglyceride levels , on the other hand statin therapy has surprisingly also been implicated in the etiology of pancreatitis. However, the exact mechanism by which statins cause pancreatitis is not known . Acute pancreatitis has been reported from some cases undergoing treatment with atorvastatin, fluvastatin, lovastatin and simvastatin . According to studies, though statin-induced pancreatitis can occur at any time, its incidence seems very uncommon early on and is more likely to arise after several months of therapy. 
Antihypertensive medications: Angiotensin-converting enzyme (ACE) inhibitors widely prescribed for treatment of hypertension are usually well-tolerated; however acute pancreatitis has been reported in a few cases treated with lisinopril, captopril, and enalapril . Case studies have also pointed towards Enalapril maleate as inducing eosinophilic gastroenteritis . Loop diuretics and hydrochlorothiazides have also been incriminated in drug-induced acute pancreatitis. 
Antibiotics and Antimicrobials: Tetracycline class of antibiotics has long been implicated as an etiologic factor in acute pancreatitis . A similar association with acute pancreatitis has also been demonstrated with sulphonamides. 
Corticosteroids: Chronic treatment with corticosteroids apparently heightens the risk of developing adverse gastrointestinal events including ulcers and bleeding in patients. The results of a recent study suggested slight risk of adverse gastrointestinal events, mainly gastritis, in patients who were prescribed inhaled corticosteroids, whereby significant amount of inhaled corticosteroid appeared in the gastrointestinal tract, notably in the lining of the oesophagus, the stomach, intestine, and the colon. 
Proton pump inhibitors: These are highly potent gastric acid-suppressants in clinical use . Intake of proton pump inhibitors has recently been associated with increased faecal calprotectin. 
Central Obesity and Gastrointestinal inflammation
Obesity, defined as the excessive accumulation of body fat, affects a massive proportion of the world’s population. However, measurement of body fat is a challenging task. Virtually, all social science research on obesity make reference to the person’s body mass index (BMI) which is a simple, rapid, and inexpensive method. According to this method, normal range is 19-24.9 kg/m2, overweight is 25-29.9 kg/m2, and obesity >/= 30 kg/m2. However, this method has been subjected to criticism because it does not distinguish fat from fat-free mass such as muscle and bone . In addition, it has also been observed that for the same value of BMI, women are, on average, fatter than men, and Asians are, on average, fatter than Caucasians . Distribution of body fat is highly important in evaluating obesity-related health risks. It has been well-established that accumulation of intra-abdominal fat, that is central obesity, shows stronger correlation with disease states in comparison with total body fat . According to a recent study, waist circumference, and not BMI, explains obesity-related health risk. 
Obesity is associated with low-grade inflammation. The inflammatory process originates and resides mainly in adipose tissue, as it is responsible for production and secretion of various proteins involved in development of obesity related adverse health effects  . Through this mechanism, increasing obesity leads to reduction of adiponectin levels, which has anti-inflammatory properties, and to elevated levels of C-reactive protein (CRP) and results in systemic inflammation, including gastrointestinal inflammations. Intestinal inflammation is a key feature in severe obesity . A study has established diet-induced intestinal inflammation as an early biomarker and mediator of obesity . Findings in adult humans and in animals have suggested that the inflammatory status at mucosal surfaces of various organs including the adipose tissue, ooesophagus, pancreas, colon, which are associated with the increase of fat mass, may be involved in the pathogenetic pathways of obesity complications . In addition, animal studies showed that obese mice display enhanced intestinal permeability . Recent epidemiological studies have demonstrated that obesity is associated functional bowel disorders, which may have resulted from a low-grade inflammation . Furthermore, obesity has been found to increase the severity of acute pancreatitis through amplification of the immune response to injury . Obesity, especially abdominal obesity, was also found to be a significant risk factor for erosive esophagitis . Very recently, an association of obesity with endoscopic gastritis was demonstrated. 
Results of a recent study pointed that circulating neutrophils are greatly activated in severely obese subjects, thereby indicating the association between obesity and activation of the innate immune response. In addition, elevated levels of faecal calprotectin, which is a non-invasive biomarker of intestinal inflammation, have been reported in individuals with high BMI . Another study demonstrated a strong correlation between circulating calprotectin levels with abdominal adiposity in Japanese men, and also showed that weight loss in the subjects led to decreased circulating calprotectin. 
Gastrointestinal inflammatory diseases may also be influenced by genetic components. Family studies have revealed strong familial association and high sibling risk ratio in etiology of eosinophilic esophagitis.  Genetic factors also play a role in pancreatitis.  In addition, increased familial risk has also revealed a genetic basis in Inflammatory Bowel Disease , and an increased faecal calprotectin concentration has also been demonstrated in asymptomatic first-degree relatives of IBD patients, thus indicating a high prevalence of subclinical intestinal inflammation in them. 
Gender may play a role in gastrointestinal inflammatory diseases. Animal studies in mice have demonstrated that females develop more severe intestinal inflammation than do males . On the other hand, a study has shown that bile reflux gastritis was more frequent to male gender . Another study found a positive correlation between the male sex and pancreatitis . Additional studies found that there is a slight preponderance of colitis ulcerosa in men and of Crohn’s disease in women .
Cigarette smoking affects ulcerative colitis (UC) and Crohn’s disease (CD) in very different ways. According to recent studies, smoking cigarettes has a negative effect on the course of CD, and that smoking cigarettes may have a protective effect in some patients with UC . Conversely, smoking cessation aggravates ulcerative colitis and improves CD . Furthermore, studies showed that smoking conferred a strong, independent and dose-dependent risk of pancreatitis that may be additive or multiplicative when combined with alcohol. .
Most cases of chronic pancreatitis are alcohol-related.  However, a recent study showed that faecal calprotectin concentrations in active-drinking alcoholics were not significantly different from the healthy controls thereby indicating the absence of a subclinical intestinal inflammation involving activation of neutrophils in the alcoholics. 
Pro- or prebiotics will directly influence the microbial flora, while immunonutrition, including omega-3 fatty acids and certain polyphenols, including green tea polyphenols, may reduce the symptoms of gut inflammation . Studies have shown that lycopene, an antioxidant which is abundantly found in foods that have a natural red color such as tomato and watermelon, may play a role in attenuating the inflammatory process . A study showed that intestinal bacteria and high fat diet interact to promote proinflammatory changes in the small intestine . Certain studies suggested that refined sugar consumption might be a risk factor for Crohn’s Disease, but not Ulcerative Colitis. Fat intake is reportedly positively associated with ulcerative colitis , whereas vegetables and fiber consumption seem to decrease GI inflammatory process as shown by decreased faecal calprotectin .
Psychological stress reportedly increases disease activity in inflammatory bowel disease by both direct and indirect mechanisms as shown below. 
Figure 1.2: Direct and indirect ways by which stress can aggravate Inflammatory Bowel Diseases
Epidemiological studies have demonstrated Inflammatory Bowel Diseases to be more prevalent among people of high socioeconomic status. Such an occurrence was explained by the ‘hyegiene hypothesis’, according to which individuals with higher standards of living may be living in cleaner environments and thus are more protected from childhood infections, but however exposure to infectious agents later in life makes them more vulnerable to chronic intestinal inflammation in adulthood . A study in China demonstrated that levels of faecal calprotectin were significantly increased in the rural infants as compared to urban ones. 
Partial gastrectomy increases the risk for chronic pancreatitis in male alcoholics . Appendectomy has possibly protective effects in ulcerative colitis but it is suggested as a risk factor in Crohn’s disease. Tonsillectomy is a risk factor for developing Crohn’s disease. 
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