Next Article in Journal
Histopathological Features of Symptomatic and Asymptomatic Honeybees Naturally Infected by Deformed Wing Virus
Next Article in Special Issue
Helicobacter pylori-Induced Inflammation: Possible Factors Modulating the Risk of Gastric Cancer
Previous Article in Journal
Fungal Development and Callose Deposition in Compatible and Incompatible Interactions in Melon Infected with Powdery Mildew
Previous Article in Special Issue
Clinical Aspects of Gut Microbiota in Hepatocellular Carcinoma Management
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review

1
Center of Biomedical Research, Institute of Nutrition and Food Technology “José Mataix”, University of Granada, Avda. del Conocimiento s/n., Armilla, 18016 Granada, Spain
2
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
3
School of Medicine, University of Crete, 70013 Heraklion, Crete, Greece
4
Children’s Hospital Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
5
Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
6
Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Pathogens 2021, 10(7), 875; https://doi.org/10.3390/pathogens10070875
Submission received: 24 June 2021 / Revised: 7 July 2021 / Accepted: 9 July 2021 / Published: 10 July 2021
(This article belongs to the Special Issue Inflammation and Gastrointestinal/Hepatobiliary Cancers)

Abstract

:
Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the stomach and can induce gastric disease and intra-gastric lesions, including chronic gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This bacterium is responsible for long-term complications of gastric disease. The conjunction of host genetics, immune response, bacterial virulence expression, diet, micronutrient availability, and microbiome structure influence the disease outcomes related to chronic H. pylori infection. In this regard, the consumption of unhealthy and unbalanced diets can induce microbial dysbiosis, which infection with H. pylori may contribute to. However, to date, clinical trials have reported controversial results and current knowledge in this field is inconclusive. Here, we review preclinical studies concerning the changes produced in the microbiota that may be related to H. pylori infection, as well as the involvement of diet. We summarize and discuss the last approaches based on the modulation of the microbiota to improve the negative impact of H. pylori infection and their potential translation from bench to bedside.

Graphical Abstract

1. Introduction

Helicobacter pylori, considered the main bacterium responsible for gastric disease and long-term complications [1], is a Gram-negative bacterium that colonizes the stomach [2]. Infection with H. pylori is very prevalent around the world. It is estimated that 48.6% of the global adult population is affected [3]. All patients infected with H. pylori suffer from inflammation of the gastric mucosa (chronic gastritis), while, in some cases, the disease becomes more developed (e.g., peptic ulcer, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma) [2,4]. In fact, H. pylori is responsible for 90–95% of duodenal ulcers and 70–85% of gastric ulcers [5].
The most important virulence factors of H. pylori are cytotoxin-associated A (CagA) and vacuolating cytotoxin (VacA). The expression of these proteins varies among H. pylori strains [6]. In the strains that carry the CagA gene, the CagA protein enters the host gastric cells upon H. pylori secretion, where it is phosphorylated and causes changes in cell morphology that lead to disturbed cell function by affecting multiple signaling pathways. CagA is related to higher rates of peptic ulcer disease and a higher probability of developing a more aggressive inflammatory disease and gastric carcinoma [7]. In the strains that express the VacA gene, H. pylori secretes the pore-forming protein VacA, which enters the host cells by endocytosis [6]. VacA accumulation in different host cell compartments can have many consequences related to gastric inflammation and, therefore, gastric carcinogenesis, such as the induction of apoptosis [8] and autophagic cell death [9], the disruption of gastric epithelial cell tight junctions [10], the suppression of host T cell proliferation and activation by yet to be discovered mechanisms [11], and the modulation of host cell metabolism [12].
H. pylori produces ammonia through urease activity, protecting itself from gastric acidity and other enzymes, such as phospholipase A2 and C, and glucosulphatase, which handle gastric mucosal damage [13] and chronic superficial gastritis, leading to atrophy of the gastric glands and resulting in reduced gastric acid secretion. Infection with H. pylori is also associated with anemia, as it impairs iron absorption as a result of chronic gastritis and gastric hypochlorhydria [3]. Infection during early childhood is associated with an augmented risk of coeliac disease [14]. Findings from epidemiologic studies point to H. pylori as an initiator of gastric cancer [2,15]. Moreover, this bacterium has been included as a class I carcinogen of gastric cancer development in the World Health Organization’s International Agency for Research on Cancer since 1994 [16]. The effect of H. pylori on oncogenesis is described by two mechanisms: (1) an indirect inflammatory reaction to H. pylori infection on the gastric mucosa, and (2) a direct epigenetic outcome of H. pylori on gastric epithelial cells development [17]. Consequently, H. pylori infection impairs the gastric tissue microenvironment, and promotes epithelial-mesenchymal transition and further gastric cancer progression [17]. In this line, dietary habits such as a high intake of green tea, fruits, or vegetables showed benefits against gastric cancer risk. Moreover, carotenoids, folate, vitamin C, and phytochemicals from fruits and vegetables seem to exert a protective role in carcinogenesis. On the contrary, salt and the availability of some transition metals can alter H. pylori virulence and accelerate carcinogenesis [18]. In addition, in the context of chronic H. pylori infection, the intersection of host genetics, immune response, bacterial virulence expression, diet, micronutrient availability, and microbiome structure influence disease outcomes [18] (Figure 1).
With the aforementioned in mind, one might suggest that changes in diet patterns, aimed to modulate microbiota in H. pylori carriers, might be exploited to improve disease risk and promote gastric health. However, the relationship of these variables remains poorly understood. In the present review, we aimed to shed light on current knowledge about the changes in microbiota induced by H. pylori infection and the impact of diet, as well as to summarize the recent approaches aimed at modulating the microbiota to avoid and reduce the negative effects caused by H. pylori.

2. The Impact of Diet Patterns in Helicobacter pylori Infection

After infection, H. pylori can induce malabsorption of several nutrients [19] and affect the physiological regulation of the intestinal metabolic hormones, such as ghrelin and leptin, which are involved in food intake, energy expenditure, and body mass [20]. Low circulating ghrelin levels were found in H. pylori-positive patients and in those with the more virulent H. pylori strain [21,22]. Infected individuals can also suffer irreversible inactivation of vitamin C through the effect of hypochlorhydria due to gastric atrophy, as intragastric pH levels increase, turning vitamin C into its less active form [23].
Many substances routinely taken in via diet have potent antibacterial activity against H. pylori and may reduce its potential for colonization [24]. By contrast, diet could affect the development and progression of H. pylori infection, because it alters the gastric environment through the host’s nutrient intake. For instance, animal studies indicated that diets with high salt intake promoted H. pylori colonization by disturbing the integrity and viscosity of the gastric mucosa, causing an inflammatory state that led to increased epithelial damage, hypochlorhydria, and gastric cancer [18,25].
Animal studies showed not only an increase in colonization capable of producing losses of parietal cells, atrophy, and intestinal metaplasia [26,27], but also high levels of gastric inflammation and oxidative stress [28]. A high-salt diet could influence gastric cancer risk by modulating H. pylori gene expression due to transcriptional alterations. In an in vitro study conducted by Loh et al., 65 genes were upregulated and 53 genes were downregulated in response to high salinity conditions [29]. The in vitro study of Voss et al. also showed that the bacterial membrane proteome was altered in response to salinity conditions [30].
By contrast, the results of sulforaphane consumption (present in broccoli sprouts) in female C57BL/6 mice infected with H. pylori Sydney Strain 1 subjected to a high-salt diet produced a reduction in gastric bacterial colonization, attenuated mucosal expression of tumor necrosis factor-alpha and interleukin (IL)-1beta, mitigated corpus inflammation, and prevented the expression of high-salt-induced gastric corpus atrophy [31]. More recently, an in vitro study showed that the concentration of salt in the environment influenced the composition of the H. pylori exoproteome and led to increased levels of a secreted VacA toxin, which would increase the risk of gastric cancer associated with the consumption of a high-salt diet [32]. In a Mongolian gerbil model, infected animals fed with diets rich in salt developed gastric ulcers significantly more frequently than those consuming a normal salt diet, and lower hemoglobin levels were found in infected gerbils consuming a high-salt and low-iron diet [33] compared to controls.
In this animal study, dietary consumption of walnuts rich in n-3 polyunsaturated fatty acids were proposed as a nutritional intervention to prevent H. pylori associated with gastric cancer. The results of walnut consumption, using a model of H. pylori-initiated gastric carcinogenesis promoted by a high-salt diet in mice, showed a significant improvement in chronic atrophic gastritis and a significant decrease in tumorigenesis compared to the control group [34]. Similarly, a mouse model of chronic atrophic gastritis and gastric tumorigenesis initiated by H. pylori and promoted by high salt content was used by Jeong et al. to evaluate the efficacy of long-term dietary administration of artemisia and green tea extracts, resulting in improvements in both gastritis and tumorigenesis. These authors found decreased expression of cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), IL-6, lipid peroxide, and activated signal of both the transducer and the activator of transcription 3 (STAT3) (relevant to H. pylori infection), as well as serum activations of TNF-α and nuclear factor kappa B [35].
Iron is an essential growth factor for H. pylori [36]. Several studies have associated H. pylori infection and iron deficiency anemia in human and animal studies [37,38]. This may be due to the fact that H. pylori-related gastritis leads to a defect in its absorption, or increases gastric pH and alters the reduction of the ferric to ferrous form (essential for the absorption of non-heme iron) [39,40]. Animals fed with low iron diets displayed increased infiltration of immune cells at the site of infection, more rapid onset of gastritis, and a higher rate of cancer development [41]. Results from a meta-analysis by Kin et al., indicated that red and processed meats rich in heme iron led to endogenous production of N-nitro compounds and increased progression of H. pylori infection by causing DNA damage and oxidative stress (a significant risk factor for gastric cancer) [42,43]. This increase in oxidative stress can be further aggravated in the stomach of individuals affected by H. pylori [44]. Thus, including sulfur-rich food, such as broccoli sprouts, in the diet can not only protect cells from oxidative stress damage, but also inhibit the viability of H. pylori and mitigate gastritis, as indicated in this study conducted in mice and humans [31]. Similarly, it was shown that, in a mouse model of infection by H. pylori, resveratrol exerted a beneficial effect against H. pylori-associated gastritis by combating oxidative stress [45], thus the consumption of resveratrol-rich foods may also have a positive effect.
As far as the consumption of cured, pickled, and smoked foods is concerned, nitrosamines (which are often present in this type of food) exert a synergistic effect with H. pylori by inducing intestinal metaplasia and intraepithelial neoplasia in a model of non-human primates through changes in multiple genes associated with cancer [46].
It is well known that high-fat diets (HFD), high-ultra-processed foods and low intake of fruits and vegetables are key factors for the development of obesity. The risk of H. pylori infection is not increased in young overweight individuals [47], but high-carbohydrate and sweetened diets were positively associated with an increased prevalence [48], whereas whole-grains, roots and tubers, vegetables, mushrooms, miscellaneous beans, vegetable oils, nuts, and seeds consumed in abundance were linked to a reduced risk of infection in humans [49].
The rejuvenation of atrophic gastritis and prevention of tumorigenesis in mice, via cancer-preventive kimchi made from a changed recipe from the Research Institute at Pusan National University [50], was also promoted by the same authors. In sum, many promising results show the importance of the impact of diet on H. pylori infection, although there are many controversies in this respect that need to be elucidated.

Diet, Helicobacter pylori, and the Gut Microbiota

Gut microbiota (defined as the community of microorganisms that subsists within the digestive tract) plays both local and remote roles in important physiological processes, particularly inflammation and immune response [51]. Diet has a considerable effect on the composition of gastrointestinal microbiota and an unhealthy diet, among other factors, alters its composition and induces gastric microbial dysbiosis [52]. The gut microbiome is the genetic material of all the microbes that live on and inside the human body [53,54,55]. H. pylori colonization results in the alteration of gastric microbiota and a reduction in bacterial diversity [56,57], thus modifying the host’s gut microbiome [58]. A growing number of studies reported greater ecosystem diversity in the gastrointestinal tract and associated H. pylori presence with variations within the structure of the microbiome [59]. Gut microbiome changes triggered by the first H. pylori acquisition could also corroborate the host immunological status and, as a result, the manifestation of several diseases. This is important due to the fact that gut microbiota is modified by antibiotic treatment, which also decreases H. pylori-induced inflammation [60].
Some studies have evaluated changes in the microbial profile related to H. pylori in humans [61,62,63]. For instance, individuals infected by H. pylori present higher levels of Succinivibrio, Coriobacteriaceae, Enterococcaceae, and Rikenellaceae, and an increased abundance of Candida glabrata and other unclassified fungi [62]. In children, gastric commensal bacteria are altered during H. pylori infection [61]. Indeed, H. pylori dominated the microbial community in infected children, while H. pylori-negative individuals showed a relative abundance of Gammaproteobacteria, Betaproteobacteria, Bacteroidia and Clostridia classes and a higher bacterial richness and diversity [63]. However, the relationship and underlying mechanisms involved need to be elucidated.
Concerning animal studies, a cocoa-supplemented diet was shown to modify the intestinal microbiota and health-promoting microbiota in diabetic rats [64], whereas the consumption of diets high in sugar induced gut dysbiosis [65]. Along the same line, the dietary pattern known as the Mediterranean diet is characterized by the high consumption of vegetables, fruits, whole grains, legumes, nuts, fish, lean meats, and virgin olive oil. This diet is associated with a health-promoting microbiota able to prevent the appearance of non-communicable diseases or cancer [66]. In contrast, an HFD produces an increase in bacteria expressing lipopolysaccharides in the gut microbiota, resulting in a pro-inflammatory state, weight gain, and increased intestinal permeability [67]. It is not clear whether the diet, by modifying the intestinal microbiota, creates helpful conditions for colonization by H. pylori, as many factors are involved. However, it is known that H. pylori-induced alterations in the composition of the intestinal microbiota are due to changes in the lifestyle and diet patterns of H. pylori-infected individuals [20]. In addition, as discussed below, H. pylori infection leads to a reduction in Lactobacillus, Lachnospiraceae, and Blautia, bacteria that have also been found to be reduced in metabolic diseases such as obesity, metabolic syndrome, and diabetes [68,69,70]. Thus, altered intestinal microbiota may lead to disease.
Animal studies showed an interaction between H. pylori and normal intestinal microbiota that is associated with intestinal metabolism and inflammation [71]. A study on C57BL/6 mice showed that H. pylori infection not only aggravated metabolic disorders induced by an HFD, but also altered the intestinal microbiota. The reported results highlighted that H. pylori-infected mice fed with high-fat diets had a different microbiota community, with a significantly higher proportion of Firmicutes and Proteobacteria and a reduction in the population of Bacteroidetes and Verrucomicrobia at the phylum level. In addition, metagenomics analysis showed that Desulfovibrionaceae and Mucispirillum spp., Helicobacter, Lachnospiraceae and Ruminococcaceae sequences were significantly increased in the H. pylori-infected group fed with an HFD [72]. Sex may have a greater impact on gut microbiota composition than diet, as shown by Peng et al. They found that microbiota composition was markedly different between male and female mice independent of diet [73].
Trimethylamine N-oxide is a diet-related microbial metabolite present in seafood and synthesized by hepatic oxidation of trimethylamine, which is produced by enzymatic bacteria in the colon via carnitine and choline. The major source of these compounds in the diet comes from meat, fish, eggs (rich in choline), and dairy products (rich in carnitine) [74,75]. These two compounds are associated with several metabolic and inflammatory disorders [76]. The effect of the presence of trimethylamine N-oxide on inflammation and intestinal microbiota was reported in a study on mice carried out by Wu et al. These authors reported an increase in the expression of growth- and metabolism-associated genes and the urease activity of H. pylori, and an increase in the production of virulence factors. The VacA concentration was not increased in the group co-treated with H. pylori and trimethylamine N-oxide when compared to the H. pylori-treated group, but CagA concentration was significantly higher by treatment with trimethylamine N-oxide when H. pylori was co-cultured with GES-1 cells. Thus, trimethylamine N-oxide enhanced H. pylori virulence by upregulating the expression of the virulence gene encoding CagA. The authors also confirmed that the intake of trimethylamine enhanced the production of inflammatory markers and reduced the richness and diversity of the intestinal microbiota [77]. Similar results suggested that the treatment of infected mice with choline aggravated both the inflammation produced by the bacteria itself and the alteration of the intestinal microbiota [78].
Despite infection by the bacteria altering the profile of the gastric and intestinal microbiota in animals [79,80], it affects the human diurnal oral microbiota [81], causes intestinal dysbiosis in bacterial-induced gastritis [82], and can influence the composition of the gastric microbiota at lower taxonomic levels (in vitro study) [83]. To date, the relationship between microbiota, H. pylori infection, and the effect of diet patterns is not fully understood and the number of studies involving the role of diet and its impact on H. pylori infection in gastric and intestinal microbiota remains limited (Table 1). Thus, future research will need to decipher the exact mechanisms of H. pylori pathogenesis on the H. pylori-microbiota axis and extend our understanding of H. pylori colonization.

3. Management of Helicobacter pylori Infection

3.1. Current Standard Treatments

There are some guidelines regarding the management of H. pylori infection, such as the Maastricht V/Florence Consensus Report [85] and the Taipei global consensus [86]. The latter is specially focused on elucidating the populations that should be screened, and it identified the best treatment (“screen and treat” strategy) to prevent gastric cancer. Although there is no universally accepted regimen for the eradication of H. pylori, the current first-line treatment is a triple therapy that combines one proton pump inhibitor and two antibiotics (clarithromycin and amoxicillin) and the quadruple therapy, which includes tetracycline, metronidazole, bismuth salts, and proton-pump inhibitors. However, resistance to clarithromycin has become very prevalent in some geographical areas. In such cases, it can be substituted by metronidazole, although resistance to this antibiotic has already developed in specific areas as well. Aside from drug resistance, antibiotics can also be problematic because they can cause side effects, in part because of the undesired killing of healthy microbiota [87,88,89]. Therefore, owing to a decrease in the therapeutic efficacy of these antibiotic-based therapies, further research is needed in this field.

3.2. New Antibiotics

Some studies have tested new antibiotics or new antibiotic regimes. On one hand, Shi et al. evaluated the efficacy of linezolid and novel oxazolidinone analogs in vitro, by culturing clinical multidrug-resistant H. pylori isolates, and in vivo, by orally inoculating mice with these isolates and then administrating the drugs intragastrically. The authors concluded that both, but especially oxazolidinone analogs, were suitable candidates to treat drug-resistant H. pylori infections [90]. Linezolid was observed to exhibit in vitro activity, with minimum inhibitory concentrations (MICs) ranging from ≤0.25 mg/L to 32 mg/L against clinical H. pylori isolates (MIC50, 2 mg/L; MIC90, 8 mg/L). The oxazolidinone analogue sy142 inhibited all of the clinical isolates, with MICs of ≤16 mg/L (MIC range, ≤0.25–16 mg/L; MIC50, 1 mg/L; MIC90, 4 mg/L), even for the multidrug-resistant isolates [90].
On the other hand, Jeong et al. subjected H. pylori-infected mice to a gentamicin-intercalated smectite hybrid-based treatment and observed reduced H. pylori burden and cytokine secretion, and less atrophy of gastric mucosa, compared to the group treated with standard triple therapy. Importantly, they also analyzed changes in fecal microbiota and concluded that microbiota composition was more similar to uninfected and infected-non-treated groups than microbiota diversity of the standard triple therapy-treated group. These results suggested that this regime may restore gut dysbiosis [91,92]. On the contrary, treatment with antibiotics of H. pylori-infected mice fed with a diet high in folate but low in vitamin K caused dysbiosis and hypovitaminosis K, which were likely related to the anemia, gastric hemorrhage, and mortality observed in these animals [93].
It is important to remark that there is active research in nanoparticles for targeted antibiotic delivery against H. pylori infection [94]. Other therapeutic options, such as nutraceuticals, have also been considered. Finally, there is also an exceptional effort being made on the generation of a prophylactic vaccine against H. pylori.

3.3. Nutraceutical Approaches

In contrast to antibiotics and pharmacological drugs, nutraceuticals, especially substances found in our daily diet and traditional herbs or plants, have a low probability of toxicity, as they have been consumed for generations in some areas. Consequently, they might be agents for H. pylori elimination. Recent literature concerning this subject is summarized in Table 2.

3.3.1. Extracts and Compounds Isolated from Food

H. pylori eradication and reversal of gastric mucosa injury was observed in vitro and in vivo using H. pylori strains isolated from patients that presented resistance to a variety of antibiotics, and H. pylori-infected mice. In this study, the authors confirmed the previously reported antimicrobial activity of ellagic acid, a polyphenol found in walnuts, strawberries, blackberries, raspberries, and pomegranates, among other dietary sources [95].
Omega-3 polyunsaturated fatty acids, present in many fish and seafood species, as well as plenty of nuts and seeds, were proposed as a therapy against H. pylori infection. A proposed mechanism for this effect is the blocking of the futalosine pathway, an alternative route for menaquinone biosynthesis. Indeed, the blockage of this pathway by supplementation with linoleic acid, an omega-6 fatty acid, inhibited H. pylori growth in H. pylori cultures and H. pylori-infected mice [96]. Some fish and seafood are also rich in other bactericidal compounds. Snakehead fish extract supplementation was described as a useful method to eradicate H. pylori in rats, although its superiority when compared to standard first-line antibiotic treatment needs to be confirmed by further studies [97]. By contrast, the effect of the extracts from the Channa striata fish on an H. pylori-induced gastritis rat model was controversial since it worsened the severity of gastritis when administrated alone, but seemed to contribute to the improvement of the disease when combined with the standard triple therapy [98]. Another study conducted in mice reported that after six weeks of supplementation with astaxanthin from shrimp cephalothorax, H. pylori-infected mice showed an increase in splenocytes synthesis of interferon-gamma, IL-2, and IL-10, although the biological meaning of the changes in the cytokine release pattern remains to be explained [99].

3.3.2. Traditional Plants or Herbs

There is a vast array of literature aimed at evaluating the potential use of traditional plants or herbs for H. pylori eradication or gastroprotection to avoid H. pylori-associated health problems. There is a remarkable number of studies focused on folk medicine plants from Asia and Brazil. For example, regarding Asian traditional herbal medicines, in vitro and in vivo results found that Hwanglyeonhaedok-tang (a herb mixture) [100] and yugeunpi (the root bark of Ulmus davidiana var. japonica (Ulmaceae)) [101] exert anti-inflammatory and anti-H. pylori effects. Palmatine, the major component of the traditional Chinese herb Tinospora sagittata (Oliv.) Gagnep. var. craveniana (SY Hu) Lo, improved H. pylori-induced chronic atrophic gastritis in rats [103] and eliminated H. pylori in infected mice and cell cultures [102]. Patchouli alcohol was described as inhibiting H. pylori urease activity and potentiating macrophage digestive activity in vitro [105], as well as limiting the H. pylori-promoted recruitment and activation of neutrophils in both rats and culture cells [104]. Berberine was also proposed as a treatment for H. pylori given its anti-inflammatory effects in H. pylori-induced chronic gastritis in mice [107] and rats [106]. Brazilian folk medicinal plants Euphorbia umbellata (leitosinha) [108] and Piper umbellatum L. (Piperaceae) [109], among many others, were studied as a potential therapy for H. pylori-caused ulcers.

3.3.3. Vitamin D3

Vitamin D3 stimulates innate immune antibacterial activity in several cell types through increase in the production of antimicrobial factors [111]. Accordingly, two different studies concluded that supplementation with vitamin D3 at different doses, for 14 days or 2 months, and treatment with vitamin D3 for 72 h in human normal gastric epithelial cells HFE145 led to H. pylori eradication [110,111]. The study conducted by Hu et al. demonstrated that H. pylori infection affected Ca2+ release from lysosomes of epithelial gastric cells, disrupting lysosomal acidification and allowing the bacteria to remain in the lysosomes. They suggested that vitamin D3 exerted its bactericidal properties by enhancing the lysosomal degradation function via the PDIA3-STAT3-MCOLN3-Ca2+ axis [111]. In contrast, Zhou et al. proposed a mechanism wherein vitamin D3 increased the expression of the vitamin D receptor (VDR) and cathelicidin antimicrobial peptides (CAMPs) in the gastric mucosa by binding of the vitamin D3 and VDR complex to the CAMPs promoter [110].

3.3.4. Probiotics

The effect of many lactobacilli species against H. pylori was tested in a wide number of publications. While most studies focused on one strain, Lin et al. proposed the combination of L. fermentum, L. casei, and L. rhamnosus, given the fact that together, the three probiotics not only eliminated H. pylori, but also restored the metabolic imbalance caused by H. pylori infection [112]. De Klerk et al. evaluated a panel of lactobacilli species and concluded that L. gasseri and L. brevis inhibited H. pylori attachment to human gastric epithelial cell lines. They also treated transgenic mice expressing human CD46 (to mimic the human stomach) with antibiotics to reduce microbiota abundance. The authors fed animals with L. gasseri, and with H. pylori, respectively, concluding that L. gasseri prevented H. pylori infection in this experimental setup [113]. In the same line, L. gasseri improved inflammation associated with H. pylori infection in the AGS human gastric adenocarcinoma cell line [114]. Moreover, Chen et al. showed that L. rhamnosus and L. acidophilus can inhibit the growth of antibiotic-resistant H. pylori, its adhesion and invasion to gastric epithelial cells, as well as the production of IL-8 by host cells. Similarly, in mice L. rhamnosus and L. acidophilus decreased H. pylori colonization and H. pylori-induced inflammation in the stomach of animals. Remarkably, these probiotics increased the population of beneficial gut bacteria, therefore supporting the reversion of dysbiosis as a mechanism against H. pylori infection [115]. Accordingly, treatment with L. paracasei decreased H. pylori adhesion and H. pylori-related inflammation in H. pylori-treated AGS human gastric adenocarcinoma cell line and mice. Moreover, histological analysis revealed fewer epithelial lesions in the stomach of L. paracasei-fed mice compared to the group that was not treated with the probiotic strain [116]. Furthermore, L. rhamnosus isolated from honey or dairy products also eliminated H. pylori and improved gastritis caused by this bacterium in mice. The observed effect was comparable to clarithromycin antimicrobial activity, although the use of L. rhamnosus seemed to avoid antibiotic-related severe dysbiosis [117,118].
In a mouse model that combined ethanol and H. pylori administration, Park et al. treated the animals with green tea-derived L. plantarum, concluding that these probiotics decreased inflammation and improved gastric ulcers, possibly by restoring healthy gut microbiota [119]. In another study by the same group, mice were fed L. plantarum before H. pylori infection. They reported that H. pylori-induced gastric mucosa inflammation and gastric dysbiosis could be prevented by pre-treatment with L. plantarum [120].
Finally, dead L. johnsonii was reported to eradicate H. pylori in vitro and from the stomach of germ-free mice, although the molecular mechanism was not clear [121].
To conclude, we mainly found studies reporting the effects of lactobacilli species against H. pylori infection. To date, it is strongly believed that probiotics can be useful for H. pylori eradication, although still with controversial results [87,122]. Nevertheless, more studies aimed at deciphering molecular mechanisms may shed light on this question.

4. Discussion

H. pylori infection is the major cause of the development of gastric and duodenal ulcers and gastric cancer worldwide, affecting almost 50% of the world’s population. Infected individuals can incur direct damage in the epithelial cells, or damage induced by the pro-inflammatory factors stimulated after infection. The affectation depends on the host’s genetic predisposition as well as other conditions (e.g., diet, age, or an altered intestinal microbiota).
Bearing this in mind, in the present review, we described the impact of dietary patterns on H. pylori infection and the modulation of microbiota to counteract its effect.
We highlighted studies that reported alterations in the microbiota caused by the presence of this bacterium and their relation to diet. Our search was focused mainly on animal studies because they present several advantages, including their reproducibility, reliability, affordability, and technical availability when compared with human studies. Our purpose was also to identify relevant recent studies addressed to treat H. pylori infection using extracts and compounds isolated from food and traditional plants or herbs reported in animal models covering the period of 2016–2020.
Gut microbiota itself, as well as dietary patterns such as high salt or sugar intake, seem to have a notable impact on the development, proliferation, and increased risk of developing more severe conditions after H. pylori infection.
By contrast, foods such as whole-grains, roots and tubers, vegetables, mushrooms, miscellaneous beans, vegetable oils, nuts or seeds consumed in abundance are linked to a reduced risk of infection. Of note, the majority of these mentioned foods have proven prebiotic, probiotic, and anti-inflammatory properties which, in turn, favor a healthy microbiota. Thus, accounting for the fact that diet has a considerable effect on the composition of the gastrointestinal microbiota and that H. pylori colonization results in alterations of gastric microbiota and reduction in bacterial diversity, it seems evident that there are mutual interactions between all three factors. However, the relationship that each of these variables has with one another remains poorly understood. Consequently, more studies connecting the gut with microbiota-host-H. pylori and dietary patterns interactions are required to understand the complete scenario of these associations and their effect on gastrointestinal health.
Studies conducted on humans have focused on the analysis of the diversity and variations in the microbiota of H. pylori infected and uninfected individuals [123], and none have considered the effect of diet.
Current standard treatments include antibiotics therapy, although this approach presents two major inconveniences: (1) the undesired killing of a healthy microbiota, and (2) the increased resistance of H. pylori to commonly used antibiotics.
In addition, the emergence of strains of H. pylori that are increasingly resistant to the use of antibiotics and the poor adherence to treatment by patients means that the efficacy of the use of these therapies is highly compromised, sometimes reaching ≤80% [124]. Alternative therapies involving the use of natural substances or compounds of certain foods are currently being pursued. Many studies have confirmed the antibacterial activity of substances in food, although the number of prospective randomized trials assessing their use in clinical practice remains scarce. Moreover, some diets contain many substances with potent antibacterial activity against H. pylori and dietary interventions may enable a decrease in H. pylori colonization and lead to the reduction of gastritis and gastrointestinal-associated diseases [24].
On the other hand, infection with H. pylori is more prevalent in developing countries [4]. Treatment regimens based on antibiotics or other drugs have a lower chance of success in these countries because socioeconomic issues limit their accessibility and availability. Thus, the establishment of alternate approaches, such as nutritional intervention, seem a suitable tool for reducing H. pylori infection and its undesired effects on gastrointestinal health. Dietary interventions and the use of supplements, such as probiotics or prebiotics, seems a more affordable strategy to, at the very least, ameliorate the damage induced by H. pylori in infected individuals. Thus, policies in this regard should be made available to the entire population.
In conclusion: (1) H. pylori infection is still an unsolved problem with potentially severe complications for gastrointestinal health, (2) recent results from studies, mainly conducted on animals models, show evidence of the mutual interactions between, diet, gastrointestinal microbiota, and H. pylori, and (3) more research aimed at shedding light on the molecular mechanisms involving diet, gastrointestinal microbiota, and H. pylori is needed and may prove helpful in the development of novel therapeutic approaches.

Author Contributions

Conceptualization, A.R.-R., T.R.-T., and A.I.Á.-M.; methodology, A.R.-R., T.R.-T., and A.I.Á.-M.; validation, A.R.-R., T.R.-T., and A.I.Á.-M.; investigation, A.R.-R., T.R.-T., J.P.-D., and A.I.Á.-M.; resources, A.I.Á.-M.; writing—original draft preparation A.R.-R., T.R.-T., J.P.-D., and A.I.Á.-M.; writing—review and editing, A.R.-R., T.R.-T., J.P.-D., and A.I.Á.-M.; visualization, A.R.-R., T.R.-T., J.P.-D., and A.I.Á.-M.; supervision, A.I.Á.-M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

Julio Plaza-Diaz is part of the “UGR Plan Propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada”. He is likewise supported by a grant to postdoctoral researchers at foreign universities and research centers from the “Fundación Ramón Areces”, Madrid, Spain.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Conti, L.; Annibale, B.; Lahner, E. Autoimmune Gastritis and Gastric Microbiota. Microorganisms 2020, 8, 1827. [Google Scholar] [CrossRef]
  2. Lee, Y.C.; Chiang, T.H.; Chiu, H.M.; Wu, M.S.; Yeh, Y.P.; Chen, T.H.H. Community-based Gastric Cancer Screening Coupled with a National Colorectal Cancer Screening Program: Baseline Results. Gastroenterology 2021, 21, 67–76. [Google Scholar] [CrossRef]
  3. Haile, K.; Yemane, T.; Tesfaye, G.; Wolde, D.; Timerga, A.; Haile, A. Anemia and its association with Helicobacter pylori infection among adult dyspeptic patients attending Wachemo University Nigist Eleni Mohammad Memorial Referral Hospital, Southwest Ethiopia: A cross-sectional study. PLoS ONE 2021, 16, e0245168. [Google Scholar] [CrossRef]
  4. Zamani, M.; Ebrahimtabar, F.; Zamani, V.; Miller, W.H.; Alizadeh-Navaei, R.; Shokri-Shirvani, J.; Derakhshan, M.H. Systematic review with meta-analysis: The worldwide prevalence of Helicobacter pylori infection. Aliment. Pharmacol. Ther. 2018, 47, 868–876. [Google Scholar] [CrossRef] [Green Version]
  5. Feili, O.; Bakhti, S.Z.; Latifi-Navid, S.; Zahri, S.; Yazdanbod, A. Contrasting association of Helicobacter pylori oipA genotype with risk of peptic ulceration and gastric cancer. Infect. Genet. Evol. 2021, 89, 104720. [Google Scholar] [CrossRef] [PubMed]
  6. Nejati, S.; Karkhah, A.; Darvish, H.; Validi, M.; Ebrahimpour, S.; Nouri, H.R. Influence of Helicobacter pylori virulence factors CagA and VacA on pathogenesis of gastrointestinal disorders. Microb. Pathog. 2018, 117, 43–48. [Google Scholar] [CrossRef] [PubMed]
  7. Yong, X.; Tang, B.; Li, B.S.; Xie, R.; Hu, C.J.; Luo, G.; Qin, Y.; Dong, H.; Yang, S.M. Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways. Cell Commun. Signal. 2015, 13, 30. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Jain, P.; Luo, Z.Q.; Blanke, S.R. Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death. Proc. Natl. Acad. Sci. USA 2011, 108, 16032–16037. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Zhu, P.; Xue, J.; Zhang, Z.J.; Jia, Y.P.; Tong, Y.N.; Han, D.; Li, Q.; Xiang, Y.; Mao, X.H.; Tang, B. Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway. Cell Death Dis. 2017, 8, 3207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Caron, T.J.; Scott, K.E.; Fox, J.G.; Hagen, S.J. Tight junction disruption: Helicobacter pylori and dysregulation of the gastric mucosal barrier. World J. Gastroenterol. 2015, 21, 11411–11427. [Google Scholar] [CrossRef]
  11. Djekic, A.; Muller, A. The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells. Toxins 2016, 8, 187. [Google Scholar] [CrossRef]
  12. Kim, I.J.; Lee, J.; Oh, S.J.; Yoon, M.S.; Jang, S.S.; Holland, R.L.; Reno, M.L.; Hamad, M.N.; Maeda, T.; Chung, H.J.; et al. Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1. Cell Host Microbe 2018, 23, 583–593 e588. [Google Scholar] [CrossRef] [Green Version]
  13. Dzierzanowska-Fangrat, K.; Dzierzanowska, D. Helicobacter pylori: Microbiology and interactions with gastrointestinal microflora. J. Physiol. Pharmacol. 2006, 57 (Suppl. 3), 5–14. [Google Scholar]
  14. Stordal, K.; Kahrs, C.; Tapia, G.; Agardh, D.; Kurppa, K.; Stene, L.C. Review article: Exposure to microbes and risk of coeliac disease. Aliment. Pharmacol. Ther. 2021, 53, 43–62. [Google Scholar] [CrossRef] [PubMed]
  15. Boltin, D.; Beniashvili, Z.; Lahat, A.; Hirsch, J.; Nyssen, O.P.; Megraud, F.; O′Morain, C.; Gisbert, J.P.; Niv, Y. European Registry on Helicobacter pylori management (Hp-EuReg): First-line Therapy in Israel. Isr. Med. Assoc. J. 2021, 23, 38–42. [Google Scholar] [PubMed]
  16. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Schistosomes, Liver Flukes and Helicobacter pylori; International Agency for Research on Cancer: Lyon, France, 1994; Volume 61, pp. 1–241. [Google Scholar]
  17. Machlowska, J.; Baj, J.; Sitarz, M.; Maciejewski, R.; Sitarz, R. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int. J. Mol. Sci. 2020, 21, 4012. [Google Scholar] [CrossRef] [PubMed]
  18. Haley, K.P.; Gaddy, J.A. Nutrition and Helicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome. Gastroenterol. Res. Pract. 2016, 2016. [Google Scholar] [CrossRef] [Green Version]
  19. Annibale, B.; Capurso, G.; Delle Fave, G. Consequences of Helicobacter pylori infection on the absorption of micronutrients. Dig. Liver Dis. 2002, 34 (Suppl. 2), S72–S77. [Google Scholar] [CrossRef]
  20. Mohammadi, S.O.; Yadegar, A.; Kargar, M.; Mirjalali, H.; Kafilzadeh, F. The impact of Helicobacter pylori infection on gut microbiota-endocrine system axis; modulation of metabolic hormone levels and energy homeostasis. J. Diabetes Metab. Disord. 2020, 1855–1861. [Google Scholar] [CrossRef] [PubMed]
  21. Isomoto, H.; Nishi, Y.; Ohnita, K.; Mizuta, Y.; Kohno, S.; Ueno, H.; Nakazato, M. The Relationship between Plasma and Gastric Ghrelin Levels and Strain Diversity in Helicobacter pylori Virulence. Am. J. Gastroenterol. 2005, 100, 1425–1427. [Google Scholar] [CrossRef]
  22. Nweneka, C.V.; Prentice, A.M. Helicobacter pylori infection and circulating ghrelin levels—A systematic review. BMC Gastroenterol. 2011, 11, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Capurso, G.; Ricci, R.; Panzuto, F.; Baccini, F.; Passi, S.; Di Giulio, E.; Delle Fave, G.; Annibale, B. Intragastric ascorbic but not uric acid is depleted in relation with the increased pH in patients with atrophic body gastritis and H. pylori gastritis. Helicobacter 2003, 8, 300–306. [Google Scholar] [CrossRef] [PubMed]
  24. Holubiuk, L.; Imiela, J. Diet and Helicobacter pylori infection. Prz. Gastroenterol. 2016, 11, 150–154. [Google Scholar] [CrossRef]
  25. Yoo, J.Y.; Cho, H.J.; Moon, S.; Choi, J.; Lee, S.; Ahn, C.; Yoo, K.Y.; Kim, I.; Ko, K.P.; Lee, J.E.; et al. Pickled Vegetable and Salted Fish Intake and the Risk of Gastric Cancer: Two Prospective Cohort Studies and a Meta-Analysis. Cancers 2020, 12, 996. [Google Scholar] [CrossRef]
  26. Bergin, I.L.; Sheppard, B.J.; Fox, J.G. Helicobacter pylori infection and high dietary salt independently induce atrophic gastritis and intestinal metaplasia in commercially available outbred Mongolian gerbils. Dig. Dis. Sci. 2003, 48, 475–485. [Google Scholar] [CrossRef]
  27. Gaddy, J.A.; Radin, J.N.; Loh, J.T.; Zhang, F.; Washington, M.K.; Peek, R.M., Jr.; Algood, H.M.; Cover, T.L. High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis. Infect. Immun. 2013, 81, 2258–2267. [Google Scholar] [CrossRef] [Green Version]
  28. Loh, J.T.; Gaddy, J.A.; Algood, H.M.; Gaudieri, S.; Mallal, S.; Cover, T.L. Helicobacter pylori adaptation in vivo in response to a high-salt diet. Infect. Immun. 2015, 83, 4871–4883. [Google Scholar] [CrossRef] [Green Version]
  29. Loh, J.T.; Beckett, A.C.; Scholz, M.B.; Cover, T.L. High-Salt Conditions Alter Transcription of Helicobacter pylori Genes Encoding Outer Membrane Proteins. Infect. Immun. 2018, 86, e00626-17. [Google Scholar] [CrossRef] [Green Version]
  30. Voss, B.J.; Loh, J.T.; Hill, S.; Rose, K.L.; McDonald, W.H.; Cover, T.L. Alteration of the Helicobacter pylori membrane proteome in response to changes in environmental salt concentration. Proteom. Clin. Appl. 2015, 9, 1021–1034. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Yanaka, A.; Fahey, J.W.; Fukumoto, A.; Nakayama, M.; Inoue, S.; Zhang, S.; Tauchi, M.; Suzuki, H.; Hyodo, I.; Yamamoto, M. Dietary sulforaphane-rich broccoli sprouts reduce colonization and attenuate gastritis in Helicobacter pylori-infected mice and humans. Cancer Prev Res. 2009, 2, 353–360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Caston, R.R.; Loh, J.T.; Voss, B.J.; McDonald, W.H.; Scholz, M.B.; McClain, M.S.; Cover, T.L. Effect of environmental salt concentration on the Helicobacter pylori exoproteome. J. Proteom. 2019, 202, 103374. [Google Scholar] [CrossRef]
  33. Beckett, A.C.; Piazuelo, M.B.; Noto, J.M.; Peek, R.M., Jr.; Washington, M.K.; Algood, H.M.; Cover, T.L. Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration. Infect. Immun. 2016, 84, 3338–3349. [Google Scholar] [CrossRef] [Green Version]
  34. Park, J.M.; Han, Y.M.; Park, Y.J.; Hahm, K.B. Dietary intake of walnut prevented Helicobacter pylori-associated gastric cancer through rejuvenation of chronic atrophic gastritis. J. Clin. Biochem. Nutr. 2021, 68, 37–50. [Google Scholar] [CrossRef]
  35. Jeong, M.; Park, J.M.; Han, Y.M.; Kangwan, N.; Kwon, S.O.; Kim, B.N.; Kim, W.H.; Hahm, K.B. Dietary Intervention of Artemisia and Green Tea Extracts to Rejuvenate Helicobacter pylori-Associated Chronic Atrophic Gastritis and to Prevent Tumorigenesis. Helicobacter 2016, 21, 40–59. [Google Scholar] [CrossRef]
  36. Pich, O.Q.; Merrell, D.S. The ferric uptake regulator of Helicobacter pylori: A critical player in the battle for iron and colonization of the stomach. Future Microbiol. 2013, 8, 725–738. [Google Scholar] [CrossRef] [Green Version]
  37. Akcam, M.; Ozdem, S.; Yilmaz, A.; Gultekin, M.; Artan, R. Serum ferritin, vitamin B(12), folate, and zinc levels in children infected with Helicobacter pylori. Dig. Dis. Sci. 2007, 52, 405–410. [Google Scholar] [CrossRef]
  38. Capurso, G.; Marignani, M.; Delle Fave, G.; Annibale, B. Iron-deficiency anemia in premenopausal women: Why not consider atrophic body gastritis and Helicobacter pylori role? Am. J. Gastroenterol. 1999, 94, 3084–3085. [Google Scholar] [CrossRef]
  39. Annibale, B.; Capurso, G.; Lahner, E.; Passi, S.; Ricci, R.; Maggio, F.; Delle Fave, G. Concomitant alterations in intragastric pH and ascorbic acid concentration in patients with Helicobacter pylori gastritis and associated iron deficiency anaemia. Gut 2003, 52, 496–501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Capurso, G.; Lahner, E.; Marcheggiano, A.; Caruana, P.; Carnuccio, A.; Bordi, C.; Delle Fave, G.; Annibale, B. Involvement of the corporal mucosa and related changes in gastric acid secretion characterize patients with iron deficiency anaemia associated with Helicobacter pylori infection. Aliment. Pharmacol. Ther. 2001, 15, 1753–1761. [Google Scholar] [CrossRef]
  41. Noto, J.M.; Gaddy, J.A.; Lee, J.Y.; Piazuelo, M.B.; Friedman, D.B.; Colvin, D.C.; Romero-Gallo, J.; Suarez, G.; Loh, J.; Slaughter, J.C.; et al. Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans. J. Clin. Investig. 2013, 123, 479–492. [Google Scholar] [CrossRef] [Green Version]
  42. Kim, S.R.; Kim, K.; Lee, S.A.; Kwon, S.O.; Lee, J.K.; Keum, N.; Park, S.M. Effect of Red, Processed, and White Meat Consumption on the Risk of Gastric Cancer: An Overall and Dose(-)Response Meta-Analysis. Nutrients 2019, 11, 826. [Google Scholar] [CrossRef] [Green Version]
  43. Iqbal, A. Effect of Food on Causation and Prevention of Gastric Cancer. J. Cancer Prev. Curr. Res. 2017, 8, 289. [Google Scholar] [CrossRef] [Green Version]
  44. Van Hecke, T.; Van Camp, J.; De Smet, S. Oxidation During Digestion of Meat: Interactions with the Diet and Helicobacter pylori Gastritis, and Implications on Human Health. Compr. Rev. Food Sci. Food Saf. 2017, 16, 214–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Zhang, X.; Jiang, A.; Qi, B.; Ma, Z.; Xiong, Y.; Dou, J.; Wang, J. Resveratrol Protects against Helicobacter pylori-Associated Gastritis by Combating Oxidative Stress. Int. J. Mol. Sci. 2015, 16, 27757–27769. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Liu, H.; Merrell, D.S.; Semino-Mora, C.; Goldman, M.; Rahman, A.; Mog, S.; Dubois, A. Diet synergistically affects helicobacter pylori-induced gastric carcinogenesis in nonhuman primates. Gastroenterology 2009, 137, 1367–1379.e1361–e1366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Kyriazanos, I.D.; Sfiniadakis, I.; Gizaris, V.; Hountis, P.; Hatziveis, K.; Dafnopoulou, A.; Datsakis, K. The incidence of Helicobacter pylori infection is not increased among obese young individuals in Greece. J. Clin. Gastroenterol. 2002, 34, 541–546. [Google Scholar] [CrossRef]
  48. Xia, Y.; Meng, G.; Zhang, Q.; Liu, L.; Wu, H.; Shi, H.; Bao, X.; Su, Q.; Gu, Y.; Fang, L.; et al. Dietary Patterns are Associated with Helicobacter Pylori Infection in Chinese Adults: A Cross-Sectional Study. Sci. Rep. 2016, 6, 32334. [Google Scholar] [CrossRef] [Green Version]
  49. Shu, L.; Zheng, P.F.; Zhang, X.Y.; Feng, Y.L. Dietary patterns and Helicobacter pylori infection in a group of Chinese adults ages between 45 and 59 years old: An observational study. Medicine 2019, 98, e14113. [Google Scholar] [CrossRef]
  50. Jeong, M.; Park, J.M.; Han, Y.M.; Park, K.Y.; Lee, D.H.; Yoo, J.H.; Cho, J.Y.; Hahm, K.B. Dietary prevention of Helicobacter pylori-associated gastric cancer with kimchi. Oncotarget 2015, 6, 29513–29526. [Google Scholar] [CrossRef] [Green Version]
  51. Zheng, D.; Liwinski, T.; Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020, 30, 492–506. [Google Scholar] [CrossRef]
  52. Maslowski, K.M.; Mackay, C.R. Diet, gut microbiota and immune responses. Nat. Immunol. 2011, 12, 5–9. [Google Scholar] [CrossRef] [PubMed]
  53. Plaza-Diaz, J.; Solis-Urra, P.; Aragon-Vela, J.; Rodriguez-Rodriguez, F.; Olivares-Arancibia, J.; Alvarez-Mercado, A.I. Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis. Biomedicines 2021, 9, 145. [Google Scholar] [CrossRef]
  54. Pastor-Villaescusa, B.; Plaza-Diaz, J.; Egea-Zorrilla, A.; Leis, R.; Bueno, G.; Hoyos, R.; Vazquez-Cobela, R.; Latorre, M.; Canete, M.D.; Caballero-Villarraso, J.; et al. Evaluation of the gut microbiota after metformin intervention in children with obesity: A metagenomic study of a randomized controlled trial. Biomed. Pharmacother. 2021, 134, 111117. [Google Scholar] [CrossRef]
  55. Plaza-Diaz, J.; Bernal, M.J.; Schutte, S.; Chenoll, E.; Genoves, S.; Codoner, F.M.; Gil, A.; Sanchez-Siles, L.M. Effects of Whole-Grain and Sugar Content in Infant Cereals on Gut Microbiota at Weaning: A Randomized Trial. Nutrients 2021, 13, 1496. [Google Scholar] [CrossRef]
  56. Li, T.H.; Qin, Y.; Sham, P.C.; Lau, K.S.; Chu, K.M.; Leung, W.K. Alterations in Gastric Microbiota After H. Pylori Eradication and in Different Histological Stages of Gastric Carcinogenesis. Sci. Rep. 2017, 7, 44935. [Google Scholar] [CrossRef]
  57. Guo, Y.; Zhang, Y.; Gerhard, M.; Gao, J.J.; Mejias-Luque, R.; Zhang, L.; Vieth, M.; Ma, J.L.; Bajbouj, M.; Suchanek, S.; et al. Effect of Helicobacter pylori on gastrointestinal microbiota: A population-based study in Linqu, a high-risk area of gastric cancer. Gut 2020, 69, 1598–1607. [Google Scholar] [CrossRef] [Green Version]
  58. Pero, R.; Brancaccio, M.; Laneri, S.; Biasi, M.G.; Lombardo, B.; Scudiero, O. A Novel View of Human Helicobacter pylori Infections: Interplay between Microbiota and Beta-Defensins. Biomolecules 2019, 9, 237. [Google Scholar] [CrossRef] [Green Version]
  59. Maldonado-Contreras, A.; Goldfarb, K.C.; Godoy-Vitorino, F.; Karaoz, U.; Contreras, M.; Blaser, M.J.; Brodie, E.L.; Dominguez-Bello, M.G. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J. 2011, 5, 574–579. [Google Scholar] [CrossRef]
  60. Dong, Q.; Xin, Y.; Wang, L.; Meng, X.; Yu, X.; Lu, L.; Xuan, S. Characterization of gastric microbiota in twins. Curr. Microbiol. 2017, 74, 224–229. [Google Scholar] [CrossRef]
  61. Brawner, K.M.; Kumar, R.; Serrano, C.A.; Ptacek, T.; Lefkowitz, E.; Morrow, C.D.; Zhi, D.; Kyanam-Kabir-Baig, K.R.; Smythies, L.E.; Harris, P.R.; et al. Helicobacter pylori infection is associated with an altered gastric microbiota in children. Mucosal Immunol. 2017, 10, 1169–1177. [Google Scholar] [CrossRef] [Green Version]
  62. Dash, N.R.; Khoder, G.; Nada, A.M.; Al Bataineh, M.T. Exploring the impact of Helicobacter pylori on gut microbiome composition. PLoS ONE 2019, 14, e0218274. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Llorca, L.; Perez-Perez, G.; Urruzuno, P.; Martinez, M.J.; Iizumi, T.; Gao, Z.; Sohn, J.; Chung, J.; Cox, L.; Simon-Soro, A.; et al. Characterization of the Gastric Microbiota in a Pediatric Population According to Helicobacter pylori Status. Pediatr. Infect. Dis. J. 2017, 36, 173–178. [Google Scholar] [CrossRef] [PubMed]
  64. Alvarez-Cilleros, D.; Ramos, S.; Lopez-Oliva, M.E.; Escriva, F.; Alvarez, C.; Fernandez-Millan, E.; Martin, M.A. Cocoa diet modulates gut microbiota composition and improves intestinal health in Zucker diabetic rats. Food Res. Int. 2020, 132, 109058. [Google Scholar] [CrossRef]
  65. Sen, T.; Cawthon, C.R.; Ihde, B.T.; Hajnal, A.; DiLorenzo, P.M.; de La Serre, C.B.; Czaja, K. Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity. Physiol. Behav. 2017, 173, 305–317. [Google Scholar] [CrossRef] [Green Version]
  66. Krznaric, Z.; Vranesic Bender, D.; Mestrovic, T. The Mediterranean diet and its association with selected gut bacteria. Curr. Opin. Clin. Nutr. Metab. Care 2019, 22, 401–406. [Google Scholar] [CrossRef]
  67. Zmora, N.; Suez, J.; Elinav, E. You are what you eat: Diet, health and the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 35–56. [Google Scholar] [CrossRef]
  68. Zhong, X.; Harrington, J.M.; Millar, S.R.; Perry, I.J.; O’Toole, P.W.; Phillips, C.M. Gut Microbiota Associations with Metabolic Health and Obesity Status in Older Adults. Nutrients 2020, 12, 2364. [Google Scholar] [CrossRef]
  69. Li, H.; Fang, Q.; Nie, Q.; Hu, J.; Yang, C.; Huang, T.; Li, H.; Nie, S. Hypoglycemic and Hypolipidemic Mechanism of Tea Polysaccharides on Type 2 Diabetic Rats via Gut Microbiota and Metabolism Alteration. J. Agric. Food Chem. 2020, 68, 10015–10028. [Google Scholar] [CrossRef]
  70. Kim, J.; Choi, J.H.; Oh, T.; Ahn, B.; Unno, T. Codium fragile Ameliorates High-Fat Diet-Induced Metabolism by Modulating the Gut Microbiota in Mice. Nutrients 2020, 12, 1848. [Google Scholar] [CrossRef] [PubMed]
  71. Khosravi, Y.; Seow, S.W.; Amoyo, A.A.; Chiow, K.H.; Tan, T.L.; Wong, W.Y.; Poh, Q.H.; Sentosa, I.M.; Bunte, R.M.; Pettersson, S.; et al. Helicobacter pylori infection can affect energy modulating hormones and body weight in germ free mice. Sci. Rep. 2015, 5, 8731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. He, C.; Yang, Z.; Cheng, D.; Xie, C.; Zhu, Y.; Ge, Z.; Luo, Z.; Lu, N. Helicobacter pylori Infection Aggravates Diet-induced Insulin Resistance in Association With Gut Microbiota of Mice. EBioMedicine 2016, 12, 247–254. [Google Scholar] [CrossRef] [Green Version]
  73. Peng, C.; Xu, X.; Li, Y.; Li, X.; Yang, X.; Chen, H.; Zhu, Y.; Lu, N.; He, C. Sex-specific association between the gut microbiome and high-fat diet-induced metabolic disorders in mice. Biol. Sex. Differ. 2020, 11, 5. [Google Scholar] [CrossRef] [Green Version]
  74. Macpherson, M.E.; Hov, J.R.; Ueland, T.; Dahl, T.B.; Kummen, M.; Otterdal, K.; Holm, K.; Berge, R.K.; Mollnes, T.E.; Troseid, M.; et al. Gut Microbiota-Dependent Trimethylamine N-Oxide Associates With Inflammation in Common Variable Immunodeficiency. Front. Immunol. 2020, 11, 2217. [Google Scholar] [CrossRef]
  75. Hamaya, R.; Ivey, K.L.; Lee, D.H.; Wang, M.; Li, J.; Franke, A.; Sun, Q.; Rimm, E.B. Association of diet with circulating trimethylamine-N-oxide concentration. Am. J. Clin. Nutr. 2020, 112, 1448–1455. [Google Scholar] [CrossRef]
  76. Barrea, L.; Annunziata, G.; Muscogiuri, G.; Laudisio, D.; Di Somma, C.; Maisto, M.; Tenore, G.C.; Colao, A.; Savastano, S. Trimethylamine N-oxide, Mediterranean diet, and nutrition in healthy, normal-weight adults: Also a matter of sex? Nutrition 2019, 62, 7–17. [Google Scholar] [CrossRef]
  77. Wu, D.; Cao, M.; Li, N.; Zhang, A.; Yu, Z.; Cheng, J.; Xie, X.; Wang, Z.; Lu, S.; Yan, S.; et al. Effect of trimethylamine N-oxide on inflammation and the gut microbiota in Helicobacter pylori-infected mice. Int. Immunopharmacol. 2020, 81, 106026. [Google Scholar] [CrossRef]
  78. Li, S.; Wu, D.; Cao, M.; Yu, Z.; Wu, M.; Liu, Y.; Zhou, J.; Yan, S.; Chen, J.; Huang, M.; et al. Effects of choline supplementation on liver biology, gut microbiota, and inflammation in Helicobacter pylori-infected mice. Life. Sci. 2020, 259, 118200. [Google Scholar] [CrossRef]
  79. Kienesberger, S.; Cox, L.M.; Livanos, A.; Zhang, X.S.; Chung, J.; Perez-Perez, G.I.; Gorkiewicz, G.; Zechner, E.L.; Blaser, M.J. Gastric Helicobacter pylori Infection Affects Local and Distant Microbial Populations and Host Responses. Cell Rep. 2016, 14, 1395–1407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Espinoza, J.L.; Matsumoto, A.; Tanaka, H.; Matsumura, I. Gastric microbiota: An emerging player in Helicobacter pylori-induced gastric malignancies. Cancer Lett. 2018, 414, 147–152. [Google Scholar] [CrossRef] [PubMed]
  81. Chua, E.G.; Chong, J.Y.; Lamichhane, B.; Webberley, K.M.; Marshall, B.J.; Wise, M.J.; Tay, C.Y. Gastric Helicobacter pylori infection perturbs human oral microbiota. PeerJ 2019, 7, e6336. [Google Scholar] [CrossRef] [PubMed]
  82. Yang, L.; Zhang, J.; Xu, J.; Wei, X.; Yang, J.; Liu, Y.; Li, H.; Zhao, C.; Wang, Y.; Zhang, L.; et al. Helicobacter pylori Infection Aggravates Dysbiosis of Gut Microbiome in Children With Gastritis. Front. Cell Infect. Microbiol. 2019, 9, 375. [Google Scholar] [CrossRef] [Green Version]
  83. Li, X.X.; Wong, G.L.; To, K.F.; Wong, V.W.; Lai, L.H.; Chow, D.K.; Lau, J.Y.; Sung, J.J.; Ding, C. Bacterial microbiota profiling in gastritis without Helicobacter pylori infection or non-steroidal anti-inflammatory drug use. PLoS ONE 2009, 4, e7985. [Google Scholar] [CrossRef]
  84. Peng, C.; Xu, X.; He, Z.; Li, N.; Ouyang, Y.; Zhu, Y.; Lu, N.; He, C. Helicobacter pylori infection worsens impaired glucose regulation in high-fat diet mice in association with an altered gut microbiome and metabolome. Appl. Microbiol. Biotechnol. 2021, 105, 2081–2095. [Google Scholar] [CrossRef]
  85. Malfertheiner, P.; Megraud, F.; O’Morain, C.A.; Gisbert, J.P.; Kuipers, E.J.; Axon, A.T.; Bazzoli, F.; Gasbarrini, A.; Atherton, J.; Graham, D.Y.; et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 2017, 66, 6–30. [Google Scholar] [CrossRef] [Green Version]
  86. Liou, J.M.; Malfertheiner, P.; Lee, Y.C.; Sheu, B.S.; Sugano, K.; Cheng, H.C.; Yeoh, K.G.; Hsu, P.I.; Goh, K.L.; Mahachai, V.; et al. Screening and eradication of Helicobacter pylori for gastric cancer prevention: The Taipei global consensus. Gut 2020, 69, 2093–2112. [Google Scholar] [CrossRef] [PubMed]
  87. De Brito, B.B.; da Silva, F.A.F.; Soares, A.S.; Pereira, V.A.; Santos, M.L.C.; Sampaio, M.M.; Neves, P.H.M.; de Melo, F.F. Pathogenesis and clinical management of Helicobacter pylori gastric infection. World J. Gastroenterol. 2019, 25, 5578–5589. [Google Scholar] [CrossRef] [PubMed]
  88. Diaconu, S.; Predescu, A.; Moldoveanu, A.; Pop, C.S.; Fierbinteanu-Braticevici, C. Helicobacter pylori infection: Old and new. J. Med. Life. 2017, 10, 112–117. [Google Scholar] [PubMed]
  89. Georgopoulos, S.; Papastergiou, V. An update on current and advancing pharmacotherapy options for the treatment of H. pylori infection. Expert Opin. Pharmacother. 2020, 12, 1–13. [Google Scholar] [CrossRef]
  90. Shi, J.; Jiang, Y.; Zhao, Y. Promising in vitro and in vivo inhibition of multidrug-resistant Helicobacter pylori by linezolid and novel oxazolidinone analogues. J. Glob. Antimicrob. Resist. 2016, 7, 106–109. [Google Scholar] [CrossRef]
  91. Jeong, S.J.; Lee, K.H.; Kim, J.H.; Park, S.Y.; Song, Y.G. Efficacy and Gut Dysbiosis of Gentamicin-Intercalated Smectite as a New Therapeutic Agent against Helicobacter pylori in a Mouse Model. Antibiotics 2020, 9, 502. [Google Scholar] [CrossRef]
  92. Jeong, S.J.; Kim, J.H.; Jung, D.H.; Lee, K.H.; Park, S.Y.; Song, Y.; Kang, I.M.; Song, Y.G. Gentamicin-intercalated smectite as a new therapeutic option for Helicobacter pylori eradication. J. Antimicrob. Chemother. 2018, 73, 1324–1329. [Google Scholar] [CrossRef] [PubMed]
  93. Quinn, L.; Sheh, A.; Ellis, J.L.; Smith, D.E.; Booth, S.L.; Fu, X.; Muthupalani, S.; Ge, Z.; Puglisi, D.A.; Wang, T.C.; et al. Helicobacter pylori antibiotic eradication coupled with a chemically defined diet in INS-GAS mice triggers dysbiosis and vitamin K deficiency resulting in gastric hemorrhage. Gut Microbes 2020, 11, 820–841. [Google Scholar] [CrossRef] [PubMed]
  94. Angsantikul, P.; Thamphiwatana, S.; Zhang, Q.; Spiekermann, K.; Zhuang, J.; Fang, R.H.; Gao, W.; Obonyo, M.; Zhang, L. Coating nanoparticles with gastric epithelial cell membrane for targeted antibiotic delivery against Helicobacter pylori infection. Adv. Ther. 2018, 1, 1800016. [Google Scholar] [CrossRef] [PubMed]
  95. De, R.; Sarkar, A.; Ghosh, P.; Ganguly, M.; Karmakar, B.C.; Saha, D.R.; Halder, A.; Chowdhury, A.; Mukhopadhyay, A.K. Antimicrobial activity of ellagic acid against Helicobacter pylori isolates from India and during infections in mice. J. Antimicrob. Chemother. 2018, 73, 1595–1603. [Google Scholar] [CrossRef] [PubMed]
  96. Matsui, H.; Takahashi, T.; Murayama, S.Y.; Kawaguchi, M.; Matsuo, K.; Nakamura, M. Protective efficacy of a hydroxy fatty acid against gastric Helicobacter infections. Helicobacter 2017, 22, e12430. [Google Scholar] [CrossRef]
  97. Yulizal, O.K.; Lelo, A.; Ilyas, S.; Kusumawati, R.L. The effect of snakehead fish extract supplementation to first-line eradication regimen on macrophage migration inhibitory factor (MIF) expression in rats induced by Helicobacter pylori infection. J. Adv. Vet. Anim. Res. 2020, 7, 209–217. [Google Scholar] [CrossRef]
  98. Yulizal, O.K.; Lelo, A.; Ilyas, S.; Kusumawati, R.L. The effect of Channa striata extract and standard eradication regimen on asymmetric dimethylarginine in Helicobacter pylori gastritis rat model. Vet. World. 2020, 13, 1605–1612. [Google Scholar] [CrossRef]
  99. Davinelli, S.; Melvang, H.M.; Andersen, L.P.; Scapagnini, G.; Nielsen, M.E. Astaxanthin from Shrimp Cephalothorax Stimulates the Immune Response by Enhancing IFN-gamma, IL-10, and IL-2 Secretion in Splenocytes of Helicobacter Pylori-Infected Mice. Mar. Drugs. 2019, 17, 382. [Google Scholar] [CrossRef] [Green Version]
  100. Park, H.S.; Wijerathne, C.U.B.; Jeong, H.Y.; Seo, C.S.; Ha, H.; Kwun, H.J. Gastroprotective effects of Hwanglyeonhaedok-tang against Helicobacter pylori-induced gastric cell injury. J. Ethnopharmacol. 2018, 216, 239–250. [Google Scholar] [CrossRef]
  101. So, H.M.; Yu, J.S.; Khan, Z.; Subedi, L.; Ko, Y.J.; Lee, I.K.; Park, W.S.; Chung, S.J.; Ahn, M.J.; Kim, S.Y.; et al. Chemical constituents of the root bark of Ulmus davidiana var. japonica and their potential biological activities. Bioorg. Chem. 2019, 91, 103145. [Google Scholar] [CrossRef]
  102. Rong, Q.; Xu, M.; Dong, Q.; Zhang, Y.; Li, Y.; Ye, G.; Zhao, L. In vitro and in vivo bactericidal activity of Tinospora sagittata (Oliv.) Gagnep. var. craveniana (S.Y.Hu) Lo and its main effective component, palmatine, against porcine Helicobacter pylori. BMC Complement Altern. Med. 2016, 16, 331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Chen, X.; Zhang, J.; Wang, R.; Liu, H.; Bao, C.; Wu, S.; Wen, J.; Yang, T.; Wei, Y.; Ren, S.; et al. UPLC-Q-TOF/MS-Based Serum and Urine Metabonomics Study on the Ameliorative Effects of Palmatine on Helicobacter pylori-Induced Chronic Atrophic Gastritis. Front. Pharmacol. 2020, 11, 586954. [Google Scholar] [CrossRef] [PubMed]
  104. Ren, W.K.; Xu, Y.F.; Wei, W.H.; Huang, P.; Lian, D.W.; Fu, L.J.; Yang, X.F.; Chen, F.J.; Wang, J.; Cao, H.Y.; et al. Effect of patchouli alcohol on Helicobacter pylori-induced neutrophil recruitment and activation. Int. Immunopharmacol. 2019, 68, 7–16. [Google Scholar] [CrossRef]
  105. Lian, D.W.; Xu, Y.F.; Deng, Q.H.; Lin, X.M.; Huang, B.; Xian, S.X.; Huang, P. Effect of patchouli alcohol on macrophage mediated Helicobacter pylori digestion based on intracellular urease inhibition. Phytomedicine 2019, 65, 153097. [Google Scholar] [CrossRef] [PubMed]
  106. Yang, T.; Wang, R.; Zhang, J.; Bao, C.; Zhang, J.; Li, R.; Chen, X.; Wu, S.; Wen, J.; Wei, S.; et al. Mechanism of berberine in treating Helicobacter pylori induced chronic atrophic gastritis through IRF8-IFN-gamma signaling axis suppressing. Life Sci. 2020, 248, 117456. [Google Scholar] [CrossRef]
  107. Wu, X.; Li, X.; Dang, Z.; Jia, Y. Berberine demonstrates anti-inflammatory properties in Helicobacter pylori-infected mice with chronic gastritis by attenuating the Th17 response triggered by the B cell-activating factor. J. Cell Biochem. 2018, 119, 5373–5381. [Google Scholar] [CrossRef]
  108. Minozzo, B.R.; Lemes, B.M.; Justo, A.D.S.; Lara, J.E.; Petry, V.E.K.; Fernandes, D.; Bello, C.; Vellosa, J.C.R.; Campagnoli, E.B.; Nunes, O.C.; et al. Anti-ulcer mechanisms of polyphenols extract of Euphorbia umbellata (Pax) Bruyns (Euphorbiaceae). J. Ethnopharmacol. 2016, 191, 29–40. [Google Scholar] [CrossRef]
  109. Da Silva Junior, I.F.; Balogun, S.O.; de Oliveira, R.G.; Damazo, A.S.; Martins, D.T.O. Piper umbellatum L.: A medicinal plant with gastric-ulcer protective and ulcer healing effects in experimental rodent models. J. Ethnopharmacol. 2016, 192, 123–131. [Google Scholar] [CrossRef] [PubMed]
  110. Zhou, A.; Li, L.; Zhao, G.; Min, L.; Liu, S.; Zhu, S.; Guo, Q.; Liu, C.; Zhang, S.; Li, P. Vitamin D3 Inhibits Helicobacter pylori Infection by Activating the VitD3/VDR-CAMP Pathway in Mice. Front. Cell Infect. Microbiol. 2020, 10, 566730. [Google Scholar] [CrossRef]
  111. Hu, W.; Zhang, L.; Li, M.X.; Shen, J.; Liu, X.D.; Xiao, Z.G.; Wu, D.L.; Ho, I.H.T.; Wu, J.C.Y.; Cheung, C.K.Y.; et al. Vitamin D3 activates the autolysosomal degradation function against Helicobacter pylori through the PDIA3 receptor in gastric epithelial cells. Autophagy 2019, 15, 707–725. [Google Scholar] [CrossRef] [Green Version]
  112. Lin, C.C.; Huang, W.C.; Su, C.H.; Lin, W.D.; Wu, W.T.; Yu, B.; Hsu, Y.M. Effects of Multi-Strain Probiotics on Immune Responses and Metabolic Balance in Helicobacter pylori-Infected Mice. Nutrients 2020, 12, 2476. [Google Scholar] [CrossRef]
  113. De Klerk, N.; Maudsdotter, L.; Gebreegziabher, H.; Saroj, S.D.; Eriksson, B.; Eriksson, O.S.; Roos, S.; Linden, S.; Sjolinder, H.; Jonsson, A.B. Lactobacilli Reduce Helicobacter pylori Attachment to Host Gastric Epithelial Cells by Inhibiting Adhesion Gene Expression. Infect. Immun. 2016, 84, 1526–1535. [Google Scholar] [CrossRef] [Green Version]
  114. Yarmohammadi, M.; Yadegar, A.; Ebrahimi, M.T.; Zali, M.R. Effects of a Potential Probiotic Strain Lactobacillus gasseri ATCC 33323 on Helicobacter pylori-Induced Inflammatory Response and Gene Expression in Coinfected Gastric Epithelial Cells. Probiotics Antimicrob. Proteins 2020, 18. [Google Scholar] [CrossRef] [PubMed]
  115. Chen, Y.H.; Tsai, W.H.; Wu, H.Y.; Chen, C.Y.; Yeh, W.L.; Chen, Y.H.; Hsu, H.Y.; Chen, W.W.; Chen, Y.W.; Chang, W.W.; et al. Probiotic Lactobacillus spp. act Against Helicobacter pylori-induced Inflammation. J. Clin. Med. 2019, 8, 90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Hong, S.S.; Lee, H.A.; Kim, J.Y.; Jeong, J.W.; Shim, J.J.; Lee, J.L.; Sim, J.H.; Chung, Y.; Kim, O. In vitro and in vivo inhibition of Helicobacter pylori by Lactobacilllus paracasei HP7. Lab. Anim. Res. 2018, 34, 216–222. [Google Scholar] [CrossRef] [Green Version]
  117. Chen, M.E.; Su, C.H.; Yang, J.S.; Lu, C.C.; Hou, Y.C.; Wu, J.B.; Hsu, Y.M. Baicalin, Baicalein, and Lactobacillus Rhamnosus JB3 Alleviated Helicobacter pylori Infections in Vitro and in Vivo. J. Food Sci. 2018, 83, 3118–3125. [Google Scholar] [CrossRef]
  118. Asgari, B.; Kermanian, F.; Derakhshan, N.; Asna-Ashari, M.; Sadat, Z.R.N.; Yaslianifard, S. Honey-Derived Lactobacillus Rhamnosus Alleviates Helicobacter Pylori-Induced Gastro-Intestinal Infection and Gastric Inflammation in C57bl/6 Mice: An Immuno-Histologic Study. Arq. Gastroenterol. 2018, 55, 279–282. [Google Scholar] [CrossRef] [PubMed]
  119. Park, H.; Cho, D.; Huang, E.; Seo, J.Y.; Kim, W.G.; Todorov, S.D.; Ji, Y.; Holzapfel, W.H. Amelioration of Alcohol Induced Gastric Ulcers Through the Administration of Lactobacillus plantarum APSulloc 331261 Isolated From Green Tea. Front. Microbiol. 2020, 11, 420. [Google Scholar] [CrossRef] [Green Version]
  120. Pan, M.; Wan, C.; Xie, Q.; Huang, R.; Tao, X.; Shah, N.P.; Wei, H. Changes in gastric microbiota induced by Helicobacter pylori infection and preventive effects of Lactobacillus plantarum ZDY 2013 against such infection. J. Dairy Sci. 2016, 99, 970–981. [Google Scholar] [CrossRef]
  121. Aiba, Y.; Ishikawa, H.; Tokunaga, M.; Komatsu, Y. Anti-Helicobacter pylori activity of non-living, heat-killed form of lactobacilli including Lactobacillus johnsonii No.1088. FEMS Microbiol. Lett. 2017, 364. [Google Scholar] [CrossRef]
  122. Kamiya, S.; Backert, S. Advances in Microbiology, Infectious Diseases and Public Health. In Helicobacter pylori in Human Diseases; Springer International Publishing: Cham, Switzerland, 2019; Volume 11. [Google Scholar]
  123. Ozbey, G.; Sproston, E.; Hanafiah, A. Helicobacter pylori Infection and Gastric Microbiota. Euroasian J. Hepatogastroenterol. 2020, 10, 36–41. [Google Scholar] [CrossRef] [PubMed]
  124. Garza-Gonzalez, E.; Perez-Perez, G.I.; Maldonado-Garza, H.J.; Bosques-Padilla, F.J. A review of Helicobacter pylori diagnosis, treatment, and methods to detect eradication. World J. Gastroenterol. 2014, 20, 1438–1449. [Google Scholar] [CrossRef] [PubMed]
Figure 1. H. pylori invades the human stomach, negatively impacting host health, which is promoted or aggravated by specific dietary patterns. The main effects are gastritis, which can lead to peptic ulcers and eventually gastric cancer, alterations in the gut microbiota, and inflammation. Animal and in vitro models are routinely used to test the efficacy of emerging treatments for the eradication of H. pylori. These approaches mainly focus on the inhibition or reversal of adverse effects by avoiding the attachment and colonization of host intestinal epithelial cells and the attenuation of the consequences of the host´s pro-inflammatory state after H. pylori infection. Abbreviations: LPS, lipopolysaccharide, TLR4, toll-like receptor 4, and TNF-α, tumor necrosis factor-alpha.
Figure 1. H. pylori invades the human stomach, negatively impacting host health, which is promoted or aggravated by specific dietary patterns. The main effects are gastritis, which can lead to peptic ulcers and eventually gastric cancer, alterations in the gut microbiota, and inflammation. Animal and in vitro models are routinely used to test the efficacy of emerging treatments for the eradication of H. pylori. These approaches mainly focus on the inhibition or reversal of adverse effects by avoiding the attachment and colonization of host intestinal epithelial cells and the attenuation of the consequences of the host´s pro-inflammatory state after H. pylori infection. Abbreviations: LPS, lipopolysaccharide, TLR4, toll-like receptor 4, and TNF-α, tumor necrosis factor-alpha.
Pathogens 10 00875 g001
Table 1. Summary of recent studies linking the effect of diet on H. pylori and microbiota.
Table 1. Summary of recent studies linking the effect of diet on H. pylori and microbiota.
Dietary PatternAnimal Model
(n)
EffectsMain Effects in MicrobiotaReference
(1) Excessive salt intake
(2) High-salt and low-iron diet
(1) Mongolian gerbil
n =108
(2) Mongolian gerbil model
n = 96
↑ Colonization by H. pylori
(1) ↑ Risk of gastric cancer, hypochlorhydria and epithelial damage,
Loss of parietal cells, and intestinal metaplasia
(2) ↓ Hemoglobin levels
NA[18,27,33]
Cured, pickled, and smoked foodsRhesus monkey
n= 23
Induction of intestinal metaplasia and
intraepithelial neoplasia
↑ Expression of oncogenes
NA[46]
Diet poor in ironMongolian gerbil
n = 10
↑ Infiltration of immune cells at the site of
infection
↑ Onset of gastritis
↑ Rate of cancer development
NA[41]
High-fat dietC57BL/6 mice
n = 10
Intestinal microbiota alteration↑ Firmicutes and Proteobacteria
↓ Bacteroidetes and
Verrucomicrobia
[72]
High-fat dietSpecific-pathogen-free C57BL/6 mice
n = 10
H. pylori infection and high-fat diet promote dysbiosis intestinal microbiota↑ Firmicutes/Bacteroidetes (F/B) ratio
Prevotellaceae-UCG-001,
Helicobacter, and Rikenella
Blautia, Lactobacillus, and
Lachnoclostridium
[84]
Meat, fish, eggs, and dairy productsBALB/c female mice
n = 40
TMA and TMAO taken by diet induced:
H. pylori development
↓ Intestinal microbiota richness and diversity
Anaerovorax, Rikenellaceae RC9 gut group, Lachnospraceae UCG 008 and Parabacteroides
Escherichia/Shigella
[77]
Abbreviations: n, number of animals; NA, not analyzed; TMA, trimethylamine; and TMAO, Trimethylamine N-oxide.
Table 2. Nutraceutical approaches to treat H. pylori infection reported in animal models (2016–2020).
Table 2. Nutraceutical approaches to treat H. pylori infection reported in animal models (2016–2020).
Nutraceutical TestedType and Nature of Strain Analyzed Sensitivity ProfileAnimal Model
(n)
EffectsMain Effects in MicrobiotaReferences
Extracts and
compounds
isolated from food
Ellagic acidSydney Strain 1 isolated from
gastroduodenal patients
In vitro minimum inhibitory concentration 15 mg/L ellagic acid, 0.015 mg/L clarithromycin, 0.5 mg/L amoxicillin, 0.25 mg/L metronidazole (resistant)C57BL/6 mice n = 6Elimination of H. pylori in cultures and mice
Reversion on H. pylori-induced gastric mucosa injury in mice
NA[95]
Linoleic acidThe nature of the strain: Not indicated. Sydney Strain 1 and TN2GF4 strains Not indicatedC57BL/6NCrl mice n = 6Inhibition of H. pylori growthNA[96]
Snakehead fish
extract
The nature of the strain: Gastric biopsy specimens of duodenal ulcer patients. Strain: unknownNot indicatedAlbino rats n = 7Elimination of H. pyloriNA[97]
Channa striata fish extractThe nature of the strain: Gastric biopsy specimens of duodenal ulcer patients. Strain: unknownNot indicatedAlbino rats n = 7In combination with standard triple therapy, reversion of gastritis NA[98]
Astaxanthin from shrimp
cephalothorax
The nature of the strain: Gastric biopsy specimens of duodenal ulcer patients. J99 strainNot indicatedBALB/c mice n = 40↑synthesis of IFN-γ, IL-2 and IL-10 in splenocytes in infected miceNA[99]
Traditional plants or herbs
Hwanglyeonhaedok-tangThe nature of the strain: Not indicated. Sydney Strain 1 In vitro minimum inhibitory concentration: 400 to 1600 μg/mL Hwanglyeonhaedok-tang;
0.00396 ~ 0.125 µg/mL amoxicillin; 0.001953 ~ 32 µg/mL clarithromycin
C57BL/6 mice n = 7Elimination of H. pylori cultures and mice
H. pylori-induced inflammation in cultures and mice
NA[100]
YugeunpiThe nature of the strain: Not indicated. 51 and 43,504 strains In vitro minimum inhibitory concentration: 25 and 50 µM bioactive compounds of Yugeunpi: (2R,3S)-2-ethoxychroman-3,5,7-triol-7-O-β-d-apiofuranoside, fraxetin, 4-O-β-d-glucopyranosyl vanillic acid, syringic acidIn vitro Murine microglia BV-2 cell lineElimination of H. pylori in cultures
H. pylori-induced inflammation in cultures
NA[101]
PalmatineThe nature of the strain: (1): not indicated; (2): Chronic atrophic gastritis. (1): Sydney Strain 1; (2): SCYA201401 and Sydney Strain 1 strains (2) In vitro minimum inhibitory concentration: strain SCYA201401 6.25 μg /mL Palmitine; Strain Sydney Strain 1, 3.12 μg/mL Palmitine(1) Male
Sprague-Dawley rats n = 6,
(2) C57BL/6 mice n = 8
H. pylori-induced chronic atrophic gastritis in rats
Elimination of H. pylori in cultures and mice
NA[102,103]
Patchouli alcoholThe nature of the strain: (1): not indicated; (2): not indicated. (1): NCTC11637; (2): ATCC43504Not indicatedMale Sprague-Dawley rats
n = 6
(1) Inhibition of H. pylori urease activity
(2) ↑ macrophage digestive activity in cultures
H. pylori-promoted recruitment and activation of neutrophils in cultures and rats
NA[104,105]
BerberineThe nature of the strain: (1): not indicated; (2): stomach tissue of a male chronic atrophic gastritis patient No. ZCDC111001. (1): CagA+/VacA+ H. pylori strain 342Not indicated(1) C57Bl/6 mice, n = not indicated (2) Sprague-Dawley rats
n = 6
Attenuates H. pylori-induced inflammation and chronic gastritis in mice and ratsNA[106,107]
Euphorbia umbellataThe nature of the strain: not indicatedNot indicatedWistar rats
n = 7
Heals H. pylori-caused ulcers in ratsNA[108]
Piper umbellatum L.The nature of the strain: not indicated. ATCC 43,504 (vacA and cagA positives) strainNot indicatedSwiss-Webster mice, n = 8Heals H. pylori-caused ulcers in miceNA[109]
Vitamin D3The nature of the strain: (1), (2): not indicated. (1) Sydney Strain 1 (2) Sydney Strain (SS)1 (VacA+ and CagA+) strainNot indicated(1) C57BL/6 mice n = 8
(2) C57BL/6 mice n = 5
Elimination of H. pyloriNA[110,111]
Probiotics
L. fermentum, L. casei and L. rhamnosusThe nature of the strain: gastritis patient. 26,695 (ATCC 700392) strainNot indicatedC57BL/6 mice n = 10Elimination of H. pylori
Restoration of H. pylori-induced metabolic imbalance
NA[112]
L. gasseri and
L. brevis
The nature of the strain: not indicated. Sydney Strain 1 Not indicatedhCD46Ge transgenic mouse line
(CD46+/+)
n = 6
Inhibit H. pylori attachment in cultures
Prevent H. pylori infection in mice
NA[113]
L. gasseriThe nature of the strain: isolated from individual infected patients with chronic gastritis and peptic ulcer disease. Strains: OC168, OC235, OC250, OC824, OC912, OC562, OC576, OC722, OC803, OC805Not indicatedIn vitro. Human gastric adenocarcinoma epithelial AGS cell lineH. pylori-induced inflammationNA[114]
L. rhamnosus and
L. acidophilus
The nature of the strain: not indicated. 26695 (ATCC 700392) strainNot indicatedBALB/c mice
n = 4–5
Inhibition of growth, adhesion and invasion of H. pylori in cultures
H. pylori-induced IL-8 production in cultures
H. pylori colonization and H. pylori-induced inflammation in mice
L. rhamnosus associated
Bifidobacterium, Proteobacteria, and A. muciniphila.
L. acidophilus associated
↓ Actinobacteria and E. coli, ↑ Proteobacteria and A. muciniphila
[115]
L. paracaseiThe nature of the strain: not indicated. Sydney Strain 1 strainNot indicatedC57BL/6 mice
n = 10
H. pylori adhesion and H. pylori-related inflammation (IL-8 expression) in cultures and mice.
↓ epithelial lesions in the stomach of mice
NA[116]
L. rhamnosusThe nature of the strain: not indicated. (1) ATCC43504 strain. (2) 26695 ATCC 700392 strain Not indicated(1) C57BL/6 mice n = 8,
(2) C57BL/6 mice n = 10
Elimination of H. pylori
H. pylori-caused gastritis
The treatment maintains the balance lactic acid bacteria/coliform bacteria[117,118]
L. plantarumThe nature of the strain: not indicated. (1) Sydney Strain 1 strain (2) Sydney Strain 1 (HpKTCC) strain Not indicated(1) (2) C57BL/6J mice n = 8
H. pylori and ethanol treatment
↓inflammation
↓gastric ulcers in mice treated with H. pylori and ethanol
Prevents H. pylori-induced gastric mucosa inflammation and gastric dysbiosis in mice
Bifidobacterium spp. and Clostridium butyricum.
Prevention of the decrease in Shannon’s diversity index and Simpson’s diversity index
[119,120]
Dead L. johnsoniiThe nature of the strain: not indicated. H. pylori No.130 strainNot indicatedGerm-free Balb/c mice
n = 10
Elimination of H. pylori in cultures and miceNA[121]
Abbreviations: n, number of animals; NA, not analyzed; IFN-γ, interferon gamma; IL-2, interleukin-2; IL-10, interleukin-10; and IL-8, interleukin-8.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Rueda-Robles, A.; Rubio-Tomás, T.; Plaza-Diaz, J.; Álvarez-Mercado, A.I. Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review. Pathogens 2021, 10, 875. https://doi.org/10.3390/pathogens10070875

AMA Style

Rueda-Robles A, Rubio-Tomás T, Plaza-Diaz J, Álvarez-Mercado AI. Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review. Pathogens. 2021; 10(7):875. https://doi.org/10.3390/pathogens10070875

Chicago/Turabian Style

Rueda-Robles, Ascensión, Teresa Rubio-Tomás, Julio Plaza-Diaz, and Ana I. Álvarez-Mercado. 2021. "Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review" Pathogens 10, no. 7: 875. https://doi.org/10.3390/pathogens10070875

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop