MIC of various antibiotics against LJ88.
Recently, many studies concerning probiotics, prebiotics, and biogenics have been performed, whereas only a few are related to the stomach (about 2% as publication number). In this chapter, we focus on recent studies on probiotics, prebiotics, and biogenics for the stomach and also describe our recent research on a novel strain of lactobacillus beneficial to stomach, Lactobacillus johnsonii No.1088 (LJ88). As probiotics for the stomach, some beneficial strains were summarized, and underlying mechanisms of anti-Helicobacter pylori activity were discussed. Prebiotics for the stomach were considered as a future potential target, since no indigenous bacteria beneficial to the stomach have been found to date. As biogenics, some plant-derived candidates were discussed. In this context, recent results on LJ88 lactobacillus were presented. Orally administered LJ88 inhibited H. pylori growth and the increase in the number of gastrin-producing cells, which side effect is caused by triple therapy for H. pylori. LJ88 had no resistance to typical antibiotics, and both living and heat-killed forms of it increased the number of bifidobacteria among human intestinal-microbiota in mice. These results suggest that LJ88 is a lactobacillus beneficial to both stomach and intestine as a probiotic and biogenic.
- Helicobacter pylori
Historically, probiotics have been thought as agents beneficial to improve the microbial environment in the intestines, but some strains of lactic acid bacteria have been used as probiotics, with the claim of providing health benefits to the stomach.
In addition to living bacteria, i.e., “Probiotics”, heat-killed “dead” bacteria retain some beneficial properties of probiotic bacteria. For example, the ability of heat-killed LJ88 to reduce excessive gastric acid production can be thought as having this property . Such food ingredients that beneficially affect the host by “direct” stimulation, suppression, etc., were defined by Mitsuoka as “Biogenics” . So we added this category to this chapter. So the title of the chapter was chosen to be “Probiotics, Prebiotics, and Biogenics for the Stomach”.
In this chapter, we review the current status of probiotics, prebiotics, and biogenics for the stomach, and also discuss novel aspects of our lactic acid bacterium, LJ88, which is beneficial to the stomach.
2. Number of publications
Figure 1 depicts yearly changes up to 2014 in the number of publications related to “probiotics OR prebiotics OR biogenics” as a whole (A) and those related to the stomach (B), based on a PubMed search. The total number of publications shown in Figure 1A was 14,417, of which those including the word “stomach” (Figure 1B) were only 290 (about 2% of the total publications). As shown in Figure 1A, the number of publications in this area increased almost linearly from year 2000, reaching 1936 publications in 2014; whereas the subset related to the stomach hit its ceiling at about 30 publications/year (Figure 1B).
As shown above, probiotics/prebiotics/biogenics involving the stomach is not a major area of this research field. However, since a variety of bacteria have been detected not only from feces or saliva but also from gastric fluid, although mainly as dead forms , it is thought that this area will expand in the future.
2.1. Anti-H. pylori activity of probiotics
2.1.1. Probiotics and virulent bacteria
Although a very recent definition of probiotics is “live microorganisms, which when consumed in adequate amounts, confer a health effect on the host” , probiotics have been thought as agents that improve the balance of microbiota mainly in the intestines. Typically, the ingestion of probiotics brings about an increase in the number of so-called “beneficial bacteria”, e.g., bifidobacteria, and a decrease in the number of so-called “bad” bacteria, e.g., clostridia. Moreover, some probiotic strains have been reported to inhibit the growth of some virulent bacteria, resulting in prevention of and recovery from diarrhea.
As regards the stomach,
2.1.2. Probiotic strains useful to reduce symptoms related to H. pylori infection
One of the well-known probiotic strains beneficial for the treatment of
2.1.3. L. johnsonii No. 1088 (LJ88) as a probiotic
Recently, we found a novel strain of lactobacillus, LJ88, in the gastric juice of a healthy human volunteer. When administered as a living form, LJ88 reduced the number of
To evaluate the probiotic property of LJ88, we examined the sensitivity of LJ88 to different types of antibiotics. Mueller–Hinton agar plates containing 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.031, 0.016, 0.008, 0.004, 0.002 or 0.001 μg/mL of different antibiotics (ampicillin, oxacillin, cefoxitin, gentamicin, clarithromycin, vancomycin, ciprofloxacin, and chloramphenicol) were prepared; and 5000 cfu of LJ88 (5 μL), after having been cultured in Mueller–Hinton broth for 24 h at 37 °C, was inoculated onto each plate. The minimum inhibitory concentrations (MICs) were determined after cultivation for 48 h at 37°C. The results are depicted in Table 1. As shown in Table 1, no resistance to any of the antibiotics used was observed, suggesting that LJ88 should be of no concern with respect to the transfer of drug-resistance genes to virulent bacteria.
To know whether LJ88 is also beneficial to intestinal microbiota, we examined the effect of live LJ88 on the number of bifidobacteria and clostridia in the feces of human intestinal microbiota-bearing mice. These mice were established as described earlier . In brief, 0.5 mL of human feces diluted 100-fold with water were administered to male germ-free Balb/c mice (4 weeks old). Then 109 cfu of LJ88 was orally administered once a day for 2 weeks. The amount of lactobacilli, bifidobacteria, and clostridia in the feces of mice were determined before and after LJ88 administration. The results are shown in Figure 3. Although lactobacilli were not detected before administration of LJ88, about 108 cfu/g of lactobacilli appeared after its administration (Figure 3A), which might reflect the administered LJ88. In association with the administration of LJ88, the number of bifidobacteria and clostridia increased and decreased, respectively (Figure 3B and C). Since bifidobacteria are reportedly beneficial to human health due to their ability to regulate intestinal microbial homeostasis , the bifidobacteria-increasing effect of LJ88 is thought to be one of its beneficial effects on the intestines. Although not all of the species belonging to clostridia are virulent, some of them are known to be harmful to human health, e.g.
2.1.4. Limitation of probiotics against H. pylori
Although many reports including in vitro, in vivo, and clinical studies have suggested the effectiveness of probiotics against
2.1.5. Possible mechanism underlying anti-H. pylori activity of probiotics
Although the exact mechanisms underlying the anti-
|Proposed Mechanisms||Described in|
|Lactic acid production||22.214.171.124|
|Production of antimicrobial products||126.96.36.199|
|Competition for adherent sites||188.8.131.52|
|Co-aggregation with ||184.108.40.206|
220.127.116.11. Lactic acid
18.104.22.168. Antimicrobial products
Some probiotic strains have reported to secrete antimicrobial substances other than lactic acid. The culture supernatants of
22.214.171.124. Immunological mechanisms
Coaggregation with pathogenic bacteria has been proposed as a mechanism by which probiotic bacteria can inhibit the growth of pathogenic bacterial. Recently, Holtz et al. reported that nonviable
2.2. Gastric acid-reducing activity of probiotics
2.2.1. Gastroesophageal reflux disease (GERD)
Gastroesophageal reflux disease (GERD) is a chronic disease caused by backflow of gastric acid to the esophagus and is subjectively recognized mainly as heartburn. Although proton pump inhibitors (PPIs) have been strongly recommended, and their effectiveness against GERD is widely recognized, hypergastrinemia is a concern as a side-effect of long-term usage of PPIs . In relation to
2.2.2. Probiotics effective in reducing the production of gastric acid
LJ88, as mentioned above, can reduce the number of
2.3. Implications of proton-pump inhibitors for viability of gastric microbiota
The stomach is considered to be a barrier to prevent virulent bacteria from entering the gastrointestinal tract due to its high acidity. However, irrespective of such a harmful condition for bacteria, a significant number of live bacteria exist in the stomach environment. Namely, in healthy persons, the number of live bacteria in gastric fluid is reportedly about 102–104 cfu/mL [9, 37]. But in subjects administered PPI, this number is reported to be increased 1000-fold or more over that of the subjects without PPI treatment, i.e., about 107 cfu/mL . Since the pH value of gastric fluid in subjects treated or not with PPI is about 3.2 or 1.6, respectively , such an increase in live bacteria in the stomach is thought to be caused by the increase in pH due to the PPI administration. Interestingly, the number of bacteria quantified by real-time polymerase chain reaction (PCR) with universal primers to bacterial 16S rRNA is about 108 cfu/mL in gastric fluid, irrespective of treatment with PPI . Because the quantitative PCR method counts not only living bacteria but also dead ones, almost all of the bacterial bodies are thought to exist in stomach as their dead form in normal subjects (>99.99% = (1–104/108) × 100). In PPI-administered subjects, about 10% (= 107/108 × 100) exist alive in the stomach, suggesting that in such a condition, probiotics ingested might affect the stomach partly as their living form. In addition to the total number (both living and dead) of bacteria in gastric fluid, the composition of bacteria at the genus level is not different between PPI-treated and not-treated groups , so that a part of the effects of probiotic bacteria will be retained in the stomach even after bacterial death due to high acidity (as biogenics; see below).
3. Prebiotics for the stomach
Prebiotics were defined by Gibson and Roberfroid as “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already resident in the colon, and thus attempt to improve host health” . So if indigenous bacteria exist in stomach beneficial to host health, e.g., those corresponding to bifidobacteria in the colon, then the concept “prebiotics for the stomach” will become meaningful. However, since we do not have any evidence showing the existence of such resident bacteria in the stomach, “prebiotics for stomach” remains as a mere hypothesis for now. Of course, some beneficial indigenous bacteria may possibly be found in the stomach in the future. In such a case, “prebiotics for the stomach” will come to have a factual basis for further research and development.
4. Biogenics for the stomach
Biogenics were originally defined by Mitsuoka as “food ingredients that beneficially affect the host by direct immunostimulation, suppression of mutagenesis, tumorigenesis, peroxidation, hyper-cholesterolemia or intestinal putrefaction” . He proposed the following agents as candidates of biogenics: i.e., biological response modifier (BRM), carotenoids, flavonoids, eicosapentaenoic acid, docosahexaenoic acid, lacto-tripeptide, immunopotentiators, etc.  Although Mitsuoka’s original concept of biogenics seems not to have included beneficial effect to the stomach, we think that agents directly affecting the stomach could be thought as a kind of biogenic as well.
4.1. Heat-killed bacteria as biogenics for the stomach
4.1.1. Gastric acid-reducing activity of heat-killed bacteria
One of the characteristic effects of our LJ88 is the reduced production of gastrin, as mentioned above. We found that such an effect is the property of not only living bacteria but also heat-killed ones [7, 36], allowing LJ88 to be thought as a kind of biogenics for the stomach. We already mentioned about a possible side effect of PPI, i.e., an increase in the number of G-cells, which might cause gastric hyperacidity after cessation of PPI. Especially, such a side effect might be of concern after triple therapy to eradicate a
To determine if LJ88 would ameliorate such a side effect of PPI in the context of triple therapy, we did an animal experiment with germ-free Balb/c mice infected with
The results are shown in Figure 4B.
Since live LJ88 were beneficial not only to the stomach but also to intestinal microbiota, as shown in Figure 3, we examined the effect of heat-killed LJ88 on intestinal bacteria by determining the number of bifidobacteria in the feces of human intestinal microbiota-bearing mice. As shown in Figure 5, heat-killed LJ88 increased the number of bifidobacteria in the feces by the administration of 1010 cells for two weeks, suggesting that heat-killed LJ88 might also be beneficial to not only the stomach but also to the intestines as well.
4.1.2 Anti-H. pylori activities of heat-killed bacteria
We already described that some probiotic strains have anti-
One possible mechanism might be competition between
Another potential mechanism might be coaggregation with
4.2 Soybean-related products as biogenics for the stomach
Historically, it has been suggested that soy products prevent the incidence of various cancers including gastric cancer, and several meta-analysis studies concluded that nonfermented and fermented soy foods reduce and increase, respectively, the risk of gastric cancer [40, 41]. However, it has also been suggested that “nonfermented” and “fermented” soy foods are possibly associated with “fruit/vegetable” and “salt intake,” respectively [40, 41]. So preventive and stimulatory effects of nonfermented and fermented soy foods should be considered taking these factors in mind. Since isoflavones are one of the proposed molecular candidates for preventing gastric cancer, a large-scale, population-based, prospective, cohort study was conducted to investigate the relationship between isoflavone-intake and risk of gastric cancer in Japan . The results suggested that higher intake of isoflavones does not prevent gastric cancer . So even if nonfermented soy foods can reduce the risk of gastric cancer, the responsible molecules might not be isoflavones in soy foods. However, since genistein, which is one of the soybean isoflavones, reportedly has a protective effect against stress-induced gastric mucosal lesions in rats , soy foods might be beneficial to the stomach even if their cancer-preventing effects are not so large.
4.3. Brassicaceae vegetable-related products as biogenics for the stomach
Vegetables of Brassicaceae classification, including cabbage and broccoli, reportedly contain S-methylmethionine, also known as vitamin U. S-methylmethionin is a useful ingredient originally found as anti-ulcerogenic factors in raw cabbage juice [44, 45], and has been used as an ingredient of gastrointestinal drugs in Japan for over 50 years, e.g., Cabagin U. . So Brassicaceae vegetables might be thought as good biogenics for the stomach for treatment and/or prevention of gastric ulcer.
Furthermore, broccoli sprouts especially contain sulforaphane, an isothiocyanate compound reported to have anti-
4.4. Other natural products beneficial to the stomach, including those with anti-H. pylori activity
Because of the wide variety and expected low toxicity of natural products, extracts and essential oils prepared from various plants have been examined their anti-ulcer and anti-
5. Future directions
In this report, we discussed probiotics, prebiotics, and biogenics for the stomach. As shown in Figure 1, this research area remains small to date, as only 2% of the total volume of publications concerning “probiotics, prebiotics, or biogenics” as a whole has focused on the stomach. However, the research efforts made related to this interesting research field, as mentioned in this review, are none the less very significant. We think future research in this field will go in the following directions:
Concerning probiotics for the stomach, a search for new probiotic strains beneficial to the stomach is warranted. Although no probiotic bacteria able to reside and grow in the stomach have yet been found, the possible existence of such a kind of so-called “extremophile”  type of probiotic bacteria cannot be denied in principle. Indeed, most researchers did not believe in the existence of indigenous bacteria in the stomach until 1984, when
However, since “extremophile” probiotics or indigenous bacteria beneficial to the stomach have not been found to date, prebiotics for such bacteria are also unknown as well. If such bacteria are found in the future, compounds supporting the growth of these bacteria in the stomach may be regarded as “prebiotics for the stomach.” Specific substances specifically utilized by supposed stomach bacteria beneficial to the host might be such candidates.
As described in this report, some strains of heat-killed bacteria are thought to be good biogenics for the stomach, as they, like LJ88, might be effective as anti-
Practically speaking, appropriate combinations of probiotics, prebiotics (putative), and biogenics might be important for stomach health.
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