The Infectious Ringleader of Chronic Gastropathies

Helicobacter pylori (H. pylori, Hp) infection has been reported worldwide (Fig. 1) and is believed to affect more than half of the world’s population¹. What makes it a trouble are the related gastropathies including chronic gastritis, peptic ulcer disease (PUD) and gastric cancer, resulting in discomfort, pains and even death. Worse yet, once individuals acquire H. pylori infection, the pathogen usually persists throughout their lifetime², which gives their quality of life an overtime cut.

Fig. 1 Global prevalence of H. pylori choropleth map. Certain regions are magnified to better display the smaller countries. (Hooi et al., 2017)

H. pylori exhibits clear infectivity and is primarily transmitted through the vomitus–oral and gastro–oral pathways, and faecal–oral transmission is also considered possible³,⁴. Direct person-to-person contact within families appears to be the predominant route of transmission, with infection clustering in households and stronger associations observed between infected children and close caregivers such as mothers and siblings⁵,⁶. Additional indirect sources of infection include contaminated food or animal products, especially milk, and occupational exposure in agricultural, fishery, or healthcare settings⁷.

H. pylori is Gram-negative, microaerophilic bacteria that are highly motile due to a unipolar bundle of sheathed flagella³. It is highly adapted to the colonization in the deep gastric mucus layer⁸, the features of which are represented by motility, urease production, adhesion, etc. Such a living habitat is inaccessible to most of the existing medicines due to the acidity of gastric juice and the thick barrier namely mucus layer⁹ (Fig. 2).

Fig. 2 Distribution of H. pylori in the mucus layer of Mongolian gerbils. (A) The tissue surface of the H. pylori-infected gerbil depicted from the luminal side of the antrum. H. pylori is highlighted in red. (B) Schematic cross section showing the distribution of H. pylori through the gastric mucosa of infected gerbil. (Schreiber et al., 2004.)

Common Therapies

Initial Success and Lasting Limitations

Conventional antibiotic-based regimens, namely triple and quadruple therapies, remain the first-line and most widely used strategy for eradicating Helicobacter pylori. These protocols, which rely on proton pump inhibitors for metabolic disturbance and potent antibiotic intervention, initially offered a promising eradication efficacy of around 90%⁸. However, decades of widespread use have exposed critical vulnerabilities, and their long-term utility is increasingly compromised by a confluence of fundamental shortcomings that cast a shadow over their initial success.

The Mounting Crisis of Antibiotic Resistance

The most pressing challenge is the rampant and progressive rise of antibiotic resistance, which significantly undermines eradication rates and leads to more frequent treatment failures in clinical practice¹⁰. This crisis is compounded by the inherent limitations of the therapy itself, including the high cost of regimens and the risk of reinfection¹¹. In addition, the efficacy of these antibiotics is often limited by pharmaceutical challenges, such as their degradation in the harsh acidic environment of the stomach and inadequate residence time at the site of infection, which further diminishes their therapeutic potential¹². Furthermore, this crisis of resistance is mechanistically exacerbated by the bacterium’s sophisticated ability to form biofilms¹³. The biofilm matrix acts not merely as a physical barrier that enhances structural protection against antibiotics, but also as a dynamic hub that facilitates genetic exchange across microorganisms, thereby accelerating the dissemination of resistance genes.

Collateral Damage to the Gut Microbiome

Compounding the problem of resistance is the non-selective, destructive nature of these broad-spectrum antibiotics. Even in therapies supplemented with probiotic components to mitigate side effects, the indispensable use of antibiotics inflicts severe collateral damage on the commensal intestinal flora¹⁰. This destructive effect on the gut ecosystem manifests in adverse clinical outcomes for individuals, including gastrointestinal discomfort, opportunistic infections, and broader metabolic disorders¹¹, thereby compromising the patient’s overall gastrointestinal health.

An Urgent Call for Novel Therapeutic Strategies

Consequently, the cumulative impact of drug resistance, microbial ecological damage, and inherent pharmacological inefficiencies underscores the urgent and unavoidable need for the development of a safe, effective, and targeted substitute for these traditional antibiotic therapies.

New Approaches

Probiotics as an Adjunctive Therapy: Mitigating Side Effects and Enhancing Efficacy

Used as auxiliaries to standard treatment¹⁴, probiotics have demonstrated significant promise, contributing to both a higher eradication rate and a reduction in therapy-related side effects. Several studies have confirmed the efficacy of probiotics as monotherapy for H. pylori eradication¹⁵,¹⁶,¹⁷,¹⁸. Their beneficial effects are achieved through a variety of mechanisms:

Competitive Inhibition: Probiotics compete with H. pylori for adhesion sites on the gastric mucosa and for essential nutrients, thereby limiting its colonization and proliferation¹⁹.

Production of Antimicrobial Substances: Certain probiotic strains, such as specific Lactobacillus species, produce antimicrobial substances including lactic acid, short-chain fatty acids (SCFAs), and bacteriocins, which directly inhibit the viability of H. pylori²⁰.

Modulation of Host Immunity: Probiotics can modulate the gastric mucosal immune response, mitigating H. pylori-induced inflammation and helping to preserve the integrity of the gastric mucosal barrier²¹.

Stabilization of Gut Microbiota: Antibiotic use can lead to dysbiosis, disrupting the balance of the gut microbiota and causing side effects. Probiotics, particularly Saccharomyces boulardii, have been proven to effectively prevent and alleviate antibiotic-associated diarrhea (AAD), thus enhancing patient tolerance and compliance with the treatment regimen²².

The Limitations of Probiotics as Monotherapy

Despite their success as an auxiliary treatment, the use of probiotics as a standalone or monotherapy for H. pylori eradication faces considerable challenges. While cutting-edge research is underway to select specific strains that can effectively target H. pylori²³, their efficacy in clinical settings has been underwhelming. Clinical studies consistently report that eradication rates for probiotic-only therapies are generally below 30%²⁴. This limited efficacy can be attributed to several critical factors:

Insufficient Specificity: The antimicrobial actions of most probiotics are broad-spectrum and more bacteriostatic than bactericidal. They lack the specific potency required to completely eliminate an established H. pylori infection.

Gastric Environmental Challenges: To be effective, probiotics must first survive the harsh acidic and bile salt-rich environment of the upper gastrointestinal tract to remain viable, a significant physiological hurdle.

The Mucus Layer Barrier: This is arguably the most critical physical obstacle. H. pylori predominantly colonizes the deep gastric mucus layer, adjacent to the epithelial cells. Probiotic whole cells face significant difficulty in penetrating this viscous mucus layer to reach the nidi of infection, preventing them from exerting their inhibitory effects directly where they are most needed.

Therefore, while the concept of a probiotic-only therapy is highly attractive, overcoming the fundamental challenges of delivery, specificity, and survival is essential for it to become a viable clinical reality.

Reference