Natural foods resources and dietary ingredients for the amelioration of Helicobacter pylori infection

Helicobacter pylori (H. pylori) is a gastric-persistent pathogen that can cause peptic ulcer disease, gastric cancer, and mucosal-associated lymphoid tissue lymphoma. This pathogen is commonly treated with antibiotic-based triple or quadruple therapy. However, antibiotic therapy could result in the bacterial resistance, imbalance of gut microbiota, and damage to the liver and kidneys, etc. Therefore, there is an urgent need for alternative therapeutic strategies. Interestingly, natural food resources, like vegetables, fruits, spices, and edible herbs, have potent inhibitory effects on H. pylori. In this review, we systematically summarized these foods with supporting evidence from both animal and clinical studies. The results have indicated that natural foods may possess temporary inhibition effect on H. pylori rather than durable eradication, and may help to reduce H. pylori colonization, enhance the effect of antibiotics and modulate the host’s immune response.


Introduction
Helicobacter pylori (H.pylori) is a gram-negative, microaerophilic spiral-shaped bacterium, which is classified as a Group I carcinogen by the World Health Organization.It can persistently inhabit in the stomach, which can lead to chronic gastritis, gastric ulcer, gastric cancer, and mucosa-associated lymphoid tissue lymphoma (MALT).About 70-80% of the world's population in developing countries are infected with H. pylori, whereas,in developed countries, the infection rate is 13-50% (1).After infection and colonization with H. pylori, gastric epithelial cells trigger a series of immune response at both the celluar and molecular levels, such as NF-κB pathway (Figure 1), eventually causing gastric diseases (3).Patients infected with H. pylori are at higher risk for gastric ulcer and cancers (2).The infection of H. pylori may increase the risk of developing gastric MALT about 50 to 73% (4).In about 1% of gastric cancer patients infected with H. pylori, there co-exists increasing inflammation of the gastric corpus, the atrophic mucous membrane in the prepyloric stomach, and reduced gastric acid secretion (5).Furthermore, H. pylori infection has also been reported to be associated with insulin resistance, However, H. pylori has co-ecolved with humans for a long time.The human body is a complex or multiorganism ecosystem in which any chang may effect human health (15,16).The interactions between microbiota and host are complicated and poorly understood (17).There are a few reports in literature suggesting that human beings benefit from H. pylori (10).For instance, H. pylori could protect children against gastrointestinal infection (18), reducing the prevalence of atopic diseases such as celiac disease, irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GORD), etc. (19).Therefore, research into alternative or novel strategies to prevent and treat H. pylori infection has recently attracted the attention of scientists.
Notably, many natural food resources have been consumed by people since ancient times to treat gastrointestinal diseases (20) and anti-cancer (21), through which recent studies have been proven to be effective and have few side effects.These natural resources are an invaluable treasure for developing or mining drugs to treat human diseases (22).Numerous studies recently have shown that natural food resources including vegetables, fruits, spices and edible herbs contain powerful and valuable anti-H.pylori activities (12).
Herein, we have systematically reviewed published literature with supporting evidence of animal and clinical studies from the PubMed, ClinicalTrials.govand Scopus databases.The following terms of Helicobacter pylori, food, vegetable, fruit, spices, plants, and / or herbs in all possible combination have been used for retrieval.
We expected sincerely that the appropriate combination of dietary ingredients from natural foods could be utilized to prevent, manage or treat H. pylori infection or / and related diseases such as gastric cancer.In this review, we have summarized the animal and clinical studies on the use of these natural food resources to relieve H. pylorirelated infection (Figure 2).In addition, a majority of individuals with H. pylori infection remain asymptomatic, but they are still at risk of developing the illness associated with this bacterium.However, the eradication of H. pylori in the case of asymptomatic patients in developing countries is not practical.Alternative therapies have proved to be useful in antiinflammation, anti-oxidative, chemoprevention and gastroprotection.Based on these results, the inclusion of foods from natural products and dietary ingredients in the diet of asymptomatic patients could reduce the risk and development of H. pylori infection.Herein, the benefits from these alternative therapies are summarized in Figure 3.The summary of vegetables, fruits, spices, and edible herbs possessing anti-H.pylori activities is presented below.

Suppressive effects of vegetables on Helicobacter pylori infection in vivo
Study showed that people with a lower dietary intake of vegetables were at higher risk of H. pylori infection (23).Recently, the effects of various vegetables on H. pylori infectionwere studied.For instance, broccoli is a common vegetable that can be consumed as food and for medicinal purposes, it showed that broccoli has both anti-cancer and anti-bacterial activity (24).Broccoli sprouts, in particular, are rich in isothiocyanate sulforaphane (SF) in the form of a precursor called glucoraphanin, which has shown potent bacteriostatic activity against H. pylori (12).Lozniewski and colleagues revealed that H. pylori infections could be eradicated in 8/11 transplants treated with 7.5 μmol sulforaphane by using human gastric xenografts model in nude mice, which also suggested individuals with H. pylori infection might benefit from sulforaphane (25).
Similarly, Yanaka et al. (26) investigated the protective effect of broccoli sprouts against high salt-induced gastritis in a mouse model of H. pylori infection.The results showed that the sulforaphane contained in broccoli sprouts was effective in inhibiting colonization, inflammation and gastric mucosal atrophy.Furthermore, the asymptomatic patients with H. pylori infection consumed broccoli sprouts (70 g/d containing 420 μmol glucoraphanin), resulted in a significant decrease in H. pylori colonization and gastric inflammation, but these effects disappeared 2 months later without following intake (26).Meanwhile, a preliminary study reported temporary eradication of H. pylori in four out of nine H. pylori infected subjects who were treated with broccoli sprouts (27).Broccoli sprouts (6 g/d sulforaphane-rich) plus triple therapy treatment could significantly decrease infected patients' systolic and diastolic blood pressure in 86 patients with type 2 diabetes (28).H. pylori density in infected patients was not significantly improved by treatment with broccoli sprouts, but Natural foods listed in this review with anti-H.pylori effect.From top to bottom, left to right, the foods figures referred to broccoli, Angelica keiskei, cranberry, grape, curcumin, garlic, liquorice, Hericium erinaceus, Tremella mesenterica, and green tea.
it reduced malondialdehyde (MDA) values, indicating that broccoli sprout could inhibit the lipid peroxidation and exert cytoprotection effects on H. pylori related gastritis (29).
In addition, a leafy green vegetable, Angelica keiskei, was found to exert inhibitory effects on H. pylori-induced gastric inflammation in mice, and the possible mechanism of action could be based on the inhibition of inflammatory mediators (IFN-γ, COX-2, and iNOS) mediated by NF-κB signaling pathways (30).Another vegetable, Nigella sativa, have many active ingredients with potent medical effects such as antimicrobial, anti-inflammatory, and anti-cancer activities (31).The result of N. sativa seeds against H. pylori infection in 88 patients with nonulcer dyspepsia showed that, the eradication rates achieved by triple therapy, 1 g, 2 g, and 3 g ground N. sativa seeds were 82.6, 47.6, 66.7, and 47.8%, respectively.Notely, there was no statistically significant difference of the eradication rate between triple therapy and 2 g of seeds powder (32).
Above all, it is evident that dietary ingredients from vegetables such as broccoli sprout, A. keiskei and N. sativa have effects on inhibition of H. pylori colonization, enhancement of antibiotic sensitiveness and suppression of H. pylori-induced inflammation or oxidative stress in vivo.All results are sorted out in Table 1.

Suppressive effects of fruits on Helicobacter pylori infection in vivo
Epidemiological studies have shown that the risk of gastric cancer was lower in people with more fruit consumption (33).Fruits raw extract or active ingredients had inhibition effects on the growth of H. pylori growth (13), and anti-cancer (34).Based on the current notion that H. pylori is a key factor in the development of gastric cancer, it is easily deduced that inhibition of H. pylori activity may play an important role in reducing gastric cancer risk.
Among numerous fruits of the berries, such as cranberry, bilberry, raspberry, elderberry and strawberry, it has been widely focused their effect on inhibiting H. pylori and enhancing antibiotics sensitive to H. pylori (40).Cranberries are a great source of dietary ingredients, such as anthocyanins and proanthocyanins with high value of health benefits (41).There are a few studies that have examined the efficacy of cranberry juice on mice or human infected with H. pylori.
Cranberry juice could eliminate 80% of H. pylori colonization in infected mice after 24 h of intervention, however, the eradication rate reached only 20% after 4 weeks of treatment (35).A double-blind, randomized, placebo-controlled study of regular consumption of cranberry juice in infected Chinese subjects had yielded significantly negative 13 C-urea breath test results (14/97 in the treatment group versus 5/92 in the placebo group) after 90 days intervention (36).The other study showed that the negative rate of H. pylori in female and male patients, who were administered with triple therapy during the first week and followed by cranberry supplements for two weeks, was 95.2 and 73.9%.The results indicated that the female patients may obtain more benefit form the addition of cranberry (37).Gotteland et al. (38) had shown that the H. pylori eradication rate reached 16.9% in asymptomatic infected children by daily intake of cranberry juice for three weeks, although the clearance effect disappears after cessation of cranberry juice consumption.
Grape may be the other fruit that has reported the positive effects on human infected with H. pylori.Brown et al. (39) tested the activity of grape skin together with quercetin did not significantly inhibit the growth of H. pylori, but was effective in reducing inflammatory cytokines including TNF-α, IL-1 and IFN-γ.
From the results mentioned above and summarized in Table 2, it is clear that fruits, especially like cranberry, could suppress the growth of H. pylori, and help infected subjects to attenuate the levels of inflammatory factors.The inhibitory effects of fruits may be sourced from polyphenols (34).Cranberry components showed synergistic effects with antibiotics.The potential mechanisms might be that The H. pylori-infected individual benefits from natural products, including anti-inflammation, anti-oxidative, chemoprevention and gastroprotection.
Frontiers in Medicine frontiersin.orgcomponents firstly damage the cell membranes of H. pylori, and then make cells more sensitive to antibiotics (34).

Suppressive effects of spices on Helicobacter pylori infection in vivo
Spices have been widely used as food flavors and therapeutic ingredients since ancient times.Until now, spices have been reported to process anti-cancer effects, particularly in gastric and colon cancer (42).H. pylori is one of the risk factors for gastric cancer, the anti-H.pylori effect of spices may play a crucial role in preventing the development of gastric cancer.Moreover, Liu et al. (34) have concluded that spices have anti-H.pylori activity.
Curcumin is a polyphenolic yellow pigment which is rich in turmeric root.Turmeric is widely used as spices, food coloring and medicines in India and Southeast Asia (43).Curcumin presented strong therapeutic effect against H. pylori infection for it not only could eradicate H. pylori, but also completely repair the gastric damage induced by H. pylori (44).200 or 600 mg/kg of curcumin had anti-inflammatory effect by suppressing expression of NF-κB p65 (45).Similarly, Kundu et al. (46) revealed that curcumin had healing-promoting effect on H. pylori infected mice and could restrict the expression of metalloproteinases-3 and 9 (46).Furthermore, clinical studies have been for exploring the inhibition effects of curcumin on H. pylori.Judaki et al. (47) investigated the clinical effect of curcumin (700 mg / three times a day for 28 days) combined with triple therapy regimens for patients with chronic gastritis-associated H. pylori infection.The result suggested that the additive curcumin could significantly decrease MDA level and glutathione peroxides, improve the total antioxidant capacity of the gastric mucosa, increase the H. pylori eradication rate compared to triple therapy alone (86.4% vs. 74.5%,p < 0.05) (47).
The other clinical study showed that standard triple therapy with curcumin significantly improves dyspeptic symptoms, despite no obvious effect on H. pylori eradication (48).Similar results have been reported by di Mario et al. (49), they found that curcumin-based therapy could relieve functional dyspeptic symptoms as well as serological signs of gastric inflammation, and increase 12% level of eradication rate (49).In another case, the H. pylori eradication rate was only 5.9% when patients were treated with curcumin alone, however, extra finding was that curcumin could modulate the production of inflammatory cytokines (50).
Garlic (Allium sativum), the other food flavoring, shares high scores in therapeutic properties (51).It has been reported that garlic consumption has therapeutic benefits in precancerous gastric lesions (52).Limuro et al. showed that the water-ethanol extract of garlic was able to inhibit H. pylori-induced early gastritis in a dose-dependent manner in Mongolian gerbils (53).Moreover, the administration of 4 g/day garlic powder increased the eradication rate of H. pylori in the treatment group (87%) compared to the placebo group (73%), although the difference was not statistically significant (54).
In general, these results pointed toward that spices have potent healing effect on gastric damage caused by H. pylori (Table 3).All above observations not only suggest the therapeutic effect of curcumin against H.pylori infections but underline the anti-inflamatory effect of curcumin.Curcumin may be as a potential therapeutic candidate for H.pylori associated disease.

Suppressive effects of edible herbs on Helicobacter pylori infection in vivo
China have rich experience in using medicinal herbs to manage stomach diseases over the long history, which is gaining popularity recently.Parts of medicinal herbs were developed as food because of their safe and functional properties.
Licorice root (Glycyrrhiza glabra L.), which could be found in almost all Traditional Chinese Medicine (TCM) regimens.It is a common practice to use G. glabra to treat gastric ulcers in TCM.Aqueous licorice root extract had shown anti-adhesion effect on H. pylori by interfering with the binding action between the bacterial adhesins and human gastric tissue (55).Administration of G. glabra extract had anti-H.pylori effect in both C57B/L mice and Mongolian gerbils (56).
Licorice root extract showed a significant reduction of H. pylori load compared to the placebo group.The results also showed that the  (59).
Hericium erinaceus referred to as the lion's mane mushroom or monkey's head mushroom (in Chinese), can be used as both edible and medicinal fungus.H. erinaceus has been widely used in TCM to treat chronic superficial gastritis and gastric ulcers (60).Wang et al. (60) showed that the ethanolic extracts of H. erinaceus significantly reduced the H. pylori colonization in the stomach of mice (60).Despite the fact that monkey head mushrooms have been used in Chinese medicine for thousands of years, however, few clinical studies have examined the suppressive effects of H. erinaceus on H. pylori infection.In addition, Tremella mesenterica is another fungus found to have anti-H.pylori activity.Clinical study showed that T. mesenterica had immunomodulatory effect on H. pylori-infected patients when administered 2 g/day for 10 days (61).
Green tea is one of the most popular beverages in China and Japan.Green tea has been found to have suppressive effects on H. pylori growth (62).Intake of green tea in advance could attenuate this microbe colonization and gastric mucosal inflammation before infection (62).Matsubara et al. had found that green tea aqueous extract exerted a dose-dependent suppressive effect under three different concentration (500, 1,000 and 2000 ppm) on gastritis and the prevalence of H. pylori in infected Mongolian gerbils (63).One of main antioxidant compounds in green tea was catechins, which showed antibacterial activity against H. pylori in vivo (51).In infected Mongolian gerbils, H. pylori was eradicated in 36% animals with the dietary intake of 2% catechins for 14 days, and with significant decreases mucosal hemorrhage and erosion (64).The authors indicated that tea catechins have an anti-H.pylori effect and may have a therapeutic effect against gastic mucosa injury induced by H. pylori.
Taken together, edible herbs share in nature the characteristics of food and medicine.Some common but important edible herbs with anti-H.pylori effect including licorice, fungus and green tea were selected for this review (Table 4).All results have shown that edible herbs inhibit H. pylori colonization to some extend and improve H. pylori-related symptoms, likely by attenuating the development of inflammation.It is worth noting that numerous edible herbs are an invaluable treasure for the Chinese and people of East Asia.The potential of edible herbs to combat gastric disorders, particularly Helicobacter pylori infection, is worthy to be explored in the future.

Conclusion
Taken together, the results in this review are not completely satisfactory because in most cases H. pylori eradication is not obtained.However, this review showed that H. pylori colonization, severity of gastrointestinal inflammation and antibiotic therapy results would be improved by dietary ingredients from natural food resources.From the human beings perspective, the alternative treatment by single or combination of dietary ingredients from natural food resources to reduce H. pylori colonization is a promising and valuable strategy.The underlined mechanism of action has not yet been well explored about these natural food resources.Meanwhile, the safety and efficacy of the active compounds isolated from these natural foods are also lack.In future, it is necessary to further formulate active ingredients and make them available for clinical use.
Given the fact that complete eradication with natural foods or dietary ingredients may be impractical.The supplement of these foodstuff may provide a useful adjunct or alternative to conventional drug treatments, and should be tested in infected human for clinical trials.The natural products and dietary ingredients might even shift the consumers' life patterns due to their low cost and relative safety after consuming for a long time.Moreover, the decline of excessive antibiotic use would have profound effects on human health and environment, including reduction of antibiotic resistance and protection of human microbiota diversity.

TABLE 1
Suppressive effects of vegetables on Helicobacter pylori infection in vivo.

TABLE 2
Suppressive effects of fruits on Helicobacter pylori infection in vivo.

TABLE 3
Suppressive effects of spices on Helicobacter pylori infection in vivo.

TABLE 4
Suppressive effects of edible herbs on Helicobacter pylori infection in vivo.
(58)ication of H. pylori by stool antigen test in GutGuard treatment group was 56% compared to 4% in the placebo group (57).Adding licorice to the clarithromycin-based triple therapy could significantly increase the H. pylori eradication rate reached 83.3% over the control group (62.5%)(58).Moreover, fermented milk in combination with licorice could significantly reduce H. pylori density and relieve gastrointestinal symptoms and histological inflammation