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Exploring the Gut Microbiome's Influence on Peptic Ulcer Disease: Mechanistic Insights, Pharmacological Implications, and Emerging Therapeutic Strategies

¹ Deepannita Roy Mukherjee, ² Sayak Tanbir, ³ Sohel Mondal, ⁴ Soumik Tarafdar, ⁵ Dona Biswas, ⁶ Soumyadeb Dutta, ⁷ Saikat Santra, * ⁸ Pinki Biswas

¹ Department of Pharmacology, JRSET College of Pharmacy, Panchpota, Chakdaha, Nadia, PIN- 741222(WB).

² Department of Pharmacology, Maulana Abul Kalam Azad University of technology (WB) Haringhata Farm, West Bengal 741249

³ Department of Pharmacology, JRSET College of Pharmacy, Panchpota, Chakdaha,Nadia, PIN-741222 (WB)

⁴ Department of Pharmaceutical Chemistry, JRSET College of Pharmacy, Panchpota, Chakdaha,Nadia, PIN-741222 (WB)

⁵ Department of Pharmaceutics, JRSET College of Pharmacy, Panchpota, Chakdaha, Nadia, PIN-741222(WB)

⁶ Department of Pharmacology, JRSET College of Pharmacy, Panchpota, Chakdaha, Nadia, PIN- 741222

⁷ Department of Pharmaceutics, JRSET College of Pharmacy, Panchpota, Chakdaha, Nadia, PIN-741222(WB)

⁸ Department of Pharmaceutics, JRSET College of Pharmacy, Panchpota, Chakdaha, Nadia, PIN- 741222(WB)

1. Introduction

Peptic ulcer disease (PUD) is mucosal break (ulcer) of the inner lining of the gastrointestinal tract caused by acid peptic digestion found when the ulcer extends beyond the muscularis mucosae to the submucosa. It occurs most commonly in the stomach and first part of the duodenum, but can be found distally in the esophagus, distally in the duodenum, and in the Meckel’s diverticulm with heterotopic gastric mucosa¹. Abdominal pain is common; it is described as a burning or gnawing sensation, not usually severe, and is associated with bloating, nausea, and changes in appetite. Infection with Helicobacter pylori and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly on a long term, are the primary causes of PUD². H. pylori is diagnosed with the help of a combination of medical history, endoscopy, and imaging and laboratory tests. Treatment strategies include medication – proton pump inhibitors (PPIs) to reduce stomach acid, antibiotics to clear out the H. pylori, and lifestyle changes to reduce the risk of ulcers. Untreated, PUD can be complicated by severe complications including gastrointestinal bleeding, perforation of stomach or intestinal walls, and gastric outlet obstruction³. Therefore, PUD management is crucial for enhancing the quality of life and preventing complications but only effective. Early diagnosis and treatment can result in recovery and reduce a psychiatric disorder’s recurrence⁴.

2. Traditional role of Helicobacter pylori in PUD

Helicobacter pylori (H. pylori) play a traditional and significant role in the development of peptic ulcer disease (PUD). This gram-negative bacterium colonizes the gastric mucosa and is considered one of the primary etiological agents of both gastric and duodenal ulcers⁵. Here are the key aspects of its role in PUD:

2.1 Colonization: H. pylori can survive in the acidic environment of the stomach by producing urease, an enzyme that converts urea into ammonia, neutralizing stomach acid and allowing the bacteria to thrive in the gastric epithelium⁶.

2.2 Induction of Inflammation: The presence of H. pylori induces chronic inflammation (chronic gastritis) in the stomach lining. The bacterium elicits an immune response that leads to the release of pro-inflammatory cytokines and immune cells, causing damage to the gastric mucosa⁷.

2.3 Mucosal Damage: H. pylori produce several virulence factors, including cytotoxins, which can directly injure the epithelial cells of the stomach. This damage disrupts the protective mucosal, chronically inflamed mucosa more susceptible to acid-peptic injury and prone to peptic ulceration⁸.

2.4 Ulcer Formation: The inflammatory response and mucosal damage caused by H. pylori contribute to the development of ulcers. Gastric and duodenal ulcers occur when the balance between protective factors (like mucus and bicarbonate) and aggressive factors (such as acid and pepsin) is disrupted^1,9.

3. Expanding understanding of the gut microbiome in gastrointestinal health

In the gastrointestinal tract exists a complex microbiological system which functions fundamentally for human health, scientific investigations of the microbiome during recent times have successfully revealed new information about how this ecosystem operates in health systems and disease contexts including PUD and various gastrointestinal diseases¹⁰.

New discoveries about gut microbiome produce essential findings about its operation and structure together with its effects on health and digestive conditions¹¹.

3.1 Diversity and Composition: The gut microbiome maintains multiple bacteria alongside archaea and viruses along with fungi which compose its structural variety. Multiple health functions require an equilibrium within the microbiome due to specific functions provided by different microorganisms which include nutrient breakdown together with immune response management¹².

3.2 Role in Digestion: During digestion, gut microorganisms break down complex fibers and carbohydrates because human enzymes lack this ability. The substrates undergo fermentation by these microorganisms to create short-chain fatty acids (SCFAs) that both generate energy for intestinal cells while simultaneously displaying anti-inflammatory properties. Microbes produce all the enzymes required for synthesizing vitamins such as B1, B9, B12 and K¹³.

3.3 Immune Function: Through mechanisms the gut microbiome establishes important regulation of the immune system capabilities. This process enables the correct identification of dangerous pathogens apart from beneficial substances to stop misdirected immune responses which result in inflammatory bowel disease and food allergies. The absence of a healthy gut microbiome makes individuals prone to develop two specific bacterial infections that affect GI tract: C. difficile and H. pylori¹³.

3.4 Interaction with Pathogens: A healthy gut microbiome protects individuals from pathogenic bacteria through its interactive mechanism including H. pylori. Healthy bacteria defend against pathogenic microbes through resource acquisition and substance production to decrease disease development including PUD and infections¹⁴.

3.6 Influence on Metabolism: The gut microbiome is involved in metabolic processes, including the synthesis of vitamins and the regulation of lipid and glucose metabolism. Dysbiosis (imbalance in the microbiome) has been linked to obesity, diabetes, and metabolic syndrome¹⁵.

3.7 Gut-Brain Axis: The microbiome communicates with the central nervous system through the gut-brain axis, influencing mood, stress responses, and behaviour. This connection highlights the microbiome's potential role in mental health and neurological conditions¹⁶.

3.8 Therapeutic Potential: Understanding the gut microbiome opens new avenues for therapeutic interventions. Probiotics, prebiotics, and dietary modifications can help restore microbiome balance, promoting gastrointestinal health and potentially alleviating conditions like PUD and IBD¹⁷.

4. Mechanism of Gut Bacteria in Peptic Ulcer Pathogenesis

Tissue underlying peptic ulcers becomes exposed after the breakdown of a protective mucosal layer enables gastric acid to damage the vulnerable area. H. Pylori serves as the most recognized bacterial factor in creating ulcers yet gut bacteria without H. Pylori also significantly contributes to ulcer development¹⁸. The bacteria damage gastric mucosa through changes to gut microbiota ecology and mucin breakdown leading to breakdown of tight junction proteins. Bacteria set off inflammation upon activation of Toll-like receptors (TLRs) on gastric epithelial cells which result in the release of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α¹⁹. The ulcer-forming process becomes accelerated because bacterial-induced production of reactive oxygen species (ROS) and oxidative stress combined with inflammation damages gastric cells. The gastric pH and mucosal permeability are altered when bacterial metabolites, particularly short-chain fatty acids (SCFAs) such as acetate and propionate butyrate trigger risk increased susceptibility to ulcers. The bacterial imbalance known as dysbiosis increases both stomach acid levels and degrades protective defense systems while permitting excessive bacterial growth²⁰. The identification of novel bacterial interactions with H. pylori provides important insights into peptic ulcer development. However, H. pylori continue to be the primary pathogenic factor which suggests new therapeutic targets based on gut microbiota management^21,22.

Figure 1: The diagram of H. pylori pathogenesis where urease neutralizes acid, disrupting the epithelial barrier and triggering apoptosis. Macrophages activate Th1 and Th2 cells, leading to cytokine release, inflammation, and immune evasion. Persistent immune responses weaken the mucosal barrier, promoting ulcer formation^23,24.

5. Gut Microbial Dysbiosis and Its Role in Peptic Ulcer Disease (PUD)

Peptic ulcer disease (PUD) is a disease of pathogenesis which is related with gut microbial dysbiosis, abnormality of the microbial community. However, even conditions of gut microbiota disruption may worsen ulcer formation, impede healing and promote treatment resistance in the presence of Helicobacter pylori (H. pylori) as the key bacterial factor²⁵. A healthy gut microbiome maintains mucosal integrity, modulates immune responses, and affects the regulation of gastric acid secretion. But when dysbiosis means problems with these protective mechanisms, the possibility of injuring the gastric mucous is enhanced²⁶. This weakness of mucosal barrier is a consequence of loss of beneficial microbes like Lactobacillus and Bifidobacterium, which produce short chain fatty acids (SCFAs) required to maintain gastric homeostasis. Increased epithelial permeability as well as makes the stomach lining more susceptible to acid related injury²⁷.

Also, holistic dysbiosis promotes the overgrowth of opportunistic pathogens, such as Escherichia coli, Klebsiella, Enterococcus and Clostridium²⁸. They release virulence factors, trigger mucin loss, and produce proinflammatory cytokines, including IL-1β, IL-6 and TNF α, which result in chronic inflammatory and oxidative stress²⁸. Moreover, microbial imbalance changes gastric signalling patterns of acid secretion to further aggravate mucosal damage. Drugs are directly influenced by dysbiosis, in terms of metabolism and efficacy. PUD treatment antibiotics in the treatment of PUD influence absorption of PPIs and antibiotics by the gut microbiota. A reduced drug effectiveness and participation in antibiotic resistance via an imbalanced microbiome may impair H. pylori eradication²⁹.

For dysbiosis in PUD management, one should address the disequilibrium by using probiotics, prebiotics, and microbiome friendly therapies. Like Lactobacillus and Bifidobacterium, probiotics help quell pathogenic bacteria, build up the mucosal barrier, and decrease the level of inflammation³⁰. Dietary modification consisting of increase Fiber intake stimulates the growth of beneficial bacteria that also increases SCFA production. Antimicrobial and anti-inflammatory natural compounds like curcumin, polyphenols, and flavonoids are microbiome friendly alternatives to conventional treatments³¹. Future therapeutic approaches may involve personalized microbiome profiling to develop targeted interventions that optimize gut health and improve PUD outcomes. By integrating microbiome-based strategies with standard medical treatments, it is possible to enhance ulcer healing, reduce recurrence, and improve overall gastrointestinal health³².

Figure 2: Role of IgA in Regulating Gut Microbiota and Its Impact on Peptic Ulcer Disease IgA regulates the gut microbiome, which is crucial in preventing gut microbial dysbiosis—a key factor in peptic ulcer disease (PUD). Dysbiosis occurs when harmful bacteria outnumber beneficial ones, triggering inflammation and mucosal damage. The immune system responds by releasing IgA, which helps maintain microbial balance by preventing harmful bacterial overgrowth. When IgA functions properly, gut microbiota return to homeostasis, reducing inflammation and protecting against ulcers³³.

6. Bacterial Interactions with Gastric Epithelial Cells

Gut bacteria can interact directly with the gastric epithelial cells, disrupting the epithelial barrier, cellular damage, and ulcer formation⁴. While H. pylori is well-known for its ability to adhere to gastric epithelial cells via specific adhesins, non-H. pylori bacteria can also colonize the stomach and contribute to mucosal injury¹⁸.

6.1 Adhesion and Colonization: Certain non-H. pylori bacteria, such as Streptococcus, Enterococcus, and Lactobacillus, can colonize the gastric mucosa. These bacteria may adhere to epithelial cells through different adhesions and surface proteins, which allow them to persist in the stomach despite the acidic environment³⁴.

6.2 Barrier Disruption: The presence of gut bacteria on the epithelial surface can disrupt tight junctions between cells. This disruption increases the permeability of the gastric mucosa, allowing stomach acids and other irritants to penetrate the epithelial layer, causing inflammation and ulceration³⁵.

6.3 Cytotoxic Effects: Some bacterial strains, such as cytotoxins or proteases, produce toxins or enzymes that damage epithelial cells. This cytotoxic effect can lead to cell death, triggering tissue damage, inflammation, and eventually ulcer formation³⁶.

7. Inflammatory Responses Triggered by Non-H. pylori Bacteria

The interaction between gut bacteria and the host's immune system is critical in peptic ulcer pathogenesis. Even without H. Pylori and other bacterial species can induce an inflammatory response contributing to ulcer formation³⁷.

7.1 Pattern Recognition Receptors (PRRs): Non-H. pylori bacteria can activate pattern recognition receptors like Toll-like receptors (TLRs) on gastric epithelial cells and immune cells. The activation of TLRs leads to the production of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α). These cytokines can promote inflammation, leading to tissue damage and ulcer development³⁸.

7.2 Neutrophil and Macrophage Activation: The inflammatory response recruit’s immune cells such as neutrophils and macrophages to the site of infection. The activated immune cells release reactive oxygen species (ROS) and proteolytic enzymes, which can damage the gastric mucosa and contribute to ulcer formation³⁹.

7.3 Microbial Dysbiosis: Imbalances in gut microbiota composition, also known as dysbiosis, can exacerbate inflammation. For example, increasing pathogenic bacteria or decreasing protective commensal bacteria may enhance the inflammatory response, leading to chronic gastritis and peptic ulcer development⁴⁰.

8. Role of Metabolites (e.g., Short-Chain Fatty Acids) in Ulcer Formation

Metabolites produced by gut bacteria, such as short-chain fatty acids (SCFAs), can also influence the pathogenesis of peptic ulcers. SCFAs are primarily produced through fermentation of dietary Fibers by gut microbiota, including acetate, propionate, and butyrate⁴¹.

8.1 Protective Effects of SCFAs: SCFAs, especially butyrate, have anti-inflammatory and protective effects on the gastric mucosa. They can help maintain the integrity of the epithelial barrier by enhancing mucus production and stimulating the proliferation of epithelial cells. However, when dysbiosis occurs, the beneficial effects of SCFAs may be reduced, leading to increased susceptibility to ulceration^17,42.

8.2 Butyrate and Mucosal Repair: Butyrate can promote mucosal healing by inducing the expression of genes associated with cell growth and repair. It also has the potential to inhibit the expression of pro-inflammatory cytokines, thus reducing inflammation and aiding in the resolution of peptic ulcers⁴³.

8.3 Dysbiosis and Altered SCFA Production: Changes in gut microbiota composition may alter the production of SCFAs. For instance, an overgrowth of certain bacteria may increase the production of toxic metabolites, such as ammonia or secondary bile acids, which can disrupt the gastric barrier and lead to ulcer formation. Reducing butyrate-producing bacteria can also impair mucosal healing and increase the risk of chronic ulcers⁴⁴.

Table: 1 Drug Use and Its Impact on Gut Microbiome in Peptic Ulcer Disease

9.

9. Natural Drugs and Phytochemicals in Modulating Gut Microbiome for Peptic Ulcer Treatment

Peptic ulcers are primarily caused by the bacterium Helicobacter pylori (H. pylori) and the prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs). A key factor in both their development and treatment is the role of the gut microbiome⁵¹. Natural drugs and phytochemicals are increasingly studied for their potential to modulate gut health and combat infections like H. pylori. Here’s how some prominent natural compounds play a role:

9.1 Role of Natural Compounds in Gut Health

9.1.1 Curcumin (from turmeric): Curcumin is a potent anti-inflammatory and antioxidant compound. It has been shown to enhance gut health by modulating the gut microbiome, promoting the growth of beneficial bacteria, and reducing gut inflammation. Curcumin’s role in inhibiting the adhesion of H. pylori to the gastric mucosa and reducing inflammatory responses makes it useful in preventing or treating ulcers. It also helps to reduce the oxidative stress caused by H. pylori, further supporting gut integrity⁵².

9.1.2 Ginger: Ginger contains bioactive compounds like gingerols and shogaols that have anti-inflammatory, antioxidant, and antimicrobial effects. Ginger helps maintain gut health by reducing inflammation and modulating gut motility. Studies have shown that ginger extracts can inhibit the growth of H. pylori and improve gastric mucosal health by increasing mucus secretion, which acts as a protective layer against acid and bacterial invasion⁵³.

9.1.3 Garlic: Garlic contains allicin, a compound with potent antimicrobial properties. Garlic has shown significant activity against H. pylori and other gut pathogens that contribute to ulcer formation. It also helps balance the gut microbiome by promoting beneficial bacteria while suppressing harmful ones. The antibacterial, antifungal, and immune-boosting properties of garlic make it effective in preventing bacterial overgrowth and enhancing gut health⁵³.

9.2 Phytochemicals and Their Antibacterial Activity against H. pylori and Other Ulcer-related Bacteria

9.2.1 Polyphenols: These are a class of phytochemicals found in fruits, vegetables, and herbs like green tea, berries, and olive oil. Polyphenols have demonstrated antibacterial activity against H. pylori by disrupting bacterial membranes, inhibiting its growth, and reducing its ability to colonize the stomach lining. Epigallocatechin gallate (EGCG), a polyphenol in green tea, has been shown to suppress H. pylori growth and reduce gastric inflammation⁵⁴.

9.2.2 Flavonoids: Flavonoids are potent antioxidants found in plants like chamomile, liquorice, and apples. Their antibacterial activity against H. pylori includes inhibiting bacterial enzymes and suppressing its urease activity, which is essential for H. pylori survival in the acidic stomach environment. Flavonoids like quercetin and rutin are effective in reducing gastric acid secretion, promoting mucus production, and enhancing gastric mucosal defence⁵⁵.

9.2.3 Tannins: Found in foods like tea, coffee, and berries, tannins possess antibacterial properties that have been found effective against H. pylori. Tannins inhibit bacterial adhesion to the stomach lining and reduce inflammation associated with ulcers⁵⁶.

10. Plant-based Therapies to Restore Microbiome Balance and Promote Ulcer Healing

10.1 Probiotics and Prebiotics: Probiotic supplements containing beneficial bacteria (e.g., Lactobacillus and Bifidobacterium species) help restore microbiome balance disrupted by H. pylori infections or the use of antibiotics in ulcer treatment. Probiotics have shown the ability to suppress H. pylori growth, modulate immune responses, and enhance the healing of gastric mucosa. Prebiotics, which are fibers that feed beneficial bacteria, can help sustain a healthy gut environment⁵⁷.

10.2 Liquorice (Glycyrrhiza glabra): Deglycyrrhizinated licorice (DGL) is often used as a natural remedy for ulcers. It helps promote the secretion of protective mucus in the stomach and acts as an anti-inflammatory agent. Licorice can also suppress H. pylori growth and enhance the healing of ulcers.

10.3 Aloe Vera: Aloe vera has soothing and healing properties that can support the healing of the gastric lining. It contains bioactive compounds with anti-inflammatory and antimicrobial effects. Aloe vera has been shown to promote mucus production, which protects the stomach lining from the harmful effects of gastric acid and bacteria⁵⁸.

10.4 Slippery Elm (Ulmus rubra): Slippery elm contains mucilage, a gel-like substance that coats and soothes the stomach lining. It has been used in herbal medicine to treat ulcers by protecting the stomach from acid and aiding in the healing of inflamed tissues⁵⁹.

10. Clinical Applications of Various Probiotics, Prebiotics and Symbiotic

Probiotics, prebiotics, and symbiotics play a vital role in managing peptic ulcer disease (PUD) by restoring gut microbiota balance, reducing inflammation, and promoting mucosal healing.

10.1 Probiotics such as Lactobacillus acidophilus, Bifidobacterium bifidum, and Saccharomyces boulardii help suppress H. pylori, enhance immune responses, and reduce antibiotic side effects. They also improve gut barrier integrity and reduce inflammation⁵⁷.

10.2 Prebiotics like inulin, fructose oligosaccharides (FOS), and resistant starch stimulate beneficial bacteria, enhance short-chain fatty acid (SCFA) production, and support epithelial repair⁶⁰.

10.3 Symbiotic, a combination of probiotics and prebiotics, further enhance gut health by improving microbial colonization, boosting immune function, and accelerating ulcer healing. These therapies serve as effective adjuncts to conventional PUD treatment, improving eradication success rates while minimizing gastrointestinal side effects⁶¹.

11. Gut Microbiota and Obesity

The gut microbes maintain the metabolic equilibrium of the host. Another study, for example, found that the gut microbiota of adult population with type 2 diabetes differs from that of non-diabetic adults, and that health of the subjects may improve by modulating their gut microflora by probiotics and prebiotics administration. Although these findings and the linkage between obesity and diabetes and abdominal fat presence, few studies have been directed at identifying putative correlation between composition of the microbiota and occurrence of inflammation and metabolic changes in humans with obesity⁶². Patients with diabetes mellitus were studied in which those individuals had a lower number of Faecalibacterium prausnitzii and higher levels of inflammatory markers. Large changes in the abundances of various bacteria from different taxa, however, were found to be associated with obesity⁶³.

Individuals with obesity have lower Bifidobacteria population (and most other organisms in the group of Firmicutes) as compared to lean individuals. As we also found in patients with type 2 diabetes mellitus to nondiabetic patients. These results indicate that Bifidobacteria might also have an involvement in the genesis of obesity and associated comorbidities. Bacteria used prebiotics such as inulin-type fructus as energy substrates when the mice were fed prebiotics such as inulin-type fructus. Levels of lipopolysaccharide, glucose tolerance, and fat mass developed were inversely correlated, and Bifidobacteria number increased much. Additionally, the prebiotic approach inhibited overexpression of many proadiposity and proinflammatory host genes⁶⁴.

11.Faecal Microbiota Transplantation

Studies show that IBD causes changes to gut microbiota diversity and includes increased pathogen levels alongside decreased commensal bacteria populations. For this reason health experts view FMT as an emerging IBD therapeutic option. FMT employs donor fecal material as a treatment method to return intestinal microbiota back to its normal state after pathology-induced changes in the recipient patient. FMT exists in two different delivery forms: the lower gastrointestinal tract and the upper gastrointestinal tract. Enema and colonoscopy and sigmoidoscopy belong to the former category while endoscopy and nasoduodenal tube and capsule ingestion constitute the latter. Research continues to evaluate the effectiveness of FMT therapy despite its proven ability in Clostridium difficile infection recurrence⁶⁵.

12. Future Perspectives

In the areas of peptic ulcer disease (PUD), future research seeks to develop novel therapies with microbiome and personalized medicine as well as highly advanced diagnostics. Such microbiome targeted therapies include probiotics, prebiotics and symbiotic etc., which are expected to restore the obliterated microbial balance and to improve gut health⁶⁶. Moreover, there are also safer and more effective treatment options, including microbiome friendly antibiotics and phytochemicals in novel drug formulations. Genomic and Microbiome profiling will apply to personalize medicine with personalized therapies based on individual susceptibility and microbial composition⁶⁷. Early detection and monitoring on microbial imbalances will be facilitated by advanced diagnostic tools such as artificial intelligence (AI) and non-invasive biomarkers. Precise ways to get rid of harmful bacteria while preserving the healthy bacteria may be provided by CRISPR-based microbiome editing as well as by genetically engineered probiotics⁶⁸. In addition, mucosal vaccines targeting H. pylori may provide a long-term prevention, and FMT as a therapy for patients with resistant cases. Further optimization of patient outcomes will continue to be achieved with holistic treatment models incorporating dietary interventions and gut brain axis therapies. Future work will also expand clinical trials and develop regulatory frameworks to validate proof of safety and efficacy of these microbiome approaches to prevention and management of PUD⁶⁹.

13. Conclusion

Peptic Ulcer Disease (PUD) is a persistent condition affected by Helicobacter pylori (H. pylori), nonsteroidal anti-inflammatory drugs (NSAIDs), and gut microbial interactions. While advances in microbiome research have enhanced the understanding of PUD pathogenesis based on microbial diversity, inflammation and metabolites (short chain fatty acids), traditional treatments remain a problem. While there are antibiotics, proton pump inhibitors (PPIs) and H2 receptor antagonists for addressing the ulcers, they also affect the microbial balance of your gut causing dysbiosis and other complications.

This calls for searching for therapeutic alternatives that are microbiome friendly. Natural compounds including curcumin, polyphenols, flavonoids and probiotics modulate gut microbiota, reduce inflammation, and improve mucosal protection and are promising. In addition, such peanuts might assist in restoring microbial homeostasis while ulcer healing while causing little side effects.

To optimize PUD treatment, future innovations in microbiome engineering and personalized medicine will be important. Interventions tailored for individual microbial compositions can be based on advanced diagnostics such as next generation sequencing and metabolomics. Restoring gut homeostasis will likely be achieved by further revolutionizing treatment from the emerging therapies like genetically engineered probiotics and fecal microbiota transplantation (FMT).

In order to bridge the conventional management of PUD and microbiome-based treatments one has to approach with a multidisciplinary research approach that integrates gastroenterology, microbiology and precision medicine. By focusing on microbiome health as much as possible, along with other treatments, healthcare providers can increase the success rates in recovery, reduce recurrence of ulcers, and minimize long term complications. A microbiome focused shift toward integrative comer of ulcer care is likely to boost efficacy and maintainability of ulcer management, and lead the way for next generation, patient centred ulcer management.

Conflict of Interest: The authors declare no potential conflict of interest with respect to the contents, authorship, and/or publication of this article.

Author Contributions: All authors have equal contribution in the preparation of manuscript and compilation.

Source of Support: Nil

Funding: The authors declared that this study has received no financial support.

Informed Consent Statement: Not applicable.

Data Availability Statement: The data supporting in this paper are available in the cited references.

Ethical approval: This study does not involve experiments on animals or human subjects.

References

1. Harsha C, Banik K, Bordoloi D, Kunnumakkara AB. Antiulcer properties of fruits and vegetables: A mechanism based perspective. Food and Chemical Toxicology, 2017; 108:104-119. https://doi.org/10.1016/j.fct.2017.07.023
2. Smith ME, Morton DG. The stomach. In: The Digestive System. 2nd ed. Elsevier; 2010:51-69. https://doi.org/10.1016/B978-0-7020-3367-4.00004-9
3. Wallace JL. Recent advances in gastric ulcer therapeutics. Current Opinion in Pharmacology, 2005; 5(6):573-577. https://doi.org/10.1016/j.coph.2005.06.004
4. Malik TF, Gnanapandithan K, Singh K. Peptic ulcer disease. In: Helicobacter pylori. Springer; 2023:635-639. https://doi.org/10.1007/978-981-97-0013-4-54
5. Malfertheiner P, Mégraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: The Maastricht III consensus report. Gut, 2007; 56(6):772-781. https://doi.org/10.1136/gut.2006.101634
6. Elbehiry A, Marzouk E, Aldubaib M, et al. Helicobacter pylori infection: Current status and future prospects on diagnostic, therapeutic and control challenges. Antibiotics, 2023; 12(2):191. https://doi.org/10.3390/antibiotics12020191
7. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: Systematic review and meta-analysis. Gastroenterology, 2017; 153(2):420-429. https://doi.org/10.1053/j.gastro.2017.04.022
8. Kayali S, Manfredi M, Gaiani F, et al. Helicobacter pylori, transmission routes and recurrence of infection: State of the art. Acta Biomedica, 2018; 89:72-76. https://doi.org/10.23750/abm.v89i8-s.7947
9. Parikh NS, Ahlawat R. Helicobacter pylori. StatPearls. Published online August 8, 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534233/
10. Schloss PD, Handelsman J. Status of the microbial census. Microbiology and Molecular Biology Reviews, 2004; 68(4):686-691. https://doi.org/10.1128/MMBR.68.4.686-691.2004
11. Bull MJ, Plummer NT. Part 1: The human gut microbiome in health and disease. Integrative Medicine: A Clinician's Journal, 2014; 13(6):17. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4566439/
12. Oami T, Chihade DB, Coopersmith CM. The microbiome and nutrition in critical illness. Current Opinion in Critical Care, 2019; 25(2):145-149. https://doi.org/10.1097/MCC.0000000000000582
13. Leonard JM, Del Toro D. Defining the microbiome components (bacteria, viruses, fungi) and microbiome geodiversity. Surgical Infections, 2023; 24(3):208. https://doi.org/10.1089/sur.2023.014
14. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell, 2006; 124(4):837-848. https://doi.org/10.1016/j.cell.2006.02.017
15. Mazmanian SK, Kasper DL. The love-hate relationship between bacterial polysaccharides and the host immune system. Nature Reviews Immunology, 2006; 6(11):849-858. https://doi.org/10.1038/nri1956
16. Dethlefsen L, McFall-Ngai M, Relman DA. An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature, 2007; 449(7164):811-818. https://doi.org/10.1038/nature06245
17. Round JL, Mazmanian SK. The gut microbiome shapes intestinal immune responses during health and disease. Nature Reviews Immunology, 2009; 9(5):313. https://doi.org/10.1038/nri2515
18. Akin OY, Tsou VM, Werner AL. Gastrospirillum hominis-associated chronic active gastritis. Fetal and Pediatric Pathology, 1995; 15(3):429-435. https://doi.org/10.3109/15513819509026978
19. Akada JK, Shirai M, Takeuchi H, Tsuda M, Nakazawa T. Identification of the urease operon in Helicobacter pylori and its control by mRNA decay in response to pH. Molecular Microbiology, 2000; 36(5):1071-1084. https://doi.org/10.1046/j.1365-2958.2000.01918.x
20. Akhiani AA, Pappo J, Kabok Z, et al. Protection against Helicobacter pylori infection following immunization is IL-12-dependent and mediated by Th1 cells. Journal of Immunology, 2002; 169(12):6977-6984. https://doi.org/10.4049/jimmunol.169.12.6977
21. Kusters JG, Van Vliet AHM, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews, 2006; 19(3):449-490. https://doi.org/10.1128/CMR.00054-05
22. Achtman M, Suerbaum S. Sequence variation in Helicobacter pylori. Trends in Microbiology, 2000; 8(2):57-58. https://doi.org/10.1016/S0966-842X(99)01676-5
23. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer, 2019; 144(8):1941-1953. https://doi.org/10.1002/ijc.31937
24. Reyes VE. Helicobacter pylori and its role in gastric cancer. Microorganisms, 2023; 11(5):1312. https://doi.org/10.3390/microorganisms11051312
25. Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nature Genetics, 2021; 53(2):156-165. https://doi.org/10.1038/s41588-020-00763-1
26. Zhao JH, Stacey D, Eriksson N, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nature Immunology, 2023; 24(9):1540-1551. https://doi.org/10.1038/s41590-023-01588-w
27. He Y, Koido M, Sutoh Y, et al. East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease. Nature Genetics, 2023; 55(12):2129-2138. https://doi.org/10.1038/s41588-023-01569-7
28. Mujadzic H, Noorani S, Riddle PJ, et al. Ulcer bleeding in the United States: Epidemiology, treatment success, and resource utilization. Digestive Diseases and Sciences, 2024; 69(6):1963-1971. https://doi.org/10.1007/s10620-024-08322-y
29. Li W, Lv BM, Quan Y, Zhu Q, Zhang HY. Associations between serum mineral nutrients, gut microbiota, and risk of neurological, psychiatric, and metabolic diseases: A comprehensive Mendelian randomization study. Nutrients, 2024; 16(2):244. https://doi.org/10.3390/nu16020244
30. Sanders ME, Merenstein DJ, Reid G, Gibson GR, Rastall RA. Probiotics and prebiotics in intestinal health and disease: From biology to the clinic. Nature Reviews Gastroenterology & Hepatology, 2019; 16(10):605-616. https://doi.org/10.1038/s41575-019-0173-3
31. Agirman G, Yu KB, Hsiao EY. Signaling inflammation across the gut-brain axis. Science, 2021; 374(6571):1087-1092. https://doi.org/10.1126/science.abi6087
32. Li J, Cai H, Zhang Y, et al. Dysbiosis of gut microbiota is associated with pathogenesis of peptic ulcer diseases through inflammatory proteins: A Mendelian randomization study. Medicine (Baltimore), 2024; 103(39):e39814. https://doi.org/10.1097/MD.0000000000039814
33. Monteiro RC, Rafeh D, Gleeson PJ. Is there a role for gut microbiome dysbiosis in IgA nephropathy? Microorganisms, 2022; 10(4):683. https://doi.org/10.3390/microorganisms10040683
34. Backert S, Clyne M, Tegtmeyer N. Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Communication and Signaling, 2011; 9:28. https://doi.org/10.1186/1478-811X-9-28
35. Wroblewski LE, Peek RM. Targeted disruption of the epithelial-barrier by Helicobacter pylori. Cell Communication and Signaling, 2011; 9:29. https://doi.org/10.1186/1478-811X-9-29
36. Alzahrani S, Lina TT, Gonzalez J, Pinchuk IV, Beswick EJ, Reyes VE. Effect of Helicobacter pylori on gastric epithelial cells. World Journal of Gastroenterology, 2014; 20(36):12767. https://doi.org/10.3748/wjg.v20.i36.12767
37. Suzuki H, Moayyedi P. Helicobacter pylori infection in functional dyspepsia. Nature Reviews Gastroenterology & Hepatology, 2013; 10(3):168-174. https://doi.org/10.1038/nrgastro.2013.9
38. Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. The Lancet, 1983; 321(8336):1273-1275. https://doi.org/10.1016/S0140-6736(83)92719-8
39. Wroblewski LE, Peek RM, Wilson KT. Helicobacter pylori and gastric cancer: Factors that modulate disease risk. Clinical Microbiology Reviews, 2010; 23(4):713-739. https://doi.org/10.1128/CMR.00011-10
40. Ali A, AlHussaini KI. Helicobacter pylori: A contemporary perspective on pathogenesis, diagnosis and treatment strategies. Microorganisms, 2024; 12(1):222. https://doi.org/10.3390/microorganisms12010222
41. Kim MS, Kim Y, Choi H, et al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut, 2020; 69(2):283–294. https://doi.org/10.1136/gutjnl-2018-317431
42. Palm NW, de Zoete MR, Flavell RA. Immune-microbiota interactions in health and disease. Clinical Immunology, 2015; 159(2):122–127. https://doi.org/10.1016/j.clim.2015.05.014
43. Shin Y, Han S, Kwon J, et al. Roles of short-chain fatty acids in inflammatory bowel disease. Nutrients, 2023; 15(20):4466. https://doi.org/10.3390/nu15204466
44. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. The New England Journal of Medicine, 2016; 375(24):2369–2379. https://doi.org/10.1056/NEJMra1600266
45. Freedberg DE, Lebwohl B, Abrams JA. The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clinics in Laboratory Medicine, 2014; 34(4):771. https://doi.org/10.1016/j.cll.2014.08.008
46. Nugent CC, Falkson SR, Terrell JM. H2 blockers. Journal of Clinical Gastroenterology, 2024; 5:143–148. https://doi.org/10.1097/00004836-198312001-00014
47. Zaman T, Haq A, Ahmad R, et al. The role of probiotics in the eradication of Helicobacter pylori and overall impact on management of peptic ulcer: A study involving patients undergoing triple therapy in Bangladesh. Cureus, 2024; 16(3):e56283. https://doi.org/10.7759/cureus.56283
48. Alkim H, Koksal AR, Boga S, Sen I, Alkim C. Role of bismuth in the eradication of Helicobacter pylori. American Journal of Therapeutics, 2017; 24(6):E751–E757. https://doi.org/10.1097/MJT.0000000000000389
49. Tai FWD, McAlindon ME. Non-steroidal anti-inflammatory drugs and the gastrointestinal tract. Clinical Medicine (Northfield Il), 2021; 21(2):131. https://doi.org/10.7861/clinmed.2021-0039
50. Ballinger A. Cytoprotection with misoprostol: Use in the treatment and prevention of ulcers. Digestive Diseases, 1994; 12(1):37–45. https://doi.org/10.1159/000171435
51. Zhang W, Lian Y, Li Q, et al. Preventative and therapeutic potential of flavonoids in peptic ulcers. Molecules. 2020;25(20):4626. https://doi.org/10.3390/molecules25204626
52. Kunnumakkara AB, Hegde M, Parama D, et al. Role of turmeric and curcumin in prevention and treatment of chronic diseases: Lessons learned from clinical trials. ACS Pharmacology & Translational Science. 2023;6(4):447–471. https://doi.org/10.1021/acptsci.2c00012
53. Mao QQ, Xu XY, Cao SY, et al. Bioactive compounds and bioactivities of ginger (Zingiber officinale Roscoe). Foods. 2019;8(6):185. https://doi.org/10.3390/foods8060185
54. Sharifi-Rad M, Roberts TH, Matthews KR, et al. Ethnobotany of the genus Taraxacum—phytochemicals and antimicrobial activity. Phytotherapy Research. 2018;32(11):2131–2145. https://doi.org/10.1002/ptr.6157
55. Sharifi-Rad M, Nazaruk J, Polito L, et al. Matricaria genus as a source of antimicrobial agents: From farm to pharmacy and food applications. Microbiological Research. 2018;215:76–88. https://doi.org/10.1016/j.micres.2018.06.010
56. de Jesus NZT, de Souza Falcão H, Gomes IF, et al. Tannins, peptic ulcers and related mechanisms. International Journal of Molecular Sciences. 2012;13(3):3203–3228. https://doi.org/10.3390/ijms13033203
57. Lukic J, Chen V, Strahinic I, et al. Probiotics or pro-healers? The role of beneficial bacteria in tissue repair. Wound Repair and Regeneration. 2018;25(6):912–922. https://doi.org/10.1111/wrr.12607
58. Rahnama M, Mehrabani D, Japoni S, Edjtehadi M, Saberi-Firoozi M. The healing effect of licorice (Glycyrrhiza glabra) on Helicobacter pylori-infected peptic ulcers. Journal of Research in Medical Sciences. 2013;18(6):532–535. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818629/
59. Slippery elm. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. Published January 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK599741/
60. Skoufou M, Tsigalou C, Vradelis S, Bezirtzoglou E. The networked interaction between probiotics and intestine in health and disease: A promising success story. Microorganisms. 2024;12(1):194. https://doi.org/10.3390/microorganisms12010194
61. Markowiak P, Ślizewska K. Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients. 2017;9(9):1021. https://doi.org/10.3390/nu9091021
62. Blottière HM. The gut microbiota and obesity. In: Energy Balance and Obesity. 2017. Accessed March 24, 2025. https://www.ncbi.nlm.nih.gov/books/NBK565809/
63. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500(7464):541–546. https://doi.org/10.1038/nature12506
64. Crudele L, Gadaleta RM, Cariello M, Moschetta A. Gut microbiota in the pathogenesis and therapeutic approaches of diabetes. eBioMedicine. 2023;97:104821. https://doi.org/10.1016/j.ebiom.2023.104821
65. Boicean A, Birlutiu V, Ichim C, Anderco P, Birsan S. Fecal microbiota transplantation in inflammatory bowel disease. Biomedicines. 2023;11(4):1016. https://doi.org/10.3390/biomedicines11041016
66. Choi KW, Chen CY, Stein MB, et al. Assessment of bidirectional relationships between physical activity and depression among adults: A 2-sample Mendelian randomization study. JAMA Psychiatry. 2019;76(4):399–408. https://doi.org/10.1001/jamapsychiatry.2018.4175