Gut Microbiota-Gastric Mucosal Defense Axis in Gastric Ulcer Pathogenesis: Impact on Drug Absorption

Burden of gastric ulcer disease

Despite improvements in acid-suppressive treatments and Helicobacter pylori eradication methods, Peptic ulcer disease (PUD) and gastric ulcers continue to be a global health concern. Approximately 4 million people get diagnosed with peptic ulcer disease, and based on epidemiological studies, peptic ulcer disease has a lifetime prevalence between 5-10 % for most people [1]. Global data reports that in 2019, we had a total of 8.09 million cases of PUD, which is an age standard of about 99 out of 100,000 people [2]. While we have seen progress with the introduction of proton pump inhibitors and H. pylori eradication protocols, which have in turn reduced mortality, this disease still plays a large role in inpatient care and the development of issues like bleeding and perforation. Also, we see this especially in the elderly and in patients who use non-steroidal anti-inflammatory drugs (NSAIDs) [3]. Also, at large, what we see is that peptic ulcer disease is still a very relevant clinical issue, which we need to put more research into in terms of its causes and also into what we can do to better prevent it.

Causes of ulcers: NSAIDs, Helicobacter pylori, stress, alcohol

The pathogenesis of gastric ulcer is multifactorial and is generally considered to result from an imbalance between aggressive factors (gastric acid, pepsin, inflammatory mediators) and mucosal defense mechanisms (mucus layer, prostaglandins, bicarbonate secretion, and mucosal blood flow) [4]. Among the etiological factors, Helicobacter pylori infection and non-steroidal anti-inflammatory drug (NSAID) use are recognized as the two most important contributors to ulcer development [5]. H. pylori infection alone has been reported to account for 70–90% of gastric ulcers and up to 90–95% of duodenal ulcers, primarily through induction of chronic inflammation, disruption of mucosal barriers, and increased acid secretion [6]. Similarly, NSAIDs cause gastric mucosal injury by inhibiting cyclooxygenase-mediated prostaglandin synthesis, which compromises mucus production, bicarbonate secretion, and mucosal blood flow [7]. In addition to these major causes, psychological stress, alcohol consumption, smoking, and systemic illness have been implicated as important risk factors that further exacerbate mucosal damage and ulcer formation [5]. The interaction of these factors ultimately disrupts gastric mucosal homeostasis, leading to epithelial erosion and ulceration.

Current Understanding

Despite extensive research, the current understanding of gastric ulcer pathogenesis remains incomplete. Traditional models primarily focus on acid secretion, prostaglandin inhibition, and H. pylori infection, often overlooking other biological systems involved in gastric mucosal defense. Moreover, a subset of ulcers occurs independently of H. pylori infection or NSAID exposure, suggesting that additional factors contribute to disease development [6]. Furthermore, the persistence of ulcer complications and recurrence in certain patients indicates that conventional pathogenic models may not fully explain disease variability, particularly in relation to host immunity, metabolic status, and microbial interactions within the gastrointestinal tract. These limitations highlight the need to explore emerging biological regulators involved in gastric mucosal integrity.

Emergence of gut microbiota in gastric diseases

Recent advances in microbiome research have revealed that the gastrointestinal tract harbours a complex microbial ecosystem that plays a crucial role in host metabolism, immunity, and mucosal barrier function [8]. Although the stomach was traditionally considered a hostile environment for microbial colonization due to its acidic pH, modern sequencing techniques have demonstrated the presence of diverse gastric and intestinal microbiota that interact with the gastric mucosa [9]. Emerging evidence suggests that microbial dysbiosis can influence gastric inflammation, epithelial integrity, and mucosal defense mechanisms, thereby contributing to the pathogenesis of gastric ulcers [10]. Additionally, stress-induced gastric injury has been shown to alter intestinal microbiota composition, which may further aggravate mucosal damage through immune and inflammatory pathways [11]. These findings have led to increasing recognition of a gut microbiota–gastric mucosal axis, highlighting the potential role of microbial interactions in ulcer development and therapeutic response.

1. PATHOPHYSIOLOGY OF GASTRIC ULCER

 Gastric ulcer formation is primarily explained by the imbalance between aggressive factors (acid, pepsin, NSAIDs, oxidative stress) and mucosal defensive mechanisms (mucus, bicarbonate, prostaglandins, mucosal blood flow, epithelial repair). When aggressive factors overwhelm protective mechanisms, the gastric mucosa becomes susceptible to erosion and ulcer formation [12].

Acid–pepsin aggression

Hydrochloric acid (HCl) and pepsin are the principal endogenous aggressive factors involved in gastric ulcer formation. Gastric acid is secreted by parietal cells through the H⁺/K⁺-ATPase proton pump, whereas pepsinogen, secreted by chief cells, is converted to pepsin in acidic conditions. Pepsin is a proteolytic enzyme capable of digesting mucosal proteins. Under normal physiological conditions, the gastric mucosa is protected by mucus, bicarbonate secretion, epithelial tight junctions, and adequate mucosal blood flow. However, when excessive acid or pepsin penetrates the mucosal barrier, it causes protein degradation, epithelial cell damage, and mucosal erosion, ultimately leading to ulceration [4]. Hypersecretion of acid may occur due to gastrin stimulation, vagal activation, histamine release from enterochromaffin-like cells, or Helicobacter pylori infection, all of which enhance parietal cell activity and increase gastric acidity. Persistent acid-pepsin exposure disrupts epithelial integrity and prevents mucosal healing, thereby promoting ulcer development [12].

NSAID-induced ulcer mechanisms

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common causes of gastric ulceration. These drugs induce mucosal injury through two principal mechanisms: prostaglandin inhibition and direct epithelial toxicity. NSAIDs inhibit cyclooxygenase enzymes (COX-1 and COX-2) responsible for converting arachidonic acid into prostaglandins. Prostaglandins (especially PGE2 and PGI2) normally maintain gastric mucosal integrity by:

• Stimulating mucus and bicarbonate secretion
• Maintaining mucosal blood flow
• Promoting epithelial restitution and repair

When NSAIDs suppress prostaglandin synthesis, these protective mechanisms are diminished, leaving the gastric mucosa vulnerable to acid-pepsin injury [13]. Additionally, NSAIDs exert topical irritant effects by disrupting phospholipid membranes of epithelial cells, increasing mucosal permeability and allowing acid back-diffusion into the mucosa. This leads to epithelial cell necrosis and ulcer formation.

Oxidative stress and inflammation

Oxidative stress plays a central role in gastric ulcer pathogenesis. It occurs when the production of reactive oxygen species (ROS) exceeds the antioxidant capacity of gastric tissues. ROS such as superoxide anions, hydroxyl radicals, and hydrogen peroxide damage cellular components, including lipids, proteins, and DNA. ROS promote lipid peroxidation of cell membranes, leading to loss of epithelial integrity and increased mucosal permeability. Oxidative stress also activates inflammatory signalling pathways such as NF-κB, resulting in increased expression of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. These cytokines further amplify mucosal inflammation and injury. In addition, oxidative stress depletes endogenous antioxidant systems such as glutathione (GSH), superoxide dismutase (SOD), and catalase, reducing the ability of gastric tissues to neutralize ROS. The combined effects of ROS accumulation and inflammatory mediators lead to progressive mucosal damage and ulcer formation [14].

Role of prostaglandin inhibition

Prostaglandins are key mediators of gastric mucosal protection and play a critical role in preventing ulcer formation. They are synthesized from arachidonic acid through the cyclooxygenase (COX) pathway in gastric epithelial cells. Prostaglandins exert several cytoprotective effects on the gastric mucosa:

• Increase mucus and bicarbonate secretion
• Maintain adequate mucosal blood flow
• Stimulate epithelial cell proliferation and restitution
• Inhibit excess gastric acid secretion

Loss or inhibition of prostaglandin synthesis, most commonly due to NSAID therapy, removes these protective effects and predisposes the mucosa to acid-induced injury. Reduced prostaglandin levels therefore represent a key step in gastric ulcer pathogenesis [15]. Experimental studies have demonstrated that exogenous prostaglandin analogues such as misoprostol can restore mucosal defense mechanisms and significantly reduce NSAID-induced gastric injury [16].

3. GASTRIC MUCOSAL DEFENSE MECHANISMS

Mucus barrier

The mucus-bicarbonate barrier represents the first line of defense against luminal acid and pepsin. Gastric surface epithelial cells secrete a viscous mucus gel composed primarily of mucins that trap bicarbonate ions, forming a protective layer over the epithelial surface. This layer creates a pH gradient, maintaining near-neutral pH at the epithelial surface even when the gastric lumen is highly acidic [17]. The mucus gel also functions as a physical diffusion barrier that limits hydrogen ion back-diffusion into epithelial cells and prevents pepsin-mediated proteolysis of the mucosa. In addition, the mucus layer can bind and neutralize various toxic agents present in the gastric lumen, thereby contributing to cytoprotection. Disruption of the mucus barrier increases epithelial susceptibility to acid injury and represents an important mechanism in gastric ulcer development.

Prostaglandins

Prostaglandins, particularly prostaglandin E2 (PGE2) and prostacyclin (PGI2), play a central role in maintaining gastric mucosal defense. These lipid mediators are synthesized from arachidonic acid via cyclooxygenase (COX) enzymes in gastric epithelial and endothelial cells. Prostaglandins enhance mucosal protection by stimulating mucus and bicarbonate secretion, inhibiting gastric acid secretion, and increasing mucosal blood flow. They also promote epithelial cell proliferation and accelerate mucosal repair following injury. The importance of prostaglandins in mucosal defense is evident from the fact that non-steroidal anti-inflammatory drugs (NSAIDs) cause gastric injury primarily by inhibiting prostaglandin synthesis [13].

Nitric oxide

Nitric oxide (NO) is another critical mediator involved in gastric mucosal defense. Produced mainly by nitric oxide synthase (NOS) in endothelial and epithelial cells, NO contributes to mucosal protection by promoting vasodilation, maintaining mucosal blood flow, and inhibiting leukocyte adhesion within the gastric microvasculature [18]. In addition, NO stimulates mucus secretion and enhances epithelial barrier function, thereby reducing susceptibility to gastric mucosal injury.

Gastric mucosal Blood flow

Adequate gastric mucosal blood flow is essential for maintaining mucosal integrity and facilitating tissue repair. The gastric microcirculation supplies oxygen and nutrients to epithelial cells while simultaneously removing toxic metabolites and hydrogen ions that diffuse into the mucosa [19]. Reduced mucosal perfusion can impair epithelial metabolism and compromise mucosal defense, increasing susceptibility to ulcer formation. Prostaglandins, nitric oxide, and sensory neuropeptides collectively regulate mucosal microcirculation and help maintain optimal blood flow under physiological conditions [20].

Epithelial restitution and regeneration

The gastric epithelium has a remarkable capacity for rapid repair following injury, a process known as epithelial restitution. This mechanism involves the migration of viable epithelial cells from adjacent areas to cover superficial mucosal defects without the need for cell proliferation [21]. Following restitution, cell proliferation and differentiation within the gastric glands restore the normal mucosal architecture. Growth factors, prostaglandins, and nitric oxide play important roles in regulating these repair processes by promoting epithelial cell migration, proliferation, and angiogenesis. Efficient epithelial regeneration is therefore crucial for maintaining mucosal integrity and preventing chronic ulcer formation [22].

4. GUT MICROBIOTA AND HOST PHYSIOLOGY

Composition and functions of gut microbiota

The human gastrointestinal tract harbours a highly diverse microbial community collectively referred to as the gut microbiota, consisting of trillions of microorganisms, including bacteria, viruses, and fungi. The dominant bacterial phyla in the human gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, which together contribute to the metabolic and physiological functions of the host. These microbial communities participate in essential processes such as the digestion of complex carbohydrates, vitamin synthesis (e.g., vitamin K and B vitamins), energy metabolism, and the maintenance of intestinal barrier integrity [23].

Gut microorganisms also produce enzymes that degrade otherwise indigestible dietary polysaccharides, generating metabolites that can be absorbed by the host. For instance, species within the genus Bacteroides possess enzymes that break down complex fibres, producing metabolites that serve as energy substrates for intestinal epithelial cells and influence host metabolism [24].

Host- microbiome symbiosis

The relationship between the host and gut microbiota is largely symbiotic, where both organisms benefit from mutual interactions. The host provides nutrients and a stable ecological niche for microbial growth, while the microbiota contributes to metabolic functions, immune system maturation, and protection against pathogenic microorganisms. This symbiotic relationship is essential for maintaining physiological homeostasis. Disruption of this balance, commonly referred to as dysbiosis, has been associated with various diseases, including metabolic disorders, inflammatory bowel disease, and gastrointestinal conditions. Metagenomic studies have shown that microbial diversity and gene richness are closely associated with host health status and immune regulation [25]. Through continuous interactions with epithelial cells and immune components in the intestinal mucosa, the microbiota participates in host signalling networks that regulate inflammation, nutrient metabolism, and barrier function.

Microbial metabolites (SCFAs, bile acid metabolism)

One of the most important mechanisms through which gut microbiota influences host physiology is the production of microbial metabolites. Among these, short-chain fatty acids (SCFAs)-including acetate, propionate, and butyrate-are generated through microbial fermentation of dietary fibres in the colon. SCFAs serve as a major energy source for colonocytes and function as signalling molecules that regulate epithelial barrier integrity, metabolic pathways, and inflammatory responses [26]. SCFAs also influence gene expression in immune and epithelial cells through mechanisms such as histone deacetylase inhibition, thereby modulating immune responses and maintaining intestinal homeostasis [27].

In addition to SCFAs, the gut microbiota plays a crucial role in bile acid metabolism. Primary bile acids synthesized in the liver are transformed by intestinal bacteria into secondary bile acids through processes such as deconjugation and dehydroxylation. These microbial metabolites regulate host metabolic pathways and interact with receptors such as farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), influencing intestinal barrier function, inflammation, and energy metabolism [28]. The microbiota–bile acid axis, therefore, represents a critical regulatory system linking microbial metabolism to host physiological functions.

Immune modulation.

The gut microbiota plays a fundamental role in the development and regulation of the host immune system. Microbial signals interact with immune cells within the intestinal mucosa, including macrophages, dendritic cells, T helper cells, and innate lymphoid cells, leading to the production of cytokines and other immune mediators. These interactions help maintain immune homeostasis and protect against pathogenic infections [29]. Microbial metabolites such as SCFAs and bile acid derivatives further regulate immune responses by influencing the differentiation and activity of immune cells, including regulatory T cells (Tregs), Th17 cells, and B cells. These interactions contribute to the maintenance of immune tolerance toward commensal microbes while enabling effective responses against pathogens [30].

5. GASTRIC AND INTESTINAL MICROBIOTA IN GASTRIC ULCER

Gastric microbiota (not only intestinal)

For decades, the stomach was considered nearly sterile because of its highly acidic environment. However, modern culture-independent sequencing techniques (16S rRNA and metagenomics) have demonstrated that the stomach contains a distinct microbial ecosystem, although the bacterial load is much lower than in the intestine. Gastric bacterial density is estimated at approximately 10²-10? CFU/mL, compared with 10¹?-10¹² CFU/mL in the colon [31]. The gastric microbial community typically includes bacterial phyla such as Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria, with common genera including Streptococcus, Prevotella, Veillonella, Rothia, and Haemophilus.

These microbes interact with gastric epithelial cells and contribute to mucosal homeostasis through modulation of immune responses, mucus secretion, epithelial barrier integrity, and inflammatory signalling pathways [31]. Although the intestinal microbiota contains far greater microbial diversity, increasing evidence indicates that the gastric microbiota itself plays an important role in gastric diseases, including gastritis and peptic ulcer disease. Dysbiosis within the gastric microbial ecosystem may disrupt mucosal defense mechanisms, promote inflammatory responses, and alter epithelial repair processes, thereby contributing to gastric ulcer pathogenesis [32].

Furthermore, gastric and intestinal microbiota are interconnected through metabolic, immune, and neuroendocrine pathways. Alterations in intestinal microbial composition may influence gastric physiology via microbial metabolites, immune signalling, and systemic inflammatory mediators, suggesting that gastric ulcer pathogenesis involves both gastric and intestinal microbial communities [11].

Influence of H. pylori on microbial community

Among gastric microorganisms, Helicobacter pylori is the most clinically significant pathogen and a major etiological factor in gastric ulcer disease. This Gram-negative bacterium colonizes the gastric mucosa by producing urease, which hydrolyses urea to ammonia and carbon dioxide, allowing the bacterium to survive in the acidic gastric environment. H. pylori infection can profoundly alter the composition and diversity of the gastric microbiota. In infected individuals, the microbial community is often dominated by the Helicobacter genus, resulting in reduced microbial diversity and suppression of other commensal bacterial taxa [33]. Importantly, H. pylori not only alter the gastric microbiota but also influences the intestinal microbial community. Population-based studies have shown that individuals infected with H. pylori exhibit significant alterations in fecal microbial composition, suggesting that gastric infection can affect microbial ecology throughout the gastrointestinal tract [34].

Effect of high-fat diet on microbiota

Dietary factors are among the most important environmental determinants of gut microbial composition. In particular, high-fat diets (HFD) have been shown to induce microbial dysbiosis in both intestinal and gastric microbial communities. Experimental studies demonstrate that high-fat diets can alter microbial diversity and increase the abundance of potentially pathogenic bacteria, particularly members of Proteobacteria, while reducing beneficial commensal microbes such as Lactobacillus. Diet-induced microbial dysbiosis is associated with increased intestinal permeability, systemic inflammation, and metabolic disturbances that may compromise gastric mucosal defense mechanisms. High-fat diet-induced microbiota alterations may also influence the severity of H. pylori infection by modifying immune responses and microbial metabolite production [35].

6. MICROBIOTA DYSBIOSIS IN GASTRIC ULCER PATHOGENESIS

Inflammation

Gut microbiota dysbiosis plays a significant role in the development of gastric ulcers by promoting chronic mucosal inflammation. Alterations in microbial composition can activate pattern recognition receptors such as Toll-like receptors (TLRs) on gastric epithelial cells, triggering downstream inflammatory signalling pathways. This leads to the production of pro-inflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, which disrupt gastric epithelial integrity and accelerate mucosal injury. Dysbiotic microbial communities may also increase the abundance of gram-negative bacteria that release lipopolysaccharide (LPS), further amplifying inflammatory responses and impairing mucosal defense mechanisms [36].

Oxidative stress.

Microbial dysbiosis contributes to the development of gastric ulcers by promoting oxidative stress in the gastric mucosa. Certain pathogenic microbial populations stimulate the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can damage lipids, proteins, and DNA in gastric epithelial cells. Increased ROS production disrupts cellular homeostasis, impairs mitochondrial function, and accelerates mucosal erosion [37].

Immune activation

Dysbiotic microbiota can dysregulate host immune responses and contribute to gastric ulcer pathogenesis through excessive immune activation. Microbial components such as LPS and peptidoglycans stimulate innate immune cells, including macrophages and dendritic cells, leading to the activation of NF-κB signalling pathways and the release of inflammatory mediators. This immune activation increases neutrophil infiltration and promotes the release of proteolytic enzymes and reactive oxygen species that damage gastric epithelial cells [38].

Microbial metabolites affecting mucosa

Gut microbiota produces a wide range of metabolites that can directly influence gastric mucosal physiology. These include short-chain fatty acids (SCFAs), bile acid derivatives, indole compounds, and microbial neurotransmitters. While some metabolites exert protective effects by strengthening epithelial barriers and regulating immune responses, dysbiosis may alter their production and lead to harmful outcomes [11]. Furthermore, microbial metabolites can interact with host signalling pathways involved in mucosal repair and immune regulation, thereby shaping the progression of gastric ulcers.

FIGURE 1: Microbiota dysbiosis drives gastric ulceration by impairing mucosal defenses and promoting inflammation-mediated epithelial barrier damage. _{[image generated by biorender.com & created with Microsoft power point]}

7. MICROBIOTA- GASTRIC MUCOSAL DEFENSE INTERACTION

Tight junction regulation

The integrity of the gastrointestinal epithelial barrier is primarily maintained by tight junction (TJ) proteins, including claudins, occludin, and zonula occludens (ZO-1), which regulate paracellular permeability between epithelial cells. Tight junctions act as the first structural barrier, preventing microbial translocation and luminal toxin penetration into the mucosal tissue. Disruption of these junctions leads to increased epithelial permeability, commonly described as a “leaky gut,” which is associated with inflammatory gastrointestinal disorders and mucosal injury [39].

In contrast, microbial dysbiosis can weaken the epithelial barrier by downregulating tight junction proteins, increasing intestinal permeability, and facilitating the translocation of bacterial products such as lipopolysaccharides (LPS). This process triggers mucosal inflammation and contributes to gastrointestinal pathologies, including ulcerative conditions and inflammatory bowel diseases [40]. Overall, microbiota-mediated modulation of tight junction proteins represents a critical mechanism through which microbial communities influence gastric mucosal defense and epithelial barrier integrity.

TLR signalling

Toll-like receptors (TLRs) are key pattern recognition receptors (PRRs) expressed on epithelial and immune cells of the gastrointestinal tract. These receptors recognize conserved microbial components known as microbe-associated molecular patterns (MAMPs), such as lipopolysaccharide, peptidoglycan, and bacterial flagellin. Activation of TLR signalling serves as a crucial interface between the host immune system and the intestinal microbiota [41]. Under physiological conditions, controlled TLR signalling helps maintain mucosal homeostasis by regulating epithelial regeneration, antimicrobial peptide secretion, and immune tolerance toward commensal microbiota. However, excessive activation of TLR pathways during microbial dysbiosis can lead to exaggerated inflammatory responses and mucosal damage [42].

Cytokine pathways (IL-1β, TNF-α)

Cytokines are key regulators of mucosal immune responses and play an essential role in mediating host–microbiota interactions. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumour necrosis factor-alpha (TNF-α) are major mediators of mucosal inflammation triggered by microbial signals [43]. Microbial components and metabolites can stimulate immune cells through pattern recognition receptors, resulting in increased production of these cytokines.

Elevated IL-1β and TNF-α levels disrupt epithelial barrier integrity by promoting tight junction disassembly and epithelial apoptosis, thereby facilitating mucosal injury and ulcer development [44]. Conversely, beneficial commensal bacteria can exert anti-inflammatory effects by suppressing pro-inflammatory cytokine production and promoting regulatory immune pathways. This delicate balance between pro- and anti-inflammatory cytokine signalling is essential for maintaining gastric mucosal homeostasis [45].

NF-κB signalling

The nuclear factor-kappa B (NF-κB) pathway is a central transcriptional regulator of inflammatory responses and innate immunity in the gastrointestinal tract. Activation of NF-κB occurs following stimulation of pattern recognition receptors such as TLRs by microbial components. Upon activation, NF-κB translocate to the nucleus and promotes the transcription of multiple inflammatory mediators, including cytokines, chemokines, and adhesion molecules that contribute to host defense against microbial invasion. However, persistent activation of NF-κB signalling can lead to chronic inflammation and tissue damage [46].

 Recent studies indicate that alterations in gut microbiota composition can modulate NF-κB signalling pathways, influencing inflammatory responses and disease progression. Microbial dysbiosis has been associated with sustained NF-κB activation and increased production of pro-inflammatory cytokines, thereby contributing to gastrointestinal inflammatory disorders [47]. Thus, microbiota-mediated modulation of NF-κB signalling plays a pivotal role in regulating mucosal immune responses and maintaining gastrointestinal homeostasis.

Interaction with the mucus layer

The mucus layer constitutes the first biochemical barrier protecting the gastrointestinal epithelium from microbial invasion. It is primarily composed of mucin glycoproteins secreted by goblet cells, forming a gel-like matrix that prevents direct microbial contact with epithelial cells [48]. The gut microbiota interacts dynamically with this mucus layer. Certain bacterial species can adhere to mucins and utilize mucin-derived glycans as an energy source, whereas others stimulate mucus production and goblet cell activity, thereby reinforcing mucosal defense mechanisms [49].

 Moreover, the mucus layer and microbiota maintain a mutualistic relationship, in which microbial colonization influences mucus structure, thickness, and glycosylation patterns, while mucus composition regulates microbial distribution and diversity [40]. Disruption of the mucus layer integrity allows bacteria to penetrate closer to the epithelial surface, triggering immune activation and inflammatory responses that contribute to gastrointestinal pathology [50]. Therefore, the bidirectional interaction between the mucus layer and gut microbiota represents a critical component of gastric mucosal defence.

8. IMPACT OF MICROBIOTA ON DRUG ABSORPTION

Changes in gastric pH

The gastrointestinal microbiota can influence drug absorption indirectly through modulation of gastric and intestinal pH, which is a critical determinant of drug solubility, ionization, and stability. Drug absorption in the stomach and proximal intestine depends largely on pH-dependent dissolution, particularly for weakly acidic or basic compounds. Alterations in microbial composition may modify gastric acid secretion and mucosal buffering capacity, thereby affecting the luminal pH environment. Microbial metabolites such as short-chain fatty acids (SCFAs) and other fermentation products can influence epithelial cell signalling and gastric acid secretion, potentially altering luminal pH conditions. Dysbiosis has been associated with impaired acid regulation and changes in the gastric microenvironment, which can affect the dissolution and bioavailability of several orally administered drugs. Furthermore, alterations in gastric pH can significantly affect the pharmacokinetics of drugs such as proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs), whose absorption profiles are strongly influenced by luminal acidity and mucosal physiology [51,52].

Altered permeability

The intestinal epithelium acts as a selective barrier regulating the passage of drugs from the intestinal lumen into systemic circulation. This barrier is maintained by tight junction proteins, including claudins, occludin, and zonula occludens-1. The gut microbiota plays a crucial role in regulating epithelial permeability through microbial metabolites and immune signalling pathways. Beneficial microbiota produces metabolites such as butyrate, which strengthen tight junction integrity and maintain epithelial barrier function. In contrast, microbial dysbiosis can disrupt tight junction proteins and increase intestinal permeability, commonly referred to as “leaky gut.” Increased permeability can alter drug absorption by facilitating the passive diffusion of certain drugs while impairing transporter-mediated uptake mechanisms [53,54]. Therefore, microbiota-mediated modulation of epithelial permeability represents an important determinant of oral drug bioavailability.

Microbial drug metabolism.

Several bacterial enzymes, including β-glucuronidases, azoreductases, and nitro reductases, participate in the metabolism of therapeutic agents. Microbial metabolism may lead to drug activation, inactivation, or the formation of toxic metabolites, thereby influencing drug efficacy and safety. Inter-individual variations in gut microbiota composition also contribute to variability in drug metabolism and pharmacokinetic responses among patients [55]. These interactions form the basis of the emerging field of pharmacomicrobiomics, which investigates how microbiota influence drug metabolism and therapeutic outcomes.

Impact on NSAIDs and proton pump inhibitors

The interaction between gut microbiota and drugs is particularly significant for non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs), which are widely used in the management of gastrointestinal disorders. NSAIDs such as indomethacin can disrupt mucosal integrity and alter the composition of the gut microbiota, resulting in increased intestinal permeability and bacterial translocation. These changes contribute to NSAID-induced gastrointestinal injury and ulcer development [56].

Proton pump inhibitors, used to suppress gastric acid secretion, can also alter the composition of the gut microbiota by increasing gastric pH and reducing the antimicrobial barrier function of gastric acid. Long-term PPI therapy has been associated with significant changes in gut microbial communities, which may influence drug metabolism and increase susceptibility to gastrointestinal infections [57].

9. THERAPEUTIC PERSPECTIVES

Increasing evidence indicates that gut microbiota plays a significant role in gastrointestinal health and disease, including gastric ulcer pathogenesis. Consequently, therapeutic strategies targeting microbial composition and function have emerged as promising approaches for the prevention and treatment of gastric ulcers. These interventions include probiotics, prebiotics, synbiotics, postbiotics, dietary modulation, fecal microbiota transplantation, and other microbiota-targeted therapies.

Probiotics

Probiotics are defined as live microorganisms that confer health benefits to the host when administered in adequate amounts. Several studies have demonstrated that probiotics such as Lactobacillus, Bifidobacterium, and Saccharomyces species can enhance gastric mucosal defense by stimulating mucus secretion, promoting epithelial regeneration, and suppressing inflammatory responses. These microorganisms also inhibit colonization by pathogenic bacteria and modulate immune signalling pathways in the gastrointestinal tract [58]. Furthermore, probiotic supplementation during antibiotic therapy for H. pylori infection has been shown to restore microbial balance and improve eradication efficacy while reducing treatment-associated gastrointestinal side effects [59].

Prebiotics

Prebiotics are non-digestible dietary components that selectively stimulate the growth and activity of beneficial microorganisms in the gut. Common prebiotics include inulin, fructooligosaccharides (FOS), and galactooligosaccharides (GOS). These compounds act as substrates for commensal bacteria, promoting the production of beneficial metabolites such as short-chain fatty acids (SCFAs). SCFAs, particularly butyrate, enhance epithelial barrier function, reduce intestinal inflammation, and inhibit colonization by pathogenic microorganisms. Through these mechanisms, prebiotics contribute to improved gastrointestinal homeostasis and mucosal protection, suggesting their potential role in preventing inflammatory gastrointestinal disorders, including peptic ulcer disease [60].

Synbiotics

Synbiotics refer to combinations of probiotics and prebiotics designed to synergistically enhance the survival and colonization of beneficial microorganisms in the gastrointestinal tract. This combination approach improves microbial stability and promotes the growth of protective bacterial populations. Studies have shown that synbiotics can enhance gut barrier integrity, reduce inflammation, and improve immune responses by increasing beneficial microbial metabolites. These effects contribute to the restoration of microbial balance and may reduce gastrointestinal inflammation associated with ulcer formation [61].

Postbiotics

Postbiotics are bioactive compounds produced by probiotic microorganisms during fermentation, including microbial metabolites, cell wall fragments, enzymes, peptides, and short-chain fatty acids. Unlike probiotics, postbiotics do not contain live microorganisms but still exert beneficial biological effects on the host. These bioactive molecules can regulate host immune responses, reduce oxidative stress, and enhance epithelial barrier function. Postbiotics are increasingly recognized as safe and stable therapeutic agents capable of modulating gut microbiota-host interactions and preventing inflammatory gastrointestinal diseases [62].

Diet

Dietary patterns strongly influence gut microbial composition and metabolic activity. Diets rich in fibre, polyphenols, and fermented foods promote beneficial microbial populations and increase the production of protective metabolites such as SCFAs. Conversely, unhealthy dietary patterns can lead to microbial dysbiosis, increased inflammation, and impaired mucosal barrier function [35]. Consequently, dietary interventions are considered an important non-pharmacological strategy for modulating gut microbiota and preventing gastrointestinal disorders, including gastric ulceration.

Fecal microbiota transplantation

Fecal microbiota transplantation involves the transfer of fecal microbial communities from healthy donors to patients in order to restore microbial balance. This approach has gained significant attention as a therapeutic strategy for gastrointestinal diseases associated with microbial dysbiosis. FMT has demonstrated effectiveness in restoring microbial diversity and improving gastrointestinal health by re-establishing beneficial bacterial populations and suppressing pathogenic microbes. Emerging evidence suggests that microbiota restoration through FMT may influence host metabolism, immune responses, and drug metabolism [63].

Microbiota-targeted therapies.

Advances in microbiome research have led to the development of microbiota-targeted therapies aimed at restoring microbial homeostasis and improving gastrointestinal health. These strategies include microbiome-based drugs, engineered probiotics, bacteriophage therapy, and microbial metabolite-based interventions. Such therapies aim to manipulate microbial ecosystems to enhance beneficial host–microbe interactions and reduce inflammation, thereby providing innovative approaches for the management of gastrointestinal disorders, including gastric ulcers and inflammatory diseases [64].

CONCLUSION

There is a lot of evidence that gut microbiota contributes to the pathophysiology of gastric ulcers by altering and regulating gastric mucosal defense mechanisms. The integrity of the epithelial barrier, inflammatory signalling, and mucosal repair processes are all impacted by microbial dysbiosis, which leads to increased vulnerability to ulcer development. Also, the microbiome impacts the metabolism, efficacy, and toxicity of pharmacological agents. The causal link, molecular mechanisms, and clinical relevance of microbiotadrug interactions in the stomach and their impact on gastric diseases are still largely unknown. It is the interdisciplinary approach of pharmacology, microbiology, and systems biology. Future studies integrating multiomics technologies, controlled experimental models, and clinical trials may contribute to the development of microbiomebased diagnostics and personalized therapeutic strategies for gastric ulcer management. Ultimately, recognizing the comprehensive interplay between gut microbiota and gastric mucosal defense will provide a new area for improving ulcer prevention, treatment, and therapeutic effect optimization.

FIGURE 2: Integrated model of microbiota–mucosal cross-talk in gastric ulcer pathogenesis, linking dysbiosis, epithelial injury, and therapeutic response. _{[image generated by biorender.com & created with Microsoft power point]}