Abstract
Helicobacter pylori is a highly prevalent human pathogen responsible for chronic inflammation of the gastric tissues, gastroduodenal ulcers, and cancer. The treatment includes a pair of antibiotics with a proton pump inhibitor PPI. Despite the presence of different treatments, the infection rate is still increasing both in developed and develo** states. The challenge of treatment failure is greatly due to the resistance of H. pylori to antibiotics and its side effects. Probiotics potential to cure H. pylori infection is well-documented. Probiotics combined with conventional treatment regime appear to have great potential in eradicating H. pylori infection, therefore, provide an excellent alternative approach to manage H. pylori load and its threatening disease outcome. Notably, anti-H. pylori activity of probiotics is strain specific,therefore establishing standard guidelines regarding the dose and formulation of individual strain is inevitable. This review is focused on probiotic’s antagonism against H. pylori summarizing their three main potential aspects: their efficiency (i) as an alternative to H. pylori eradication treatment, (ii) as an adjunct to H. pylori eradication treatment and (iii) as a vaccine delivery vehicle.
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Introduction
H. pylori resides in more than half of the population on earth (Dunne et al. 2014). They are highly pathogenic when bound to gastric epithelial cells (Hessey et al. 1990). They are Gram negative, helical, flagellated, and microaerophillic organisms, known to cause chronic gastritis, which if uncured eventually may result in duodenal ulcer and gastric cancer (Dunne et al. 2014). H. pylori infections have increased prevalence in develo** states (Moayyedi and Hunt 2004). High prevalence about 80% or more have been documented in parts of China and some South American and Eastern European states (Roberts et al. 2016; Graham et al. 1991). H. pylori has been grouped under class I carcinogen by International Agency for Research on Cancer (Covacci et al. 1999). It is the only bacterium linked with gastric malignancy (IARC 1994), estimated to be the cause of 60% of gastric cancer cases (Parkin 2006). Other than gastric diseases, H. pylori is also associated with MALT (mucosa-associated lymphoid tissue lymphoma), vitamin B1 deficiency, iron deficiency, and idiopathic thrombocytopenic purpura (Kuipers 1997). For the prevention of H. pylori-associated complications, inhibition of infection is pivotal. Combinations of several treatments are available; triple therapy, including antibiotics and a proton pump inhibitor, is widely used (Toracchio et al. 2000). Increasing incidence of resistant H. pylori strains to antibiotics including clarithromycin and metronidazole reduces the effectiveness of triple therapy (Graham 1998). The resistance of H. pylori strains differs worldwide, varying from 10 to 90% for metronidazole and 0 to 15% for clarithromycin (Toracchio et al. 2000). Moreover, the adverse effects of antibiotics such as diarrhea, nausea, and vomiting and expensive nature of the treatment have led to the reduced compliance rate of the patients. H. pylori infection in childhood may persist through life if not treated (Mcnulty et al. 2012; Arslan et al. 2017). Despite the fact that most infected individuals remain asymptomatic, its eradication is important as it may cause chronic gastritis, dyspepsia, and gastroduodenal ulcers (Smith et al. 2014). Considering the declining efficacy of triple therapy due to increasing resistance of H. pylori to antibiotics, adverse effect of the antibiotics, patients’ non-compliance, and cost of the treatment regime, search for a better and safe alternative approach is critically needed. Probiotics have been extensively explored as an adjunct to antibiotics treatment for H. pylori infection (Patel et al. 2014). Different studies have described the therapeutic potential of probiotics to effectively cure several gastric diseases (Goderska et al. 2018; Behnsen et al. 2013; Sarowska et al. 2013).
Probiotics are defined as “living micro-organisms which provide beneficial effect on the host’s health when administered in adequate amount” (Ruggiero 2014). There are many microbial species that could potentially function as probiotics, like Lactobacillus, Bifidobacteria, Saccharomyces, Streptococcus etc., of which Lactobacillus and Bifidobacteria are the most commonly studied. Probiotics stabilize the intestinal microflora by inhibiting pathogens, which is mostly attributed to their competitiveness for food and binding sites (Denev 2006), production of antimicrobial substances, and immunomodulation (Isolauri et al. 2001). Beside antagonistic properties of probiotics, their abilities to survive high pH and bile salts and to colonize gastrointestinal surfaces are critical to assign them among the most promising and potential probiotic candidates. These properties have attracted researchers’ interest to investigate new strains and gain insight into their beneficial properties (Holzapfel et al. 2001). Numerous studies related to the antagonistic activity of probiotics against H. pylori have shown promising results in reducing antibiotic side effects, improving eradication of H. pylori infection and reducing cell injury (Lesbros-Pantoflickova et al. 2007; Wilhelm et al. 2011; Patel et al. 2014). Despite the fact that every probiotic strain is not beneficial to improve H. pylori eradication treatment, several probiotics appear to mitigate the disease and side effects of the treatment. In an assessment study of H. pylori infection after its eradication by conventional therapy in children, 30% of the children were found to be re-infected after 2 years (Magistà et al. 2005); considering this, use of probiotics as an eradication adjunct or as a vaccine delivery tool would be very useful. In the previous literatures, potential of probiotics against H. pylori in in vitro, in vivo, and clinical trials has been described without providing much knowledge about their potential as an effective vaccine delivery vehicle. In this review, we have highlighted all the potentialities of probiotics against H. pylori from their mechanism of action, preclinical and clinical journey to their use in vaccines with successful examples. Limitations in the above mentioned potentials and suggestions for the future studies have been summarized as well.
Helicobacter pylori: pathogenesis
All H. pylori-infected individuals are not likely to develop peptic ulcers. H. pylori colonize the stomach for years and cause continuous infection, but only minority show symptoms. Right after H. pylori colonization to the epithelial tissues of the stomach, the activation of the host’s innate and adaptive immune response takes place (Cadamuro et al. 2014). Prolonged existence of chronic inflammation by H. pylori may advance to atrophic gastritis, dysplasia, metaplasia, and ultimately gastric carcinoma (Fox and Wang 2007). Studies have shown that genotypic and phenotypic variance in H. pylori strains is mainly responsible for different clinical outcomes (Blaser and Berg 2002). H. pylori colonization and the successful onset of pathogenesis usually take place in steps, such as survival in low pH, movement towards epithelium mediated by flagella, strong interaction with host cell receptors, and release of several toxins (Kao et al. 2016). Primarily, the infection is developed upon H. pylori’s adhesion to the gastric mucosa. The persistent colonization which results in chronic inflammation is facilated by different virulence factors such as the production of urease enzyme and presence of flagella. Urease helps H. pylori survival in the low pH of the stomach by generating ammonia (Eaton et al. 1991; Marshall et al. 1990). Urease is composed of four sub-units, UreA, UreB, UreC, and UreD. UreB is the strongest immunogen of H. pylori (Corthesy-Theulaz et al. 1995) which has been studied widely in the development of anti-H. pylori vaccine (Gu et al. 2009; Zeng et al. 2015). H. pylori adheres and colonizes the host’s epithelial cells by using a number of adhesins including BabA, SabA, HopZ (Odenbreit et al. 2002), AlpA/B (Peck et al. 1999), urease etc. BabA and SabA bind to fucosylated and sialylated blood group antigens. Studies have shown SabA-mediated activation of neutrophils (Unemo et al. 2005). Neutrophils upon activation, either by H. pylori soluble factors or as a result of inflammation, further produce ROS which cause epithelial cell DNA damage leading to apoptosis (Bagchi et al. 1996). Urease as an adhesin attaches to MHC class II and CD74 on antigen presenting cells which induce apoptosis of the epithelial cells and stimulate secrection of IL-8 (Fan et al. 2000; Barrera et al. 2005). Thus, attachment of H. pylori to the gastric mucosal layer induces inflammation resulting in the mucosal surface injury due to the release of different cytokines and chemokines (Engstrand et al. 1989; Peek Jr et al. 1995). Production of urease enzyme and flagellated structure of H. pylori are important virulent factors for successful colonization, which is present in almost all strains. As mentioned above, not all infected individuals develop an ulcer or other complications of H. pylori, which is due to variation in virulence of different H. pylori strains. Among different virulence factors VacA and CagA, toxin genes are the main virulence factors expressed in specific H. pylori strains. CagA is a part of pathogenecity island (CagPAI). Some of the CagA genes code for T4SS (type IV secretory system) which plays an important role in injecting bacterial components into the host’s epithelium leading to the stimulation of macrophages which further triggers the production of IL-8 and INF-γ ultimately disrupt the epithlial barrier (Boonyanugomol et al. 2011). These changes further cause epithelial damage leading to tumor formation. Several studies reported H. pylori-mediated over-expression of IL-8 in the host to be significantly linked with stomach cancer (Lee et al. 2013; Macrì et al. 2006). It has been observed that individuals with CagA+ H. pylori infection more often develop severe gastric disease and cancer (Kusters et al. 2006). VacA or vacuolating toxins form vacuoles in the host’ s epithelial cells and cause disruption in membrane potential. Mitochondrial membrane potential is also disrupted leading to apoptosis (Cover et al. 2003). VacA alter antigen presentation by B cells and inhibit T cell proliferation making it an important virulence factor to establish chronic infection (Cover and Blanke 2005). VacA is present in all H. pylori strains, but its pathogenecity depends on it genotypes (Winter et al. 2014). Despite the stimulation of H. pylori-mediated immune response, the infection persists which is mainly associated with its potential to evade host’s inflammatory response. H. pylori avoids TLRs (toll-like receptors) mediated recognition by modulating its LPS and flagellin surface proteins (Cullen et al. 2011). O-antigen on the bacterial outer polysachharide resembles human blood group antigens. This molecular mimicry of H. pylori protects it from recognized by the TRLs. Modification of lipid A portion of LPS alters the net charge of its surface resulting in inability of CAMP (cationic antimicrobial peptide) to bind to its surface (Cullen et al. 2011). Besides modulation of LPS, H. pylori’s LPS loosely binds to its host’s receptor which results in reduced activation of immune cells (Sutton and Chionh 2013). Different studies have also suggested that CagA and VacA virulence genes protect H. pylori from phagocytic cells (Ramarao et al. 2000; Zheng and Jones 2003). H. pylori also stimulates expansion of regulatory T cell (Treg) which downregulate inflammatory response by actively modulating the differentiation of dendritic cells and T cells (Beswick et al. 2007; Lundgren et al. 2003) (Fig. 1).
Overview of possible complications of H. pylori infection
How probiotics work against H. pylori
Several experimental studies have been able to propose various possible probiotic’s antagonistic effect on H. pylori, though the precise mechanisms have yet to be uncovered. Probiotic’s abilities to compete for binding receptors, modulate immunity, strengthen the mucosal barrier, and co-aggregate the pathogens are generally attributable to their effectiveness against various pathogens.
The mucosal barrier
The epithelium lining the gastrointestinal mucosa acts as a powerful barrier for the pathogens. Intestinal epithelial cells being the primary cell type to encounter the invading pathogens provide the first line of defense against harmful organisms. Upon invasion of pathogens, epithelial cells initiate an innate immune response which stimulates the secretion of chemokines and cytokines that connect the innate and adaptive immune response. Additionally, epithelial cells also produce mucus layer, which further provides protection to the mucosal surfaces from pathogens. Disruption of the mucosal barrier leads to different disease conditions. Probiotics can positively affect the epithelial barrier function which is strain specific (Seth et al. 2008; Karczewski et al. 2010). H. pylori damages the gastric mucosa using its virulence factors, like CagA and VacA (Backert et al. 2016). In cases of gastritis caused by H. pylori, decreased mucus secretion in a damaged epithelium has been observed (Lesbros-Pantoflickova et al. 2007). Moreover, in a study with human gastric cell line, H. pylori suppressed MUCI and MUC5A gene expression (Byrd et al. 2000) and caused disruption of the mucosal barrier, as mucins being high molecular weight glycoproteins are useful for gastric epithelium stability.
Probiotics protect the mucosal barrier from damage by different mechanisms including modification of the expression of mucus and epithelial junction proteins and releasing bioactive molecules to stabilize the barrier, thus preventing its disruption by the pathogens. Different studies demonstrated the increased production of IgA by probiotic strains, which is helpful in strengthening the mucosal barrier against pathogen invasion (Perdigón et al. 2000; Viljanen et al. 2005). As seen in in vitro studies, L.plantarum strain 299v and L.rhamnosus GG enhance the MUC2 and MUC3 gene expression providing strength to the mucus barrier (Mack et al. 1999). Another study on H. pylori gastritis proves increased thickness of mucus layer upon intake of L. johnsonii in fermented milk (Pantoflickova et al. 2003). Bergonzelli et al. (2006) reported an efficient binding of recombinant GroEL from Lactobacillus johnsonii LA1 to the HT29 cells and hypothsized its potential in pathogens’ exclusion.
Competition for adhesion
H. pylori binds to the gastric epithelium in order to colonize and initiate infection. Probiotics ability to prevent H. pylori from binding to the epithelial cells usually brought about by different mechanisms such as competing for the adhesion sites or nutrients, causing steric hindrance and secreting antimicrobial substances. Several reports describe the adhesion of probiotics to the specific binding receptors, L. reuteri was found to compete for specific binding receptor site asialo-GMI and sulfatide and inhibit H. pylori adhesion (Mukai et al. 2002). Another study reports affinity of S. boulardii to sialic acid receptor followed by inhibition of H. pylori from binding (Sakarya and Gunay 2014). Some Lactobacilli strains such as L. acidophilus LB (Coconnier et al. 1998) and L. johnsonii La1 (Michetti et al. 1999) secrete antimicrobial substances to inhibit attachment of H. pylori to the epithelium. Competitive exclusion of H. pylori by potential probiotic strains is also evident by several in vitro studies with L. acidophilus LB (Coconnier et al. 1998), L. johnsonii (Michetti et al. 1999), L. salivarius (Kabir et al. 1997), and W. confusa (Nam et al. 2002). W. confusa strain PL9001 significantly inhibits H. pylori from binding to the gastric cell lines (Nam et al. 2002). Some studies provide evidence of reduced H. pylori colonization in germ-free mice which were previously colonized by probiotics (Kabir et al. 1997; Johnson-Henry et al. 2004). Anti-adhesion property of probiotics is one of the crucial mechanisms to counteract pathogens from invading the host. It would be interesting to investigate the underlying molecular mechanism of probiotics for their increased affinity towards the binding receptors.
Secretion of antimicrobials
H. pylori survival in the acidic environment of the stomach is mediated by urease production, which increases the pH of the gastric surrounding by converting urea into ammonia and CO2. Probiotics secrete antimicrobials as a result of fermentation, such as lactic acid, acetic acid, and hydrogen peroxide (Vandenbergh 1993). Lactic acid secreted by probiotic lowers down the surrounding pH making it unfavorable for H. pylori’s growth (Aiba et al. 1998; Midolo et al. 1995; Sgouras et al. 2004). Besides lowering the pH, lactic acid was also found to have inhibitory activity against urease (Sgouras et al. 2004). A number of authors have reported the inhibitory action of lactic acid produced by Lactobacilli against H. pylori, for example, L. casei subsp. Rhamnosus and L. acidophilus (Midolo et al. 1995; Bhatia et al. 1989).
It is worth noting that not all lactic acid-producing Lactobacilli are capable of anti-Helicobacter pylori activity, as L. johnsonii La10, despite producing lactic acid, does not show inhibition of H. pylori, whereas L. johnsonii La1 does (Michetti et al. 1999). This also suggests that antagonistic activity of Lactobacilli against H. pylori is strain specific. Other antimicrobial products have also been reported to have antagonistic effect against H. pylori. Culture supernatant of L. johnsonii La1 (Michetti et al. 1999) and L. acidophilus LB (Coconnier et al. 1998) effectively inhibits H. pylori in in vitro as well as in mice. Lorca et al. (2001) described inhibition of H. pylori, mediated by autolysin of L. acidophilus CRL 639, and suggested that it released after cell lysis. Strong inhibitory activity against H. pylori has been observed by lacticins A164 and BH5 of L. lactis subsp. A164 and BH5 (Kim et al. 2003). The exact nature of these antimicrobial substances has not been investigated. Bacteriocins are proteinaceous antimicrobial peptides which have been studied extensively (Cotter et al. 2013). Bacteriocin production by probiotics has been considered as one of their most essential properties (Dobson et al. 2011). Bacteriocin-mediated inhibition of H. pylori has been reported by Bacillus subtilis (Pinchuk et al. 2001) and W. confusa (Nam et al. 2002). Inhibition by B. subtilis was shown by animocumacins, grouped under isocoumarin antibiotics (Pinchuk et al. 2001). de Klerk et al. (2016) demonstrated direct action of L. gasseri Kx110A1 and L. brevis ATCC14869 conditioned medium on H. pylori and reported a reduction in SabA gene expression mediated by an unknown effector molecule. The authors suggested the effector molecule to be either an anti-microbial substance or a bacterial surface molecule released into the conditioned medium. Reuterin from L. reuteri ATCC 55730 reported to inhibit VacA gene expression of H. pylori (Urrutia-Baca et al. 2017).
SabA and VacA are important virulence factors of H. pylori, inhibition of their expression is critically important to regulate inflammation and prevent tumor formation.
Immunomodulation mechanism
H. pylori infection stimulates inflammation, and several inflammatory mediators like cytokines, chemokines etc. are released. Interleukin 8 (IL-8) triggers the secretion of neutrophils and monocytes to the gastric mucosal surfaces. Following this, the dendritic cells and monocytes activate the secretion of TNF-α, IL-1, and IL-6 (Noach et al. 1994). The stimulation of CD 4 + T cells (type 1) by IL-1 and IL-6 produces various cytokines such as IL-4, -5, -6, and IFN-γ (Harris et al. 1996); however, the H. pylori infection prevails. Immunomodulation is a well-known characteristic of probiotics. They interact with gastric epithelial cells and reduce the inflammation and gastric activity as a result of secretion of anti-inflammatory cytokines (Wiese et al. 2012). Experimental studies in mice reported a reduction in IgG immunoglobulins specific to H. pylori infection after probiotic intake (Aiba et al. 1998; Sgouras et al. 2004). The culture supernatant of L. acidophilus strain LB effectively reduces H. felis density, urease activity, and cures the inflammation in mice (Coconnier et al. 1998). L. casei strain Shirota decreased H. pylori-mediated inflammatory response in experimental mice (Sgouras et al. 2004). The strength of probiotics to weaken the H. pylori infection and inflammatory response varies from strain to strain. This can be exemplified in a study in which L. salivarius significantly reduced inflammation caused by H. pylori in gnotobiotic mice as compared to L. acidophilus or L. casei (Aiba et al. 1998). Lactic acid produced by probiotics has been shown to reduce inflammation by regulating inflammatory cytokines in several animal studies (Coconnier et al. 1998; Murosaki et al. 2000). CagA virulence gene of H. pylori has been strongly linked with increased gastric malignancy (Blaser and Berg 2002) which is suggested to be due to CagA-mediated enhanced IL-8 levels in the gastric mucosa (Peek Jr et al. 1995). Some probiotics L. bulgaricus (Zhou et al. 2008), L. acidophilus (Yang et al. 2012), and L. salivarius (Kabir et al. 1997) have been reported to down-regulate IL-8 secretion by H. pylori. This characteristic of some probiotic strains would open doors to discover new strategies to manage gastric cancers. Variations in immunomodulation process have been observed in different probiotic strains which may be due to polymorphism in the host’s immunity (Noach et al. 1994), which is a complex process to extrapolate. Thus, it is evident from various animal studies that probiotics are significantly effective to reduce the degree of inflammation and outcome of H. pylori infection.
Co-aggregation and aggregation
Co-aggregation is the binding of organisms of diverse species, while aggregation or auto aggregation is the attachment of the organisms of similar species (Rickard et al. 2003; Schembri et al. 2001). Exclusion of pathogens binding to the intestinal mucosa as a result of aggregating property of probiotics has been described previously (Tareb et al. 2013). L. reuteri DSM17648 significantly co-aggregated with H. pylori in in vitro and in vivo studies (Holz et al. 2015). Similarly, H. pylori inhibition by L. gasseri occurred on account of co-aggregation in vitro (Chen et al. 2010). Studies also reported aggregation of H. pylori by L. johnsonni La1 (NCC533) recombinant GroEL protein receptor in a specific manner (Bergonzelli et al. 2006). Other probiotic strains are suggested to be investigated for this property.
It is crucial to identify the precise molecular mechanism underlying probiotics action on health and disease conditions. Once identified in vitro efficacy, their potential in physiological conditions is equally important (Fig. 2, Table 1).
Mechanisms of antagonism of probiotics against H. pylori
Clinical studies
Numerous clinical studies have been documented to investigate the anti-H. pylori activity of probiotics and their potential to ameliorate the antibiotic-associated side effects. (Table 2, Table 3). Different clinical researches with probiotic strain L. johnsonii La1 have been described (Felley et al. 2001; Pantoflickova et al. 2003; Ojetti et al. 2012; Michetti et al. 1999). The strain was administered either as a live bacterium added in fermented milk or as a cell-free culture supernatant (Michetti et al. 1999). All results showed a significant reduction in H. pylori density. L. acidophilus when administered as a cell-free culture supernatant showed anti-urease activity in asymptomatic individuals (Coconnier et al. 1998). In clinical studies, probiotics are generally examined either as an alternative or an adjunct to antibiotics.
Potential of probiotics as an alternative to antibiotics
A double-blind controlled clinical study including 252 asymptomatic children previously tested by C-urea breath test as H. pylori positive has been conducted (Cruchet et al. 2003). The children were arranged in groups and administered with live L. johnsonii La1, heat-killed L. johnsonii La1, live L. paracsei ST11, heat-killed L. paracasei ST11 daily for a month. At the end of the trial period, only children who received live L. johnsonii La1 showed a significant reduction in urease activity as compared to the other groups. Similarly, Wang et al. (2004) demonstrated a decrease in H. pylori colonization and gastritis in dyspeptic patients after ingestion of L. acidophilus La5 and B. lactis Bb12 containing yoghurt. Gotteland et al. (2005) investigated L. acidophilus or S.boulardii plus inulin effect on H. pylori-infected children and also compared the effect as an adjunct to standard triple therapy. Significant decrease in urease activity in inulin group was observed; however, H. pylori eradication rate with L. acidophilus and inulin group was not significant (6.5% and 12%, respectively) as compared to standard triple therapy (66%). Similarly, Francavilla et al. (2014) administered a daily dose of L. reuteri mixture and placebo to the groups of 50 patients each. L. reuteri group showed 75% eradication rate whereas 65% of placebo were eradicated. Few patients receiving L. reuteri mixture reported side effects as compared to placebo. Different probiotic strains L. johnsonii La1 (Gotteland and Cruchet 2003), L. gasseri OLL 2716 (Sakamoto et al. 2001), L. reuteri ATCC 55730 (Francavilla et al. 2008), and B. bifidus BF-1(Miki et al. 2007) as single therapy did not eradicate H. pylori in adults rather modulate its colonization. Different level of efficacy is due to different strains of probiotics tested. Further studies are required to address the efficacy of anti-H. pylori property of probiotics and evaluation of the specific immune mechanism involved in probiotics immunomodulation is suggested to provide scientific evidence for the clinical benefit of individual probiotic strain (Table 2).
Potential of probiotics as an adjunct to antibiotics
Studies on the effect of probiotics in alleviating the side effects of standard H. pylori treatment have been increasing, usually owing to their usefulness in increasing the patient’s compliance rate (Goderska et al. 2018). Ojetti et al. (2012) investigated the effect of co-administration of L. reuteri ATCC 55730 with antibiotics on H. pylori-infected subjects, which significantly increased H. pylori eradication rate; additionally, the adverse effects of antibiotics were also reduced. In the same way, Myllyluoma et al. (2005) reported a significant reduction in H. pylori load and gastritis after treating the patients with a combination of probiotics as a complement to H. pylori treatment. A study by Du et al. (2012) demonstrated improvement in H. pylori eradication when L. acidophilus was used as a supplement to triple therapy; however, symptoms were not reduced with probiotic alone. No significant eradication was observed upon administration of L. reuteri ATCC 55730, though side effects were reduced to some extent (Lionetti et al. 2006). Similar results were observed in a study by Armuzzi et al. (2001) in which L. rhamnosus GG was supplemented as a complementary therapy. In view of the potential of probiotics against H. pylori infection, researchers have also examined the combination of different species of probiotics complementary to the triple therapy. In a double-blind placebo-controlled study, 66 H. pylori-infected children were administered combination of probiotics including L. rhamnosus, L. acidophilus, L. bulgaricus, L. casei, S. thermophilus, B. breve, and B. infantis along with triple therapy. A total of 90.09% of the children supplemented with probiotics as an adjunct to antibiotic therapy were successfully cured from H. pylori infection whereas 69.69% of children in the control group receiving placebo were cured. The significant rise of approximately 20% in eradication rate of the treated group remarkably proves the efficacy of probiotics as an adjunct to H. pylori eradication therapy (Ahmad et al. 2013). Emara et al. (2014) demonstrated the administration of a mixture of L. reuteri DSM 17938 and L. reuteri ATCCPTA 6475 as a complementary therapy. After the treatment, patients were re-examined for the presence of H. pylori antigen in stool, and histology of the biopsy specimen was carried out. Increased eradication from H. pylori infection was detected with reduced adverse effects of the eradication therapy and improved histology of H. pylori as compared to placebo group. Contrastingly, no effect had been observed upon co-ingestion of probiotic containing yoghurt with antibiotic treatment for H. pylori infection in children (Goldman et al. 2006) (Table 3).
Meta-analyses on the available outcomes of clinical trials using probiotics as a therapeutic agent are useful to understand the vitality and drawbacks of the clinical research. Recently, Feng et al. (2017) compared the potential of 17 probiotics as an adjunct to triple therapy versus as a sole therapy and found L. casei to be the most potent probiotic used as monotherapy, whereas L. casei, L. plantarum, L. acidophilus, L. reuteri, L. rhamnosus, L. salivarius, L. sporogenes, B. infantis, B. longum, and S. thermophilus as a multi-species probiotic combination showed promising result in reducing treatment-related side effects. Zheng et al. (2013) conducted a meta-analysis of 9 RCT (randomized controlled trial) including 1163 patients. They compared the potential of probiotic supplements as an adjunct to triple therapy or sequencial therapy with that of placebo. Upon comparing the outcome of probiotics intervention, they found 78.18% eradication in the treated group and 68.54% eradication in the placebo (control) group, showing approximately 10% increase in the eradication rate of the treated group. However, decrease in the side effect was not significant (31.21% decrease in the treated group vs 34.86% decrease in the control group). In the same study, subgroup analysis of five trials showed significant increase of 17% in eradication rate of the treated group when compared to the control group upon administering Lactobacillus species only, whereas only 2.8% eradication was observed when multi-strain probiotics were supplemented. It was concluded that Lactobacillus containing probiotic may have enhanced benefits as compared to combination of species of probiotics. In a comprehensive study, Wang et al. (2017) compared the potential of probiotic supplement for H. pylori eradication, most probiotics were successful in eradicating the H. pylori infection, while single probiotic strain showed improved result as compared to multi strain therapy. Contrastingly, Dang et al. (2014) found a probiotic supplement to be active in H. pylori eradication only when the antibiotic treatment failed.
In a recent study co-administeration of L. casei rhamnosus (LCR 35) effectively reduced antibiotic side effects but no significant difference in the eradication rate in the tested and control group was observed. The authors suggest that the low difference may be due to the use of better antibiotic regime (Uitz et al. 2017). McNicholl et al. (2018) conducted a controlled double-blind clinical trial with two probiotic strains L. plantarum and Pediococcus acidilactici, which were previously found effective in vitro in other studies (Kaur et al. 2014; Sunanliganon et al. 2012). No success in the improvement of the side effect and H. pylori colonization was observed. This clearly suggests that clinical trials are crucial to evaluate potential of the probiotic strain tested in vitro. B. animalis subsp. lactis significantly increase the eradication rate with decreased side effects upon its co-administration with conventional antibiotics (Çekin et al. 2017).
The differing results, though apparently indicate probiotics potential against H. pylori eradication, may be due to many factors related to deviating experimental design and setup. Thus, consistency in experimental protocol with a defined combination of probiotic supplement would be useful to get accuracy in the outcome.
Vaccine development
Efforts in the development of vaccines against H. pylori started soon after its discovery by Marshall. BJ and Warren RM (Marshall and Warren 1984). The gastric cancer due to this notorious bacterium is the main reason of establishing a potent vaccine, as it is the third major cancer causing agent worldwide (IARC 2012). The two main approaches are prophylactic and therapeutic administration of the vaccines. As the infection is usually contracted at an early age (Mitchell et al. 1992), prophylactic immunization of children is crucial. Recently, a phase 3 clinical trial in China has been reported in which recombinant urease B vaccine successfully immunized 70% of the children (Zeng et al. 2015). This is a breakthrough in the development of potent vaccine prompting further research in this field.
The second approach is a therapeutic vaccine which can be given at any period; however, stimulation of immunosupressive mechanism by H. pylori to establish chronic infection is a major challenge. Therapeutic protections in mice have been reported previously in different studies (Doidge et al. 1994; Sutton et al. 2000); hence, its efficacy in human is yet to be achieved.
Probiotics as vaccine delivery system for H. pylori infection
With the advancement in the field of genetic engineering, probiotics have emerged as a useful tool to deliver vaccines. Many probiotic organisms are considered GRAS (generally regarded as safe) by the Food and Drug Administration. Owing to their GRAS nature, they are widely used in food industry. Lactococci have been suggested as an ideal recombinant vaccine vehicle, mostly due to their potential to induce both acquired and innate immunity in the host. Production of recombinant H. pylori antigens like UreB, CagA, NapA etc. have been widely demonstrated in L. lactis followed by their efficacy in pre-clinical studies which showed varied outcomes (Gu et al. 2009; Lee et al. 2001; Kim et al. 2009). Previously, in an attempt to develop H. pylori vaccine, we have successfully expressed Ure-B antigen in L. lactis. The recombinant L. lactis produced significant anti-Ure B serum antibody and protected the mice against gastritis (Gu et al. 2009). We detected increase in IgG level, while IgA specific to Ure-B were detected in fresh feces which declined after 38 days. In a similar experiment by Lee et al. (2001), no immunization has been observed, upon administration of recombinant Ure-B L. lactis to H. pyloi SS1 challenged mice. Interestingly, Ure-B-specific serum IgG were detected. This suggests that presence of both IgG and IgA is important to elicit effective immune response. In order to study surface display expression of H. pylori antigens in probiotics, we successfully constructed a recombinat UreBE-SpaxX (Ure B fragment E and fragment Spax of Staphylococcus aureus) (Song and Gu 2009). SpaxX is a cell wall anchor of S. aureus and its fusion with Ure BE would provide enhanced adjuvant activity. Western blotting of the recombinant L. lactis cell wall extract with polyclonal chicken antiserum confirmed its effecacy. 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This work was funded by the following organizations: The National Science Foundation of China (Grant numbers: 318755 and 316014489); International Science and Technology Cooperation Program of China (Grant number: 2013DFA32330); and National Science Foundation of Zhejiang Province (Grant number LY16C200002).
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Qureshi, N., Li, P. & Gu, Q. Probiotic therapy in Helicobacter pylori infection: a potential strategy against a serious pathogen?. Appl Microbiol Biotechnol 103, 1573–1588 (2019). https://doi.org/10.1007/s00253-018-09580-3
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DOI: https://doi.org/10.1007/s00253-018-09580-3