Probiotics are living bacteria that provide several advantages to the body and are used orally to treat gastrointestinal problems (Losurdo et al., 2018). Probiotic preparations are available in a variety of formats, including capsules, solutions, powders, and probiotic foods (Kiepś and Dembczyński, 2022). Probiotics have a lot of potential as antibiotic replacements. Following the investigation by Yoon et al. (2019), a reduction in H. pylori density and histologic inflammation improvement could be detected in individuals treated with fermented milk containing Lactobacillus paracasei HP7 and herbal extract (Glycyrrhiza glabra). In a randomized double-blind placebo-controlled clinical trial, the decrease in the mean H. pylori stool antigen titer showed a significant difference between Saccharomyces boulardii and the control group, indicating that S. boulardii could positively reduce H. pylori colonization in the human gastrointestinal system, but it is incapable of eradication as monotherapy (Namkin et al., 2016). As a result, probiotic monotherapy cannot be utilized to treat H. pylori, even though it may suppress bacterial growth. Probiotics have a good influence on digestive health, reinforce the mucosal barrier on mucus against pathogens, improve immune system, and anti-pathogen action via antimicrobial factor release, aggregation and co-aggregation by attachment to pathogens (Agraib et al., 2021; Keikha and Karbalaei, 2021; Daelemans et al., 2022; Du et al., 2022). In addition, probiotics are used in the treatment of gastrointestinal cancer (Zhang et al., 2021). Clinical experiments have shown that probiotic lactic acid-producing bacteria are a simple, safe, and effective way to prevent cancer patients against radiation-induced diarrhea. Patients with colorectal cancer were randomly assigned to take L. rhamnosus GG supplements and fiber throughout treatment. Patients who took Lactobacillus experienced less grade 3 or 4 diarrhea, reported less abdominal discomfort, required less hospitalization, and had fewer chemotherapy dosage decreases owing to bowel damage. There was no Lactobacillus-related harm found (Delia et al., 2007; Österlund et al., 2007). The study concludes that Lactobacillus GG supplementation is well tolerated and may minimize the incidence of severe diarrhea and abdominal pain associated with 5-FU-based chemotherapy. Generally, probiotics have been added to dairy products such as yogurt and other fermented products.

Lactobacillus and Bifidobacterium are the two most common species found in probiotic products such as yogurt (Xiong, 2018; Ye et al., 2020). In the past, the positive effects of dairy products such as yogurt on digestion were proven (Whiteside et al., 2021; Zhao et al., 2022). Other species accessible on the market include Bacillus spp., Enterococci, E. coli, Weissella spp., and Saccharomyces. Classical probiotic strains containing Lactobacilli and Bifidobacterium have been granted Generally Regarded as Safe (GRAS) status in the United States and are eligible for EFSA (European Food Safety Authority) safety certification. Microbial strains in multi-species probiotics include Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Eubacterium faecium, Lactobacillus acidophilus, Lactiplantibacillus plantarum, Lacticaseibacillus casei, and Streptococcus thermophilus. Researchers discovered that probiotic mixes including many strains outperformed single-strain probiotics in terms of pathogenic growth inhibition (Singh et al., 2022). These bacteria may colonize the human gastrointestinal tract and compete with H. pylori for attachment to the host’s mucous membrane (Espinoza et al., 2018). Lactobacillus secretes chemicals that inhibit H. pylori urease activity and colonization. Bifidobacterium reduces H. pylori adherence to intestinal mucus by site competition, and it has been found to lower IL 8 levels in vivo and in vitro H. pylori activity (Koca et al., 2021). In the Maastricht V Consensus Report, it has been agreed that some probiotic strains may have favorable effects on H. pylori elimination (Malfertheiner et al., 2017). Given these findings, it is plausible to expect that utilizing a combination of probiotics that act on H. pylori through diverse routes might result in a synergistic impact. Probiotics used in combination with antibiotics have been demonstrated in studies to improve Helicobacter eradication. When double probiotics were added to the medication, the number of significant adverse effects decreased by 11.2%. Helicobacter eradication was accomplished in 68% of patients in the control group and 89% of patients in the trial group following therapy completion. When double probiotics were added to the therapy, the eradication success rate improved by 21% (Koca et al., 2021). While H. pylori disturbs the normal flora in the stomach microbiota, antibiotic therapy causes a long-term decline in normal strains in the intestinal flora. Probiotics protect the intra-stomach microbiota against the detrimental effects of H. pylori and restore the degraded intestinal flora. Helicobacter pylori can cause an inflammatory response by altering the acid–base balance of the digestive system and, as a result, the gut microenvironment (Chen et al., 2018; Yoon et al., 2019). Hence probiotic supplementation may be beneficial in the treatment of inflammatory and infectious diseases (Chen et al., 2018). Figure 1 shows the use of probiotics in the digestive tract schematically. Epithelial commensals and probiotics promote barrier integrity. Probiotics play a significant function in maintaining immunological balance in the gastrointestinal system by interacting directly with immune cells. Probiotic strains increase IgA synthesis and secretion by altering the cytokine milieu in the gut mucosa. Also, bacteriocins are antimicrobial peptides generated by the majority of bacterial species. They have been thought to contribute to probiotic efficacy by assisting with colonization, direct pathogen eradication, and acting as signaling molecules to other bacteria or the host immune system.

Probiotics have few adverse effects associated with bacterial-host interactions. Individuals suffering from immunodeficiency, heart valve disease, short bowel syndrome, or preterm newborns are at risk of severe responses and should avoid using these items (Doron and Snydman, 2015; Singhi and Kumar, 2016). Probiotic therapy is a first medication for H. pylori treatment in order to optimize eradication regimens and reduce antibiotic adverse effects (Chey et al., 2017). As H. pylori has long been seen as a difficult-to-treat disease, due mostly to developed resistance to routinely used antibiotics, there is a rising interest in using probiotics in combination with antibiotic regimens to remove the bacteria. Certain Lactobacillus species produce antibacterial chemicals similar to the bacteriocin class. Bacteriocins are proteinaceous toxins with anti-H. pylori properties. They are tiny, dialyzable peptide structures that possess antibacterial properties. The antibacterial activity of the bacteriocins differed depending on the H. pylori strain and the kind of bacteriocin generated by Lactobacillus sp. Some bacteriocins exhibit more antibacterial action against H. pylori strains than others (Kim et al., 2003). Based on clinical trials with probiotics against H. pylori, probiotics cannot be considered an alternative to anti-H. pylori treatment; however, their use together with standard anti-H. pylori treatment may improve H. pylori treatment by increasing eradication rates while decreasing the adverse effects of current medications. Lactobacillus acidophilus was a little better choice for 7- and 14-day triple therapy, whereas S. boulardii was better suited to 10-day triple therapy. When combined with H. pylori eradication medication, most probiotic regimens proved to be more successful than placebos. Additionally, probiotics are indicated to enhance triple treatment in kids. To augment triple treatment, L. casei was discovered as the best for H. pylori eradication rates, and multi-strain of L. acidophilus and L. rhamnosus for overall adverse effects (Feng et al., 2017; Wang et al., 2017). While it may be generally acknowledged that probiotics may help in the eradication of H. pylori and reduce adverse effects of standard therapy, certain probiotic bacteria species can also benefit pharmacotherapy. The growing prevalence of antibiotic resistance and the decrease in patient compliance with traditional treatment further illustrate the need for alternative therapies. Fakhry et al. (2023) found that patients who received probiotics (Lactobacillus and Bifidobacterium) in addition to regular medicine (triple treatment) had a higher percentage of H. pylori eradication than those who received only conventional therapy. Adding probiotics reduced diarrhea as a side effect of antibiotic treatment. Probiotics may help to repair gut dysbiosis, as demonstrated by stool PCR for Lactobacilli and Bifidobacteria before and following drugs. Probiotic supplements may assist to reestablish a favorable gut microbial composition, especially following eradication treatment.

The composition of the human gastrointestinal microbiota tract has been extensively examined, and various studies have been undertaken to explain the links between microbiota diversity in the human gastrointestinal tract and its impact on health and illness. Differences in gastric bacterial community topologies may govern diverse pathways, affecting stomach physiology and leading to varied H. pylori infection responses (Ge et al., 2018). Commensal gastric microorganisms or their metabolites impact H. pylori’s capacity to colonize the stomach and its pathogenic and carcinogenic potential via influencing host immune responses (Espinoza et al., 2018). Non-H. pylori bacteria may survive as an antigenic stimulation or form a partnership with H. pylori to increase eventual inflammation (Rook et al., 2017). Studies discovered that stomach microbial populations considerably enhanced their alpha-linolenic acid and arachidonic acid metabolism. Therefore, Zheng et al. (2021) hypothesized that the balance between Treg and Th17 cells might be biased toward Treg cells, which is beneficial to bacterial persistence, and the gastric microbiota might generate short-chain fatty acids and small molecules to modulate mucosal Treg responses in H. pylori-infected patients. Furthermore, Satoh-Takayama et al. (2020) demonstrated that ILC2s, controlled by local commensal populations through IL-7 and IL-33 upregulation, are the main ILC subset in the stomach and protect against H. pylori infection via B-cell activation and IgA production.

Probiotics can change the structure of the stomach microbiota. Probiotic therapy increased the amount of beneficial short-chain fatty acid (SCFA) generating bacteria, including Bacteroides, Alloprevotella, and Oscellibacter, in the stomachs of H. pylori-infected mice (He et al., 2022). Sodium butyrate, a typical SCFA, suppressed H. pylori growth, CagA and VacA expression, as well as the host NF-κB pathway by lowering toll-like receptor expression in host cells, resulting in decreased TNF-α and IL-8 production (Huang et al., 2021). However, another bacterial metabolite, trimethylamine N-oxide (TMAO), boosted H. pylori viability and virulence and aggravated H. pylori-induced inflammation (Wu et al., 2020). The synergistic effects of H. pylori and TMAO boosted inflammation-related gene expression, including IL-6, CXCL1, CXCL2, FOS, and complement C3 in the gastric epithelium (Wu et al., 2017). Trimethylamine (TMA) is the TMAO precursor. Firmicutes (e.g., Staphylococcus) are the primary producers, while Bacteroidetes generate it infrequently (Fennema et al., 2016). Overall, probiotics may raise the proportion of helpful metabolite-producing bacteria and/or lower the number of detrimental metabolite-producing bacteria (Zhang et al., 2023). Probiotics can help repair the stomach dysbiosis produced by eradication therapy, however, young adults infected with H. pylori may not need to take probiotics alone (Yuan et al., 2021).

Synbiotics are a mix of probiotics (“live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”) and prebiotics (“indigestible foods that lead to enhancement of probiotic bacteria colonization in the gut”) that can operate synergistically. Several studies have found that some probiotic lactobacilli exhibit anti-H. pylori action and prevent H. pylori colonization in gastric cell lines (Pourmasoumi et al., 2019). A randomized, open-labeled trial examined the efficacy of a synbiotic combination (containing lactobacillus, enterococcus, and bifidobacterium) in clarithromycin-based triple eradication treatment for H. pylori. The data showed no significant difference between the two groups. However, the level of adverse effects and rates of eradication differed considerably between groups. The eradication rate in the synbiotic group was 88.4%, compared to 68.8% in the control group. The inclusion of synbiotics in triple treatment reduces the incidence of antibiotic-related adverse effects. It also improves H. pylori eradication in clarithromycin-based triple treatment (Sahin et al., 2013). A meta-analysis of six randomized controlled studies revealed that synbiotics could increase H. pylori eradication rates while reducing side effects (Pourmasoumi et al., 2019).

A novel biotherapeutic technique includes using microbial bioactive compounds (postbiotics) that display optimal compatibility and intimate interaction with the host’s immune system (Hosseini et al., 2023). Postbiotics can also compete with pathogens for adhesion sites if their adhesions (such as fimbriae and lectins) are still functional after pretreatment. Lactobacillus acidophilus in lyophilized and inactivated form significantly boosts H. pylori eradication rates when added to a standard anti-H. pylori regimen, owing to its strong adhesion to human intestine absorptive and mucous-secreting cells. Given its safety and high patient compliance, it is a simple addition to traditional anti-H. pylori antibiotic treatments (Ma et al., 2023). There is scant evidence that postbiotics are effective in treating human diseases. We uncovered two separate clinical studies using postbiotics for H. pylori infection. Canducci et al. (2000) found that treating patients with H. pylori with clarithromycin, rabeprazole, and amoxicillin with inactivated Lactobacillus acidophilus increased the rate of eradication. Yang et al. found that adding nonviable L. reuteri to triple therapy (esomeprazole, amoxicillin, and clarithromycin) did not increase the rate of H. pylori eradication, but did help to establish a beneficial microbial profile and reduce the occurrences of abdominal distention and diarrhea (Hamzavi and Bashiri, 2023).

The positive benefits of probiotics are well recognized, but other components such as plant extracts, oils, and derivatives of some natural chemicals can help reduce pathogenesis and cancer growth.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetaminophen, ibuprofen, diclofenac, and acetyl Salic acid are among the most commonly used antibacterial agents in the world (Zimmermann and Curtis, 2017). Salicylic acid (SAL) has been proven in studies to reduce the growth of H. pylori and Klebsiella pneumonia (Reshetnyak et al., 2019). Other NSAIDs can have an effect on bacteria; for example, ibuprofen can reduce the binding of Escherichia coli to intestinal epithelial cells or uroepithelial cells (Whiteside et al., 2019; Figure 2). Another study published in 2018 found that diclofenac loaded with chitosan nanoparticles may inhibit the growth of S. aureus and B. subtilis (Alqahtani et al., 2019). Resveratrol (RSV) and its derivatives are a kind of natural phenol with anti-inflammatory and antibacterial properties (Vestergaard and Ingmer, 2019). RSV works by inhibiting the urease enzyme and, as a result, preventing the formation of an alkaline environment (Marini et al., 2019; Krzyżek et al., 2020). Several investigations have demonstrated that anti-helicobacter drugs such as levofloxacin have higher bacterial toxicity when combined with Resveratrol and its derivatives (Bouarab Chibane et al., 2019; Di Lodovico et al., 2019; Di Fermo et al., 2020). Polaprezinc (PZN) or zinc carnosine (L-carnosine) are zinc chelate compounds that protect the digestive mucosa (Mahmoud et al., 2022). This antioxidant compound is particularly efficient in protecting against H. pylori and promoting ulcer healing, and unlike other antibiotics, it does not cause drug resistance (Teng et al., 2020; Ibrahim et al., 2022; Mahmoud et al., 2022). PZN has been shown in several trials to be useful in reducing apoptosis and inflammation, healing skin and stomach wounds, and preserving tight junctions (Furihata et al., 2020; Ibrahim et al., 2022). Hence, this substance may be introduced later in the H. pylori treatment protocol (Kawahara et al., 2018; Mahmoud et al., 2022). Palmatine (Pal) is a herbal combination derived from Coptidis Rhizoma that may relieve or diminish chronic atrophic gastritis (CAG) caused by H. pylori. Pal most likely does this by suppressing inflammatory compounds including interleukin 8 (IL-8) and chemokine 16 (CXCL-16; Chen et al., 2020). Silibinin, derived from milk thistle seeds, possesses potent anti-Helicobacter and anti-gastric tumor cell properties (Bittencourt et al., 2020). This chemical affects Penicillin Binding Protein (PBP) and interferes with wall formation, resulting in changes in the bacterial structure. It also has anti-inflammatory properties by decreasing cytokine release by inhibiting macrophages activated by H. pylori (Bittencourt et al., 2020; Cho et al., 2021). Vergara et al. (2005) found that eradicating H. pylori was successful in NSAID-naive users but not in chronic users.

Some foods, edible plants, and natural dairy products exhibit antibacterial characteristics in vitro or in vivo, including H. pylori. Most of these drugs’ effective composition is known (Takeuchi et al., 2014). The most well-known compounds that are effective against bacteria that cause stomach ulcers include bovine milk (by Lactoferrin), ginger (6-shogaol or phenolic acids), broccoli sprout (sulforaphane), green tea (Catechin compounds), and garlic (Allicin, diallyl sulfur components; Cellini et al., 1996; Sachdeva and Nagpal, 2009; Sachdeva et al., 2014; Omar et al., 2020; Zhao et al., 2022). In vitro tests showed that bovine lactoferrin (bLF) had a strong antibacterial impact on resistant H. pylori and a synergistic antibacterial effect when paired with clarithromycin. Furthermore, in vivo investigations indicated that bLF might enhance the degree of gastric mucosa damage and minimize the area of the stomach ulcer (Wang et al., 2023). According to the findings of researchers, the methanolic extract of ginger, which contains gingerol, zingiberene, and thymol as major compounds, has potential antibacterial and antibiofilm properties against various multidrug-resistant clinical isolates of H. pylori, as well as anti-inflammatory activity. The results mentioned demonstrate a considerable improvement of gentamicin effectiveness against multidrug-resistant H. pylori when combined with methanolic ginger extract (Elbestawy et al., 2023). To find out if regular broccoli sprout consumption had a similar effect in humans, researchers enrolled 50 H. pylori-infected individuals in a clinical trial. When measurements obtained at baseline were compared with those taken after one or 2 months of intervention, significant decreases in the number of bacteria were evident in individuals eating broccoli sprouts (Tuma, 2006). Yanagawa et al. (2003) demonstrated that epigallocatechin-3-gallate (from green tea) enhanced the antibacterial activity of an antibiotic treatment, with excellent efficacy against H. pylori growth in vitro. García et al. (2023) found that solvent-free garlic extracts containing ethanol and acetone suppressed H. pylori development in vitro under simulated stomach PH conditions at human body temperature. These results imply potentially major medicinal uses of such extracts, which eliminate the usage of proton pump inhibitors during the treatment of H. pylori infections in human patients.

Bactericidal, antitoxin, and antibiofilm properties of vitamin and garlic supplements can protect those at risk of stomach cancer (Li et al., 2019; Bhatwalkar et al., 2021). Garlic contains chemicals that protect the genome structure by suppressing reactive oxygen and radical scavenging (Vega-Hissi et al., 2019). According to these findings, food and other consumable things should be used in combination with antibiotics (Takeuchi et al., 2014). Numerous plants and vegetable oils, such as Chinese chive, are being studied, although the mechanism of action is unknown (Guerra-Valle et al., 2022). Some research has revealed that essential oil components (EOCs) have anti-H. pylori potential, and their mode of action is through immobilized antimicrobials (Ruiz-Rico et al., 2020). Table 1 lists the most important chemicals found in foods and spices, as well as the known mechanisms involved in anti-H. pylori action.