Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal (GI) tract that is believed to arise from an inappropriate immune response to intestinal microorganisms; oxidative stress in human IBD correlates with disease activity (De Cicco 2018).
Inflammatory bowel disease
The more common forms of IBD are ulcerative colitis (UC) and Crohn`s disease (CD). Symptomatic IBD is characterized by abdominal pain, diarrhea, rectal bleeding, fever and weight loss, with significant impact on quality of life. IBD can be difficult to diagnose because symptoms are typical of other illnesses and diseases and can vary from person to person. UC typically involves the rectum and colon, whereas CD may involve any region of the GI tract. In 10-15% of cases, a definitive diagnosis of either UC or CD cannot be made because of idiosyncrasies in the presentation: in such instances a diagnosis of indeterminate colitis is warranted.
In 2015, UC and CD affected about 11.2 million people worldwide and about 3 million adults in the USA were diagnosed with IBD (either CD or UC). Although the IBD incidence in developed areas such as the US and Western Europe has been relatively stable, recent epidemiological studies suggest a significant increase in IBD incidence and prevalence in Asia, Africa, and Eastern Europe, where it was less common.
In 2019, a comprehensive and systematic review on IBD indicates that it is expanding rapidly in the South American countries. While the incidence and prevalence of IBD in that region currently remain below those of USA, Australia and the UK, the data shows a significantly higher burden of disease in Brazil, Argentina, Colombia and Uruguay compared to Asian countries such as mainland China, Hong Kong, Indonesia, Malaysia, Singapore, Sri Lanka and Thailand (Selvaratnam 2019). Considering that the total population of South America exceeds 430 million, South America’s IBD burden will comprise a large portion of IBD worldwide.
Strong evidence indicates that IBD patients have an elevated risk of endothelial dysfunction and coronary artery disease (Roifman 2009, Gandhi 2012) while UC patients are at risk of developing infections by Clostridioides difficile (also known as C. diff) and cytomegalovirus. In the USA, C. diff is estimated to cause almost 500,000 illnesses each year, where 1 in 6 patients with C. diff will get it again in the subsequent 2-8 weeks, and 1 in 11 people over 65 generally dies within a month of diagnosis.
There is an observed correlation between IBD and heart failure (HF). A study by the Mayo Clinic in Rochester found a twofold heart failure incidence increase in IBD patients compared to control subjects. They noted that 40-year-old and older females with UC had the highest risk of developing HF. The study also noted that HF risk increased with the use of systemic steroids, and that HF rates correlate with IBD flares.
UC and CD are not currently curable by pharmacological means. One in five patients with CD is admitted to hospital each year, and half of those with this disease will require surgery at some point over a 10-year period.
Like many other chronic, inflammatory diseases, CD may cause a variety of systemic symptoms: among children, inability to sustain growth is common; among older individuals, CD may manifest through weight loss —usually related to decreased food intake and loss of appetite.
In about 15% of patients, CD causes neurological complications (commonly seizures, stroke, peripheral neuropathy, headache and depression). CD may also affect the skin, cardiovascular system (through thrombosis and embolism) and the endocrine system, and it increases the risk of osteoporosis and cancer of the small intestine. In CD, anal discomfort may be prominent, as well as fecal incontinence, aphthous mouth ulcers, uveitis, and episcleritis.
IBD may require immunosuppression to control the symptoms with drugs such as prednisone, azathioprine, methotrexate or 6-mercaptopurine in addition to anti-inflammatory drugs, for instance mesalazine or budesonide and/or biologicals (TNF inhibitors).
Colorectal cancer (CRC) is the third most common cancer worldwide and one of the major causes of morbidity and mortality throughout the world. The risk of CRC in UC patients is 2% after 10 years, 8% after 20 years, and 18% after 30 years of disease. Oxidative stress and chronic intestinal inflammation are the primary risk factors in the development of gastrointestinal malignancies (De Cicco 2018).
Ileus is a disruption of the normal propulsive ability (peristalsis) of the intestine. Postoperative ileus (POI) is a physiological arrest of gastrointestinal transit in response to surgical stress; it is also a major concern for surgeons since POI increases duration of hospitalization, cost of care, and postoperative morbidity (Venara 2016). About 20% of patients develop POI after abdominal surgery and about 50% of patients who undergo major abdominal surgery. To date, pharmacological prevention is limited because of a lack of effective drugs.
In the specific case of POI after colorectal surgery within state-of-the-art enhanced recovery programs (ERPs), it has been recently found (Venara 2019) that 15.4 % of patients experienced POI, with severe POI occurring in 6.1% of all patients.
POI has become a public health problem; its consequences can be severe, since it causes gastrointestinal paralysis with a risk of nausea and vomiting, which may be complicated by pulmonary aspiration. Besides this extremely serious complication, POI may cause dehydration, electrolyte imbalance, sepsis, hernia formation and wound dehiscence.
POI develops in three phases: the initial phase involves neurological processes, while a second phase involves hormonal and inflammatory mechanisms and a third phase comprises parasympathetic nervous activation (Venara 2016). Manipulation of the intestines induces an inflammatory response, and — during the second phase — the permeability of the intestinal epithelial barrier increases, resulting in bacterial translocation and increased inflammation.
Gastroesophageal reflux disease (GERD), also known as acid reflux, is a chronic condition in which stomach contents rise up into the esophagus. Common complications include esophagitis, esophageal stricture and Barrett’s esophagus. In the Western hemisphere, between 10 and 20% of the population is affected by GERD.
Esophagitis is a disease characterized by inflammation of the esophagus; if it remains untreated, it may cause scarring and an esophageal ulcer or develop into Barrett’s esophagus and eventually into esophageal cancer. Esophagitis is found in approximately 20% of patients with upper gastrointestinal symptoms who seek a gastroenterologist’s advice.
Barrett’s esophagus is a premalignant condition characterized by a metaplastic change in the cells lining the lower portion of the esophagus. This condition is associated to a high incidence of further transition to esophageal adenocarcinoma, an often-deadly cancer. The prevalence of Barrett’s esophagus has been estimated to be between 1.3 and 1.6% in two European populations (Italians and Swedes), and 3.6% in the South Korean population.
The incidence of esophageal adenocarcinoma in the Western world has increased significantly in recent years. This condition is found in about 10% of patients who seek medical care for GERD. The risk of malignancy is highest in the USA in Caucasian men over 50, and this malignancy has a mortality rate of over 85%. Importantly, most patients with esophageal carcinoma die within one year.
Peptic ulcer disease (PUD) is a discontinuity in the inner lining of the stomach (gastric ulcer), the first part of the small intestine (duodenal ulcer), or the lower esophagus (esophageal ulcer). Complications may include gastrointestinal bleeding, perforation, blockage of the stomach and cancer, with bleeding occurring in about 15% of cases.
Peptic ulcers are present in about 4% of the population. In 2015, new ulcers were found in around 87.4 million people worldwide, about 10% of whom will develop a peptic ulcer at some point in their life. Most peptic ulcers and gastritis are caused by Helicobacter pylori (H. pylori), a bacterium that colonizes the GI tract; in Western countries, the percentage of people with H. pylori infections roughly matches age: 20% at age 20, 30% at age 30… 80% at age 80, etc. Prevalence is higher in third world countries, being estimated at about 70% of the population, whereas developed countries show a maximum of 40%.
Peptic ulcers may also be caused by the extensive use of nonsteroidal anti-inflammatory drugs NSAIDs, other medications such as alendronate, and abuse of tobacco and alcohol (Tarasconi 2020).
Abundant preclinical evidence overwhelmingly supports the evaluation in humans of H2S-based treatments of all the aforementioned pathological conditions:
Two H2S donors were found to reduce intestinal inflammation and restore transit in a mouse model of postoperative ileus (Van Dingenen 2019);
H2S protects gastric mucosa of rats against alendronate injury (Magierowski 2016);
Exposure to NSAIDs and suppressing H2S synthesis leads to altered structure and impaired function of the esophagus and esophagastric function of rats (Zayachkivska 2015);
H2S was found to prevent NSAID-enteropathy in rats with compromised gastric mucosal defense (Blackler 2014);
H2S was found to exert cytoprotective effects in novel rat models of non-erosive esophagitis (Zayachkivska 2014);
H2S confers colonoprotection against induced colitis in rats (Kupai 2018);
H2S provided intestinal protection to a murine model of necrotizing enterocolitis (Drucker 2018);
Endogenous and exogenous H2S promotes resolution of colitis in rats (Wallace 2009);
H2S enhances ulcer healing in rats (Wallace 2007);
H2S regulates gastrointestinal smooth muscle function in mice, rabbits and humans (Nalli 2013);
H2S can suppress H pylori-induced expression of proinflammatory factors and ameliorate the H pylori-induced injury to gastric mucosal cells (Xu 2013);
H2S synthesis by Helicobacter hepaticus-infected mice colon cells was reduced 100-fold after induction of colitis (De Cicco 2018);
Chronic oral administration of an H2S donor (diallyl trisulfide) to H. hepaticus-infected mice reduced colon inflammation, as well as levels of proinflammatory mediators (De Cicco 2018);
Diallyl trisulfide (DATS), an efficient H2S donor, was found to dose-dependently inhibit the growth of Helicobacter pylori by targeting proteins involved in energy metabolism and biosynthesis (Liu 2010);
Diallyl trisulfide (DATS), an efficient H2S donor, was found to inhibit H. pylori production of two important virulence-associated proteins, thereby considerably reducing generation of reactive oxygen species, gastric mucosal inflammation and pathogenicity (Liu 2010).