Management of H. pylori Induced Peptic ulcer – A Phytotherapeutic Approach

A peptic ulcer is a chronic infectious disease that creates erosion on the epithelial lining of the stomach. It is a commonly encountered problem in the gastrointestinal tract (GI tract). Patients failed multiple regimens due to resistant H. pylori infection. H. pylori show maximum resistance towards Clarithromycin. Due to the consistent increase in resistance there is urgent need for the development of new drugs. Paying much for the antibiotic treatment one should go for the natural treatments with no side effects. Modern treatment of peptic ulcers emphasizes diet with routinely recommend hospitalization of several weeks. Currently, a lot of medications are coming out of natural products. the phytotherapeutic approach for the resistant H.pylori treatment is assessed. the plant produces many secondary metabolic substances which have a lot of beneficial roles in maintaining human health. Administration of plant products would prevent disease and able to eradicate resistant H.pylori . this review includes many phytoproducts having a wide range of antimicrobial activity. Reviewed phytoproducts includes Phytoceutical, Caffeic acid, phenethyl ester, Flavonoid, Capsaicin, Carotenoid, etc are effective treatment against H.pylori . to see their effect on the resistant H.pylori and to manage this resistant bacteria with an application of plant products is the prime concern of this review. the linkage between phytochemical and peptic ulcers will provide a novel framework for the future.


INtRODUCtION
The stomach is a glandular 'J' shaped organ lined with epithelial cells and it has a considerable amount of mucus mass and is constantly influenced by digestive enzymes, hydrochloric acid, microbes, and bile which in turn encounter producing mucus, prostaglandins, and bicarbonate to maintain the integrity of its lining, and this equilibrium is persistently synchronized and called mucosal defense. A peptic ulcer is due to an imbalance between mucosal protective mechanisms against damaging forces. 1 It can be defined as the roughened area or cavity which is found in the stomach. Due to the hypersecretion of acid, it attacks the epithelial lining of the stomach which in turn causes soreness and is termed an ulcer. The ulcer is of two types that is a duodenal ulcer and gastric ulcer and combinedly termed as peptic ulcer.
The human body is exposed to numerous microorganisms in the environment every day. These organisms play important role in both health and diseases. H.pylori has been the main focus of study for gastrointestinal tract diseases for a long. It is a Gram-negative, microaerophilic organism that is associated with a variety of diseases like chronic gastritis, peptic ulcer, non-cardio gastric adenocarcinoma, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. 2,3 However, it's important to understand at the outset that the vast majority of people who were infected with H. pylori when they are young are infected for life, and about three-quarters of these people or more have no symptoms in their whole lifetime. They would never know they had H. pylori unless somebody either cultures them or does another kind of test. A subset of people who have H. pylori develops gastritis. Some of these people go on to develop ulcer disease.
Duodenal ulcers and 70% of gastric ulcers are due to H. pylori infection. 4 H. pylori-infected persons develop gastric damage. Among those infected patients, only 17% develop peptic ulcers. 5 Triple therapy and quadruple therapy are used for the eradication of H. pylori but the rate of efficacy varies between 75% -95% and the main reason for failure is due to antibiotic resistance. 6 Despite several drug treatments that have been developed for various types of ulcer diseases, it has pernicious side effects. Emerging more resistant H. pylori is a worldwide problem and it demands the replacement of antibiotics with natural products. We believe that a combination of natural plant products that have anti-H. pylori activity could give the best result. This review was carried out with the help of bibliographic databases such as Google scholar, web of science, and PubMed.

epidemiology and Prevalence of Peptic Ulcer
The rate of prevalence of H.pylori in developing countries is very high, that is about 80-90% in the case of adults in comparison with developed countries which is about 10-50% and this is due to low socioeconomic conditions. 7 H. pylori infection is very common and in fact, is one of the most common infections worldwide. The rate of peptic ulcers brings down from before, but it has become more powerful than before and the occurrence of this disease are linked with age, sex, geographic environmental factors, and occupation. 8,9 the frequency of peptic ulcers is between 19.4 -57.0 per 100,000 people, with the number increasing every year. 10 According to a study of 1335 peptic ulcer patients in Iran, the prevalence of peptic ulcers differed between male and female patients, with 60% and 30% respectively, and 62% of patients developed peptic ulcers as a result of H. pylori colonization and 30% as a result of environmental variables. 11

Major Factors
The first most common cause of peptic ulcer is infection with H. pylori and the second major cause of peptic ulcer is excessive secretion of hydrochloric acid (HCl). Higher concentration and higher volume of HCl secretion can alter the protective epithelial lining of the stomach and gastric cells because the amount is more than what the body can resist. 8 The third cause is antiinflammatory drugs like aspirin [ Figure 1]. Studies showed that these drugs irritate the lining of the stomach and impair the barrier properties of the mucosa and increase the suppression of antiinflammatory gastric prostaglandins, reducing gastric mucosa blood flow which affects the defense and repair of the lining of the stomach. 12,13

Helicobacter pylori Pathogenesis
The most common cause of peptic ulcer is infection with H. pylori. It is a gram-negative, spiral-shaped bacteria having flagella that help in motility. The root of transmission is by fecal-oral route or through oral-oral route. 14 The important virulence factor that H. pylori possess includes lipopolysaccharide which helps in adhering the cells, so it can attach itself to the gastric cells of the stomach by secreting adhesion molecule which is recognized by glycan structure that is expressed on the surface of gastric epithelial cells and the surface of mucus layer lining ( Figure 2). Another important virulence factor of H. pylori is the enzyme on the surface known as urease and this enzyme protects from acidity as urease converts urea to ammonia and CO 2 . Further ammonia helps the bacteria from acidity by increasing pH to neutral as it is alkaline. 15 This bacteria also secrete some exotoxins such as Vac A and Cag A. Vac A is a fairly potent kind of poison that causes apoptosis of cells and Cag A is responsible for disrupting cellular integrity and structure, and promotes inflammation. Cag A stimulates the production of certain chemokines such as IL-8 within its cells which in turn attracts neutrophils into the area. Neutrophils are highly inflammatory and can damage the stomach tissues ( Figure 3). The combination of Cag A and Vac A causes stomach cells to break down, resulting in ulcer formation. 16 According to Khademi et al. 21 the generality of resistance for clarithromycin is excessive than other antibiotics and that is about 64.9% which has been shown on the graph [ Figure  4] [ Table 1]. The prevalence of resistance for amoxicillin shows very little [ Table 1]. [17][18][19] Our diet is rich in red meat, junk food, sugar, starch, etc. We do not consume the number of vegetables and fruits that we are supposed to take, and do not intake the right balance of foods that balance out our body systems and therefore end up with a lot of different diseases. A lot of natural supplements do help in regulating our bodies. Table 1. Illustrates the resistance of different antibiotics in different years.

Polyphenol
Polyphenol is a bioactive secondary metabolic compound, generally obtained from fruits and vegetables, can suppress the negative effects of H. pylori in the GI tract. Traditionally, it is used for prevention of many diseases like cancer, neurodegenerative, osteoporosis, etc. It is potentially involved in inhibiting telomerase, cycloxygenase enzymes. 32,33

Capsaicin
Capsaicin is a natural compound, extracted mostly from chili pepper shows a wide range of significant effects in maintaining the GI-   tract. It shows cytoprotective effect, antioxidant property, anti-inflammatory, anti-proliferative effects, and inhibitory effect at 50ug/ml. Cancer cell line like MKN-45 in the stomach induces the production of IL-8, which is ultimately suppressed by administration of capsaicin. It can suppress the activation of NF-kB, whose activation is induced by H. pylori infection. 34,35 Caffeic Acid Phenethyl ester Caffeic acid phenethyl ester are extracted products of propolis, have antioxidant, anti-carcinogenic, immunomodulatory, antiinflammatory properties. 23

Flavonoids
Flavonoids are the main constituents of most herbal products. According to Toshio fukai et al. Flavonoids (licoricone, gancaonol , vestitol and 1-methoxyphaseollidin) extracted from Glycyrrhiza glabra is a potential herbal medicine against resistance H. pylori as it shows inhibitory effect on both amoxillin and clarithromycin resistance strain. 36 In stress condition, flavonoids are released from plants as secondary metabolic polyphenolic substances and protect the plant from a pathogen. 37

Quercetin
Quercetin is found broadly in most vegetables and fruits and has strong antioxidant properties. The skeletal structure of Quercetin is quite similar to flavone. According to Xin-Ting et al. gastroprotective mechanism has been observed with the application of Quercetin. When Quercetin is applied on gastro epithelial cells, it is observed that loss of cell viability due to hydrogen peroxide, reduces drastically. It is also found that it suppresses Calcium ion influx and reactive oxygen species activity. 38

Curcumin
It has anti-oxidant, anti-inflammatory, anticarcinogenic, and antimicrobial properties. It inhibits iNOS, COX-2, LOX, mediated signaling pathways. It reduces the inflammation which is caused by certain cytokines like TNF-a, IL-6, and IL-1β. 39,40 Carotenoids Carotenoids can act more efficiently than metronidazole. The minimum inhibitory concentration of carotenoids is considerably high than the amoxicillin and clarithromycin but Carotenoids can act more efficiently than metronidazole. Carotenoids like neoxanthin and luteoxanthin show more effective results than other carotenoids. 31

ethanol extract
It is observed that the application of garlic can give a significant result. About 1-4% of garlic intake can suppress the gastric lesion in H. pyloriinfected individuals.
It can be used for various pharmacological functions like wound healing, anti-cancer, anti-oxidant, immunomodulatory potential, antiinflammatory, etc. It inhibits the growth of different strains of bacteria and fungi. Allicin and ethanol bioactive chemicals present in garlic make it more potent against various kinds of diseases. 41 Table 2 Emphasizes the plant products having a wide range of antimicrobial properties. Phytoceutical which is obtained from broccoli, garlic, green tea, etc. And polyphenol from apple peel can be used in the management of H.pylori products.

CONClUSION
Many plants having anti-ulcer and other medicinal properties were used as ethnomedicine worldwide. It is obtained from the data that Phytoproducts like Phytoceutical, flavonoids, and carotenoids, protect the lining of the stomach by preventing colonization of H. pylori and also has erosion healing activity. Its antioxidant property provides defense towards reactive oxygen species. Further, more clinical trial is needed concerning the following points-1. Standardization of plant products is necessary to deal with peptic ulcers. 2. We can normalize Eh and the pH of the stomach using Phytoproducts. A comparative study should be carried out with a large sample size on different populations with different diets to rule out the efficacy of plant products in the management of H. Pylori induced peptic ulcers.