Scientists from the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) have come to a consensus that defines probiotics as “living microorganisms that, when consumed in sufficient quantities, can provide health benefits to the host”(Hill et al., 2014). Most probiotics are colonized in the human intestinal tract, and some of them, such as Lactobacillus, are colonized in the human stomach and directly or indirectly fight against H. pylori (Ji and Yang, 2020). There is already evidence that probiotics have a therapeutic effect on a variety of diseases, such as some diarrheal diseases include acute infectious diarrhea, antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea. On top of that, there are digestive disorders, including hepatic encephalopathy, ulcerative colitis, irritable bowel syndrome, functional gastrointestinal disorders, and necrotizing enterocolitis (Yousefi et al., 2019).

Importantly, it has been shown that probiotics are also effective against H. pylori infection. The mechanism of probiotics in treating H. pylori can be divided into immune and non-immune mechanisms. The main immunological mechanism is that probiotics can reduce the release of inflammatory chemokines and regulate the secretion of anti-inflammatory cytokines by interacting with epithelial cells, thus reducing inflammation caused by H. pylori infection (Eslami et al., 2019; Sousa et al., 2022). In the non-immune mechanism, probiotics can compete with H. pylori for epithelial cell adhesion sites or inhibit the expression of adhesion-related genes in order to reduce H. pylori colonization (Sakarya and Gunay, 2014; Klerk et al., 2016). Probiotics can lower the pH of the environment in which H. pylori lives, thus reducing bacterial activity and inhibiting urease activity (Sgouras et al., 2004). Probiotics can also inhibit or kill H. pylori by secreting short-chain fatty acids and antibiotics (Homan and Orel, 2015). In addition, probiotics can reduce the expression of virulence genes of H. pylori (Urrutia-Baca et al., 2018).

In recent years, there have been many reports of integrating probiotics as adjuvant therapy into the standard treatment regimen of H. pylori. Firstly, probiotics can improve the eradication rate of H. pylori. For instance, Viazis et al. (2022) carried out a study on the combination of probiotic regimen with standard H. pylori eradication therapy in eight tertiary hospitals. They found the eradication rate was 92.0% in the probiotic group and 86.8% in the placebo group, with an odds ratio of 1.76 (95% CI 1.06–2.94). Secondly, probiotics can reduce the incidence of side effects. Zhao et al. conducted a clinical trial of Saccharomyces boulardii (S. boulardii) combined with quadruple therapy. It was found that the supplementation of S. boulardii can significantly reduce the incidence of eradication-related adverse events (AEs; OR: 0.378, 95% CI: 0.117–0.807). In particular, it reduced the duration of diarrhea (5.0 vs. 7.7 days, p = 0.032) and the incidence of severe diarrhea (4.7 vs. 10.1%, p = 0.040, 56). In addition to the above, probiotics can also reduce the effect of antibiotics on the gastrointestinal flora. He et al. studied the effect of probiotics combined with a quadruple bismuth-containing regimen on the eradication rate of H. pylori, gastrointestinal adverse events (GAE), and gastrointestinal microbiota. They found a lower incidence of gastrointestinal adverse events in the probiotic group than in the placebo group (23.6 vs. 37.7%), but no significant difference in eradication rates. After H. pylori eradication, probiotics partially counteract the effects of antibiotics on the intestinal flora and reduce fluctuations in the gastric microbiota. It can be seen that probiotics have already performed well as an adjuvant therapy (He et al., 2022).

Several systematic reviews and meta-analyses show that probiotic monotherapy has a minimal impact on the eradication rates of H. pylori. However, when used in supplementary therapy, probiotics are effective in increasing eradication rates with reduced side effects (Losurdo et al., 2018; Zhou et al., 2019; Zhang et al., 2020; Penumetcha et al., 2021). The Maastricht VI/Florence consensus report also states that probiotics can increase the eradication rate of H. pylori by reducing side effects associated with eradication therapy rather than through direct effects on H. pylori, but the benefit only apply to certain strains of probiotics (Malfertheiner et al., 2022). Although the Toronto guidelines do not encourage the routine use of probiotics to reduce adverse reactions or improve radical treatment rates, they are beneficial and unlikely to be harmful in certain high-risk cases (Fallone et al., 2016). Meanwhile, the American Gastroenterological Association (AGA) considers probiotics beneficial, but uncertainties about the optimal dose, timing of administration and duration of treatment should be addressed before their widespread use (Chey et al., 2017).

Although the eradication rate of probiotic monotherapy remains unsatisfactory, it is widely accepted as adjuvant therapy. Indeed, probiotics are widely thought to have huge potential; however, more data is needed to evaluate the direct efficacy of probiotics against H. pylori. Moreover, their effects on H. pylori eradication and the intestinal microflora warrant further study.

Oxygen plays a vital role in the lives of many microbes. Helicobacter pylori is generally considered a micro-aerobic microorganism and needs to be cultured by lowering oxygen levels. It survives in a micro-aerobic environment with an oxygen content of 5–10% (volume/volume%) in the air (Kelly, 2001; Wallace et al., 2016). Given the microaerobic environment is a prerequisite for the survival of H. pylori, the oxygen-enriched environment may not be conducive to the growth of H. pylori or even lead to its failure to survive (Di et al., 2020). For example, Jia et al. reported eradicating H. pylori by establishing an oxygen-enriched environment with hydrogen peroxide (Di et al., 2020), and satisfactory results were obtained in vivo and in vitro for four H. pylori strains, with the destruction of H. pylori cell membranes.

In addition, hyperbaric oxygen therapy has bactericidal or bacteriostatic effects against aerobes and anaerobes (Vatansever et al., 2013). Hyperbaric oxygen therapy can suppress pathogens or improve patient symptoms in various ways. Hyperbaric oxygen therapy can directly resist pathogenic microorganisms by forming reactive oxygen species (ROS; Memar et al., 2019). Meanwhile, hyperbaric oxygen can inhibit mucosal inflammation, improve the anoxic environment of the lesion and surrounding tissues, and enhance the ability of immune cells to phagocytize and kill bacteria (Al-Waili and Butler, 2006; Almzaiel et al., 2013; Memar et al., 2019). Hyperbaric oxygen has been reported to yield a synergistic antibacterial effect with antibiotics (Turhan et al., 2009). A Chinese study on the efficacy of hyperbaric oxygen combined with antibiotics in treating H. pylori-positive patients found that negative conversion increased, symptoms disappeared quickly, and the recurrence rate was low (Gan et al., 2015). These findings suggest that we can use hyperbaric oxygen or establish oxygen-enriched conditions to eradicate H. pylori or as an adjuvant therapy against H. pylori. However, some studies have found differences in the response of different genomes to oxygen pressure in H. pylori, suggesting that H. pylori may be an aerobic bacteria that requires high carbon dioxide levels to grow (Park and Lee, 2013).

In short, there are few studies on treating H. pylori with oxygen enrichment or hyperbaric oxygen, and the effect of oxygen concentration on H. pylori eradication warrants further study. At the same time, hyperbaric oxygen therapy has been popularized in most hospitals, so it is worth carrying out research on hyperbaric oxygen as adjuvant therapy combined with antibiotics to treat infection of drug-resistant strains.

Photodynamic therapy is a modern, non-invasive treatment method used primarily for various types of cancer treatment (Kwiatkowski et al., 2018). Given the emergence of antibiotic resistance, photodynamic therapy has become an alternative therapy for treating pathogenic microorganisms.

Antimicrobial photodynamic therapy (aPDT) uses endogenous or exogenous photosensitizers to absorb harmless visible light at appropriate wavelengths and react with oxygen molecules inside and around cells to produce cytotoxic reactive oxygen species (ROS) or singlet oxygen molecules. These cytotoxic reactive oxygen species produced in situ can destroy biological macromolecules, resulting in bacterial cell death (Morici et al., 2020). This method can effectively kill a variety of bacteria without causing the development of drug resistance (Al-Mutairi et al., 2018). Current evidence suggests that H. pylori can spontaneously produce endogenous photosensitizer porphyrin, mainly consisting of protoporphyrin IX (PPIX) and coproporphyrin I and III (CPI and CPIII), with a characteristic absorption peak at 415 nm (Battisti et al., 2017a; Battisti et al., 2017b). When the appropriate wavelength of light reacts with the photosensitive porphyrin and surrounding oxygen, it can produce cytotoxic reactive oxygen species (ROS), which can damage bacterial cells and lead to the death of H. pylori.

It is reported that photodynamic therapy can kill H. pylori while ignoring the drug resistance. Moreover, H. pylori-targeted photosensitizers can avoid the undesired phototoxicity to normal cells (Yang et al., 2022). Im et al. (2021) proposed an H. pylori-targeted photodynamic therapy system-p3SLP, which yielded significant antibacterial activity and had no adverse side effects on normal tissues and intestinal flora. Ma et al. found that a blue light-emitting diode (LED) could inhibit the proliferation of drug-resistant strains of H. pylori in vitro (Ma et al., 2018). Moreover, LED endoscopic capsules combined with active motion systems have been designed based on the combined action of vision and actuation to move precisely to the target area to kill H. pylori (Luzzi and Tortora, 2022).

Overall, much emphasis has been placed on addressing the problems caused by antibiotic resistance. Photodynamic therapy has made good progress in drug-resistant H. pylori strains, but additional in vitro and in vivo studies and well-designed clinical trials are needed to further prove the advantages of this treatment.

Nanomaterials have unique physical and chemical properties, such as small size and excellent biocompatibility, which enable them to penetrate most physiological barriers. The high surface area to volume ratio and targeted action on the lesion sites increases their interaction with pathogen biofilms while exhibiting good stability (Santos et al., 2018; Patil-Sen, 2021). Importantly, we can manipulate the size and shape of these particles and their specific ligands to improve efficacy and therapeutic index and reduce side effects (Van Giau et al., 2019; Mba and Nweze, 2021). Also, they exhibit excellent synergistic effects with antibiotics and enhancing drug delivery and release (Mba and Nweze, 2021). And nanomaterials used for the treatment of H. pylori can be described in two aspects: organic and inorganic nanomaterials.

The main organic nanomaterials used for the treatment of H. pylori are nanoemulsions, liposomes, nanostructured lipid carriers and polymeric nanoparticles. They are often used as drug delivery systems to increase the stability, release properties of drugs, as well as combat antibiotic resistance (de Souza et al., 2021). Among them, nanoemulsions are highly biocompatible and have long-term stability, which can improve the stability, solubility and bioavailability of the loaded drug (Lai et al., 2022). For example, Tran et al. have developed an delivery system of nanoemulsion encapsulated with erythromycin, which significantly enhanced the stability of erythromycin for the eradication of H. pylori (Tran et al., 2017). Liposomes are considered to be the most widespread nanosystems for the delivery of antimicrobial drug owing to the similar composition with cell membrane and good safety. Additionally, liposomes can integrate with other materials to exhibit good targeting specificity (Li et al., 2019; Eleraky et al., 2020). Gottesmann et al. loaded amoxicillin onto pectin-coated liposomes, which had a significant killing effect on H. pylori. At the same time, pectin coating enabled liposomes to target H. pylori (Gottesmann et al., 2020). Nanostructured lipid carriers also have biocompatibility and stability, as well as high storage capacity and encapsulation efficiency (de Souza et al., 2021). Furthermore, they are specific for H. pylori and do not affect the gut microbiota (Seabra et al., 2018). Sharaf et al. (2021) loaded hesperidin (Hesp) and clarithromycin (CLR) into nanostructured lipid carriers, which effectively extended the sustained release time of the two drugs, and showed effective targeting of H. pylori in the simulated gastric juice experiment in vitro. Finally, polymer nanoparticles have high loading capacity to drugs (Cardos et al., 2021), and chitosan (CS) is the most effective and versatile polymeric material from natural sources (Eleraky et al., 2020). They also exhibit excellent positioning properties in combination with other materials. For example, Arif et al. (2018) prepared Cys-CS/PMLA nanoparticles for encapsulation of amoxicillin using cysteine conjugated chitosan (Cys-CS) and polymalic acid (PMLA), which exhibited good ph-sensitive properties and delayed the release of amoxicillin in stomach acid, thereby eradicating H. pylori more specifically.

The inorganic nanomaterials used in the treatment of H. pylori are mainly metal nanomaterials, such as silver, gold, and zinc. Metal nanoparticles can kill bacteria by generating reactive oxygen species or disrupting cell membranes, genetic material or proteins (Safarov et al., 2019). They can be directly used to treat H. pylori (Yang et al., 2020), especially in the eradication of multidrug-resistant strains, because of their inherent antibacterial activity (Lai et al., 2022). For example, Amin et al. use Peganum harmala L. seed extract synthesized Ag-NPs, which showed strong anti-H. pylori activity in vivo and in vitro. Compared with amoxicillin and other antibiotics, drug resistance was not observed after repeated exposure for up to 10 times (Amin et al., 2014). Similarly, Zhi et al. (2019) coupled gold nanostars with cis-aconitate modified anti-H. pylori polyclonal antibodies to obtain the pH-sensitive gold nanostars@H.pylori-antibody nanoprobes (GNS@Ab), which could kill H. pylori by destroying the cell membrane and could enter cells to generate active oxygen and affect the metabolism of H. pylori. No disruption of the gut microbiota balance was observed. In addition, the combination of metal nanomaterials with materials such as hydrogels has shown excellent performance in positioning. For example, Zhang et al. encapsulated ascorbate palmitate (AP) hydrogel on the pH-responsive metal–organic framework hydrogen-generation nanoparticles (Pd(H) @ ZIF-8; Zhang et al., 2022), which could target the site of inflammation and kill the H. pylori effectively. Notably, it also relieves inflammation, repairs the gastric mucosa, and does not cause imbalance in the intestinal flora.

Despite nanomaterials have been widely used in medical research, the toxicity and difficulty in degradation remain problems to be solved (Patil-Sen, 2021). Besides, nanomaterials are used as delivery systems for antibiotics, which may also cause drug resistance of H. pylori. Therefore, it remains promising to study nanomaterials that can directly act on H. pylori, especially metal nanomaterials. Perhaps the next step should focus on the study of biodegradable metal nanomaterials that can maintain the balance of intestinal ecosystem. Of course, its biological safety should be evaluated before clinical transformation for H. pylori eradication.

Various organisms can produce antimicrobial peptides (AMPs), which represent a component of innate immunity responsible for protecting host cells from pathogens. These peptides usually consist of < 50 amino acids and are called amphipathic peptides (Neshani et al., 2019). Due to the growing problem of antibiotic resistance, antimicrobial peptides have been used as an alternative to fight against related pathogenic microorganisms (Xu et al., 2020).

The study found that antimicrobial peptides can quickly and efficiently kill various pathogens, with a variety of mechanisms (Pérez-Peinado et al., 2018; Chen et al., 2019). Firstly, AMPs have a net positive charge, which interacts with the negative charge of the microbial cell membrane, resulting in increased membrane permeability, pore formation, and, ultimately, microbial cell lysis. In addition, AMPs can not only transfer across the cell membrane to the bacterial cytoplasm, but also further inhibit the synthesis of cell wall, DNA, RNA, protein and cell division (Brogden, 2005; Mahlapuu et al., 2016). Notably, AMPs are effective against multidrug-resistant (MDR) bacteria, and the incidence of pathogens developing resistance to AMPs is relatively low (Chung and Khanum, 2017). Also, AMPs have significant selectivity to bacterial cells, broad-spectrum activity, and low synthesis cost (Mba and Nweze, 2022).

Various AMPs, such as defensins, are present in gastric epithelial cells and they play an important role in the innate immune response to H. pylori infection. Although AMPs produced by gastric epithelial cells have a protective effect, H. pylori continues to colonize, indicating that H. pylori exhibits selective drug resistance to host AMPs (Nuding et al., 2013; Pero et al., 2017, 2019). In addition, there are still many disadvantages of most AMPs, such as instability, poor bioavailability, short half-life and cytotoxicity (Li et al., 2022). Natural antimicrobial peptides are unstable in the gastrointestinal tract, poor absorption and rapid metabolism, which leads to low bioavailability (Luong et al., 2020). Therefore, it is necessary to synthesize AMPs analogues or develop new technologies such as genetic engineering to effectively overcome these shortcomings (Sousa et al., 2022). Jiang et al. (2020) reported that Cbf-K₁₆ had good antibacterial activity against clarithromycin-and amoxicillin-resistant H. pylori SS1 both in vivo and in vitro. Zhang et al. synthesized recombinant PGLa-AM1(rPGLa-AM1), which has the advantages of low toxicity and high stability with good anti-H. pylori activity in vitro and in vivo (Zhang et al., 2017).

Although antimicrobial peptides have certain limitations, the emergence of new technologies such as genetic engineering can effectively overcome these shortcomings. Therefore, antimicrobial peptides are widely considered to have great clinical application prospects.

Bacteriophage (phages) are virus particles that infect bacteria. According to their relationship with host bacteria, bacteriophages can be divided into virulent (or obligately lytic) phages and temperate (or lysogenic) phages. Virulent phages recognize bacterial surfaces and inject their nucleic acids into host cells, where they then assemble, multiply, and eventually destroy bacterial cells while releasing phage progeny that infects new bacterial cells (Sulakvelidze, 2005; Muñoz et al., 2020).

Traditional phage therapy is defined as using virulent phages or their cleaved proteins to induce the lysis of host bacterial cells, thereby eliminating bacterial infection (Viertel et al., 2014). After the temperate phages bind to the host, the temperate phages are removed from the bacterial genome under environmental changes or other physiological conditions, which can eventually destroy the host cell as well (Kortright et al., 2019). Phage therapy has many advantages. For instance, phages are relatively easy to isolate and only affect the target strains since phages, and phage lyases are highly specific (Muñoz et al., 2020). In addition, phages mutate more frequently than bacteria, which can help eradicate phage-resistant bacteria (Ghannad and Mohammadi, 2012). Phages also do not require multiple doses to be effective, they rapidly replicate exponentially, and rapidly enter a death phase when the target bacteria are reduced, without causing adverse immune responses and affecting the human microbiome (Anyaegbunam et al., 2022). Phage therapy has proved effective in treating various infections and even curing chronic infections (Abedon, 2019).

To date, there are few studies on H. pylori specific phage. Abdel-Haliem and Askora (2013) reported that anti-H. pylori phages φHPE1 and φHPE2 isolated from wastewater could adapt to the acidic environment of the human stomach and exhibited high thermal stability. However, the physiological conditions inside the stomach can also hinder the ability of most phages to fight H. pylori. For example, the acidity of gastric juice and digestive enzymes greatly change the biological and structural composition of phages, thus reducing their proliferation and concentration at the infected site (Nobrega et al., 2016; Vinner et al., 2019). Therefore, phages have also been combined with other materials to increase stability in the stomach. For example, Cuomo et al. reported that H. pylori-specific lytic phage combined with lactoferrin adsorbed on hydroxyapatite nanoparticles (Hp φ + LF-HA) against H. pylori infection could effectively reduce bacterial colonization and related inflammatory reactions with host cells. It is worth noting that the nanoparticles (LF-HA) significantly increased the antibacterial activity of H. pylori-specific lytic phage (Hp φ; Cuomo et al., 2020).

Although bacteria may also resist phage and may lead to an immune system response that reduces efficacy (Principi et al., 2019), phage remains a promising treatment for H. pylori given the significant challenge of antibiotic resistance leading to treatment failure. The next step we should focus on the search and design of H. pylori-specific phage.

The phage uses two-component lysis systems to destroy the bacterial cell wall composed of holins and endolysins (lysins), which work together to form the holin–lysin systems (Cisek et al., 2017). Holins are involved in the triggering process of host cell lysis; their function is to open holes in the host cell cytoplasmic membrane, thus providing the opportunity for endolysins to act on the cell wall (Cisek et al., 2017). Lysins are phage-encoded enzymes that lyse host bacterial cells at the end of the lytic cycle, and lysins target the peptidoglycan (PG) layer, which is an important component of the bacterial cell wall (Lai et al., 2020). Holins and lysins are widely thought to play a synergistic role and eventually destroy the host cells (Kakasis and Panitsa, 2019).

In recent years, significant inroads have been made in intracellular lysins of Gram-positive bacteria, while research on intracellular lysins of Gram-negative bacteria has barely progressed due to interference from the outer membrane (OM; Abedon, 2019). Given that H. pylori is a Gram-negative bacterium, it has an outer membrane outside the cell wall, which prevents lysins from destroying the cell wall when they act on the bacterium alone (Ghose and Euler, 2020). Studies have found that these lysins are easy to obtain, they can be further designed and modified by genetic engineering, and they are also easy to express and purify, and at the same time, they are suitable for industrial production (Xu et al., 2021). Therefore, in addition to discovering lysins with the inherent ability to penetrate the outer membrane, people began to design a variety of modified lysins. For example, Xu et al. (2020) reported that the two-component lysis systems of H. pylori phage KHP30 fused a hydrophobic peptide, which can penetrate the bacterial biofilm, thus obtaining modified lysins. The bacteriostatic experiment in vitro also achieved good results. Subsequently, lysins and holins combined with a polypeptide that can penetrate the outer membrane were designed, and the complex was named “arlysins”(Xu et al., 2021). In vitro antibacterial experiments showed that the arlysins have a strong anti-bacterial effect on H. pylori, leading to the perforation and destruction of its outer membrane.

The use of lysins can cause an immune response, producing cytokines and neutralizing antibodies in the body, which may cause the inactivation of lyases (Abdelrahman et al., 2021). However, developing improved lysins through new techniques, such as gene recombination, is still possible to overcome these immune responses to lysins. There are few reports on treating H. pylori with modified lysins, but with the continuous development of genomics, more research will be conducted in this area.