The prospect of probiotics in -induced peptic ulcer disease: A perspective review

Pathophysiology of PUD

The mechanism of occurrence results from an imbalance between the destructive and defensive factors. The major underlying causes predisposing to the development of PUD disease are a history of ulcers, some illnesses such as liver, kidney or lung disease, drinking alcohol regularly, physiological stress, smoking, and the intake of iron supplements have been associated with gastric pathology too and other factors which increase the level of acid, so all these factors will attenuate typical mucosal defence and healing mechanisms.^[6] But studies have shown two leading causes of ulcers: H. pylori bacteria and frequent use of NSAIDs (Aspirin, Naproxen, Ibuprofen).^[7] It usually begins with damage to the mucosa, which extends to the muscularis mucosa and the inner layers exposed to acidity result in bleeding or perforation.^[8]

Helicobacter pylori (H. pylori) bacteria

Gastric ulcers have been associated with H. pylori, a gram-negative bacillus belonging to the Epsilon proteobacteria class. ^[9] They induce inflammation and chronic gastritis in the upper gastrointestinal tract by employing a spiral motion of their flagella to traverse the mucus and adhere to the epithelial cells. This condition compromises the integrity of the protective lining by elevating gastric pH via the secretion of urease, which hydrolyses urea (a byproduct of protein catabolism by cellular organisms). Consequently, an alkaline environment is produced to shield the bacteria from acid, diminishing the acidic environment they inhabit. ^[10] Numerous H. pylori strains generate proteins such as VacA, which functions on mucosal cells to enhance urea movement in the stomach, and CagA, which induces alterations in the morphology and surface elements of the cells. ^[10] Furthermore, H. pylori fosters the production of reactive oxygen species (ROS), induces oxidative DNA damage in the gastric mucosa of infected humans, and induces apoptosis of gastric epithelial cells. ^[11] The colonisation of the gastric epithelium can be attributed to its ability to navigate through secretions and its predilection for areas of stomach injury. ^[12] It frequently infects the stomach, and approximately fifty percent of the population is asymptomatic with an H. pylori infection. This is owing to its capacity to endure short-lived pH levels below 4, although growth is inhibited at such levels; infection exclusively transpires within a restricted pH spectrum of 5.5 to 8.0. ^[13] Individuals aged fifty and above have a higher susceptibility to contracting the infection.

Several conditions are associated with reduced gastric acid secretion and help in H. pylori infection

Chronic gastritis is the first symptom that occurs after H. pylori colonization. The severity of the chronic inflammatory process depends on several factors: host genetics, immune system response, diet regimen, characteristics of the colonizing strain and acid production level. ^[2] Acid makes the luminal content of the stomach and small intestine relatively sterile by killing swallowed microorganisms, including H. pylori. The average stomach is rich in microbiota but is lower than other gastrointestinal parts because of the high acid level. ^[14] Although an acute infection with H. pylori decreases acid secretion, chronic infection may increase or decrease acid secretion. Anyway, the presence of H. pylori changes the composition of the gastric microbiota. ^[15] There are many other factors which increase the probability of infection like age (people over 65 years have low levels of hydrochloric acid, so the infection of H. pylori increases with age), ^[16] psychosocial factors (stress, depression and anxiety), surgery (Bariatric surgery reduce the secrete of hydrochloric acid), ^[17] vitamins deficiency (Vitamin B12, Vitamin C, Vitamin D, folic acid and calcium), chronic atrophic gastritis and malnutrition cause gastric hypoacidity, fever may inhibit gastric acid secretion in humans and medication. ^[18] The effective treatment with one or more antibiotics, like prolonged use of clarithromycin and other macrolides in respiratory infections, reduces the success of antibiotic treatment to less than 80 % because of their resistance to H. pylori. ^[19] In addition, antibiotics have adverse effects on the microflora of GIT because they don't kill only the pathogens but also the normal microflora responsible for maintaining the stomach's acid environment.^[20] Taking antacids or other medications to treat ulcer or acid reflux for a long time, such as proton pump inhibitors (PPIs) and H2-antagonists, may lead to hypochlorhydria and could inhibit normal gastric acid secretion by up to 99 % and affect the composition of the gastric microbiota. ^[21] Furthermore, the composition of the gastric microbiota changes in the setting of H. pylori by inducing the host to secret antimicrobial peptides that indirectly kill the other bacteria. ^[22]

Treatment of peptic ulcer

Treatment depends on the case. Usually, this includes the eradication of H. pylori, minimizing the use of NSAIDs, and providing elements that help heal.

Different medications treat H. pylori.^[23] For example, clarithromycin exhibits antibacterial properties by inhibiting bacterial protein biosynthesis; fluoroquinolones impede the operation of the bacterial gyrase enzyme, which regulates DNA transcription, recombination, proliferation, and structural stability. ^[24] Levofloxacin, a fluoroquinolone medication, is employed as a second-line treatment due to the expeditious development of resistance.^[25] H. pylori contains ferredoxin-like enzymes, NADPH nitro reductase, and NADPH-flavin oxidoreductase, all utilized by metronidazole. By interfering with peptidoglycan synthesis, amoxicillin prevents the synthesis of bacterial cell walls and degradation. ^[26] Anti-tuberculosis agent rifabutin can inhibit the H. pylori reverse transcriptase (RT) beta subunit. Tetracycline disrupts protein biosynthesis by inhibiting amino acid transferase activity and exerts an influence on the 30S subunit of the ribosome. ^[27]

(Proton pump inhibitors (PPIs): a drug used to treat H. pylori infection with antibiotics like Omeprazole, Esomeprazole, Pantoprazole and Lansoprazole. Those block H+/K+ ATPase or gastric proton pump irreversibly in the partial gastric cell, the last step in gastric acid secretion. ^[28] However, PPI has been reported with severe side effects in long-term use, such as a higher risk for infection (enteric or pneumonia), chronic renal disease, bone fracture and symptomatic hypomagnesemia. ^[29]

Medications to reduce acid production: histamine (H2) blockers or acid blockers; these medications relieve the pain of ulcers by reducing the amount of acid in the stomach but, in general, are not used alone to heal the ulcer. Acid blockers include Famotidine, Cimetidine and Nizatidine. ^[29]

Bismuth quadruple therapy: This treatment lasts fourteen days and includes two antibiotics, like Tetracycline and Metronidazole, with Bismuth and PPI. It is used as a first-line treatment when the resistance of clarithromycin is high or as a second-line treatment when the triple therapy fails. ^[30]

Probiotics: Probiotics are live microorganisms promoted with claims that they provide health benefits when consumed, generally by improving or restoring the gut microbiota; ^[31] it was proposed by Russian Nobel Laureate Elie Metchnikoff in 1908 due to its effect on preventing the overgrowth of harmful bacteria, improving the function of the epithelial barrier and enhancing the resistance of the gut. ^[32] Probiotics are used more as preventive medicine than therapeutics.^[33] Previous studies have shown that probiotics are helpful in the treatment of many gastrointestinal diseases (GIT) like inflammatory bowel disease, functional digestive disorders, acute diarrhoea and antibiotic-associated diarrhoea; in addition, they can reduce the consumption and side effects of antibiotics and improve health conditions for that probiotics can be beneficial for infection with H. pylori in several mechanisms depending on their ability to survive the acidity of the stomach, bile and hydrolytic enzymes. ^[34]

Mechanism of action of probiotics against H.pylori

There are two functional mechanisms by which probiotics can treat and eliminate the infection of H. pylori:

Physiological or non-immunological mechanisms like (a) production of antimicrobial peptides and other substances which are the end products of lactic aid fermentation like lactic, acetic acid and hydrogen peroxidase by stimulated gastric epithelil cells.^[35] (b) Reduction of the pH in the gastric by secreting SCAFs that can inhibit H. pylori growth.^[22] (c) Increase mucin production to improve epithelial barrier function and inhibit bacterial adhesion to the mucosal layer by creating competitive conditions (competitive with H. pyloi for adhesion in the gastric mucosa, which is essential to determine the result in H. pylori disease).^[36]

Immunological mechanisms such as inhibiting the production of IL-8, stimulating anti-inflammatory cytokines, suppressing the inflammatory function of lymphocytes and their cytokines via probiotics and their products through activating dendritic cells, and increasing the production of IgA by B cells due to changes in cytokines profiles through effects on dendritic cells. ^[37] Some studies showed that linoleic acid and linolenic acid can inhibit the effect of H. pylori.^[38]

First-line treatment for H. pylori infection includes proton pump inhibitors and antibiotics, especially (Amoxicillin and Clarithromycin).^[38] Still, due to the high resistance and percentage of side effects of antibiotic therapy, recent studies have shown they proposed using probiotics as an auxiliary or supplementation during the treatment. This is useful because it decreases the undesirable effects of antibiotics, improves the eradication rates, and improves compliance.^[39]

Clinical/preclinical effect of probiotics in treating peptic ulcers caused by H. pylori

Probiotics are live microorganisms that confer a health benefit on the host when administered in adequate amounts. While they are commonly associated with promoting gut health and aiding digestion, their role in managing peptic ulcers has recently gained attention. ^[49] Probiotics have been investigated for their potential role in managing peptic ulcers through several mechanisms.

Various clinical and preclinical studies have recently been performed to establish the efficacy and safety of probiotics therapy in managing H.pylori-induced peptic ulcer; a few examples are cited in [Table 1]. One of the randomized clinical studies was performed in Xijing Hospital of Digestive Diseases, where triple therapy comprising Clostridium butyricum and Bacillus coagulans, esomeprazole, clarithromycin and amoxicillin, shows eradications of H.pylori in the peptic ulcer patients after six weeks.^[50] Similarly, the efficacy of the combination of probiotics is comprised of Lactobacillus rhamnosus GG, L. rhamnosus LC705, and Propionibacterium freudenreichii ssp. shermanii JS and Bifidobacterium breve Bb99 against 39 H.pylori-infected patients, showing slight alteration of infection after nine weeks of treatment.^[51]

As summarised in [Table 1], Probiotics can be used as adjunct antibiotic therapy to treat H. pylori-induced ulcerations. They can manage the dysbiosis caused by antibiotic treatment and help reduce the side effects caused by it. Probiotic strains like Bifidobacterium and Lactobacillus improved antibiotic tolerability during H. pylori treatment and enabling the replenishment of normal flora post-treatment. Probiotics can also modulate the host's immune response by producing anti-inflammatory cytokines and promoting conditions that reduce inflammation, promote mucosal integrity and alleviate ulcer-related symptoms.