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Abstract Some strains of lactic acid bacteria are reported to inhibit the growth of Helicobacter pylori and proposed to be useful to support so-called triple therapy for H. pylori. Although most strains must be alive to exert their anti-H. pylori activity, some lactobacilli strains are effective even when dead. One possible underlying mechanism of such an activity of non-living lactobacilli is reportedly co-aggregation with H. pylori. In this study, we found that a non-living heat-killed form of Lactobacillus johnsonii No.1088 (HK-LJ88) and also that of some other lactobacilli inhibited the growth of H. pylori in vitro. Furthermore, the number of H. pylori in the infected stomach of germ-free mice was significantly decreased by the repeated oral administration of HK-LJ88. Observation by scanning electron microscopy revealed that no co-aggregation had occurred between H. pylori and HK-LJ88; instead, deformations of H. pylori (e.g. disappearance of spiral, bending of cell body, coccoid formation, degradations, etc.) appeared after incubation for 24 h with HK-LJ88. These results suggest that HK-LJ88 inhibited H. pylori activity probably not by co-aggregation but by some unknown mechanism involving HK-LJ88's cell surface molecules and that even non-living lactobacilli are possibly useful to support H. pylori eradication therapy. Non-living heat-killed form of Lactobacillus johnsonii No.1088 was found to have anti-Helicobacter pylori activity not by the co-aggregation mechanism.

Gut lumen serotonin (5-hydroxytryptamine: 5-HT) contributes to several gastrointestinal functions such as peristaltic reflexes. 5-HT is released from enterochromaffin (EC) cells in response to a number of stimuli, including signals from the gut microbiota. However, the specific mechanism by which the gut microbiota regulates 5-HT levels in the gut lumen has not yet been clarified. Our previous work with gnotobiotic mice showed that free catecholamines can be produced by the deconjugation of conjugated catecholamines; hence, we speculated that deconjugation by bacterial enzymes may be one of the mechanisms whereby gut microbes can produce free 5-HT in the gut lumen. In this study, we tested this hypothesis using germ-free (GF) mice and gnotobiotic mice recolonized with specific pathogen-free (SPF) fecal flora (EX-GF). The 5-HT levels in the lumens of the cecum and colon were significantly lower in the GF mice than in the EX-GF mice. Moreover, these levels were rapidly increased, within only 3 days after exposure to SPF microbiota. The majority of 5-HT was in an unconjugated, free form in the EX-GF mice, whereas approximately 50% of the 5-HT was found in the conjugated form in the GF mice. These results further support the current view that the gut microbiota plays a crucial role in promoting the production of biologically active, free 5-HT. The deconjugation of glucuronide-conjugated 5-HT by bacterial enzymes is likely one of the mechanisms contributing to free 5-HT production in the gut lumen.

Low-molecular-weight metabolites produced by the intestinal microbiome play a direct role in health and disease. However, little is known about the ability of the colon to absorb these metabolites. It is also unclear whether these metabolites are bioavailable. Here, metabolomics techniques (capillary electrophoresis with time-of-flight mass spectrometry, CE-TOFMS), germ-free (GF) mice, and colonized (Ex-GF) mice were used to identify the colonic luminal metabolites transported to colonic tissue and/or blood. We focused on the differences in each metabolite between GF and Ex-GF mice to determine the identities of metabolites that are transported to the colon and/or blood. CE-TOFMS identified 170, 246, 166, and 193 metabolites in the colonic feces, colonic tissue, portal plasma, and cardiac plasma, respectively. We classified the metabolites according to the following influencing factors: (i) the membrane transport system of the colonocytes, (ii) metabolism during transcellular transport, and (iii) hepatic metabolism based on the similarity in the ratio of each metabolite between GF and Ex-GF mice and found 62 and 22 metabolites that appeared to be absorbed from the colonic lumen to colonocytes and blood, respectively. For example, 11 basic amino acids were transported to the systemic circulation from the colonic lumen. Furthermore, many low-molecular-weight metabolites influenced by the intestinal microbiome are bioavailable. The present study is the first to report the transportation of metabolites from the colonic lumen to colonocytes and somatic blood in vivo, and the present findings are critical for clarifying host-intestinal bacterial interactions.

Low–molecular-weight metabolites produced by intestinal microbiota play a direct role in health and disease. In this study, we analyzed the colonic luminal metabolome using capillary electrophoresis mass spectrometry with time-of-flight (CE-TOFMS) —a novel technique for analyzing and differentially displaying metabolic profiles— in order to clarify the metabolite profiles in the intestinal lumen. CE-TOFMS identified 179 metabolites from the colonic luminal metabolome and 48 metabolites were present in significantly higher concentrations and/or incidence in the germ-free (GF) mice than in the Ex-GF mice ( p < 0.05), 77 metabolites were present in significantly lower concentrations and/or incidence in the GF mice than in the Ex-GF mice ( p < 0.05) and 56 metabolites showed no differences in the concentration or incidence between GF and Ex-GF mice. These indicate that intestinal microbiota highly influenced the colonic luminal metabolome and a comprehensive understanding of intestinal luminal metabolome is critical for clarifying host-intestinal bacterial interactions.

•Anti-H. pylori urease IgY is prepared by immunizing hens.•Lactobacillus johnsonii No.1088 (LJ88) has anti-H. pylori activity.•Their synergistic anti-H. pylori effect is demonstrated both in vitro and in vivo.•Not only living but also heat-killed LJ88 is effective when combined with the IgY.•Their combination might compensate and/or augment standard anti-H. pylori regimens. Helicobacter pylori is a pathogenic bacterium that infects the stomach, causing chronic gastritis; and it is also considered to be related to the occurrence of gastric cancers. Although some eradication regimens including multiple antibiotics have been developed, the emergence of resistance to antibiotics becomes problematic. Therefore, other approaches to compensate or augment the effects of standard regimens are needed. In this study, we examined the possible synergistic effects of anti-H. pylori urease IgY and Lactobacillus johnsonii No.1088 (LJ88) both in vitro and in vivo. Anti-H. pylori urease IgY was purified from egg yolks laid by the hens immunized with urease purified from H. pylori. LJ88 is a unique strain of lactic acid bacterium isolated from human gastric juice, and it has been reported to inhibit H. pylori both in vitro and in vivo. The in vitro mixed culture study showed that anti-H. pylori urease IgY augmented the anti-H. pylori activity of LJ88 against both clarithromycin-sensitive and -resistant H. pylori strains. In a germ-free mice infection model, combined administration of daily anti-H. pylori urease IgY and weekly living LJ88 significantly reduced H. pylori infections, whereas either monotherapy did not. In an in vivo human gut microbiota-associated mice model, not only daily administration of living LJ88 but also heat-killed one significantly reduced an H. pylori infection in the stomach when combined with anti-H. pylori urease IgY. The extent of reduction of the stomach H. pylori by such a combination therapy was larger than that reported for LJ88 monotherapy. These results taken together revealed a synergistic effect of anti-H. pylori urease IgY and living or heat-killed LJ88, thus suggesting that such a combination might be a promising therapy to possibly compensate and/or augment standard anti-H. pylori regimens.

The accumulation of certain species of bacteria in the intestine is involved in both tissue homeostasis and immune-mediated pathologies. The host mechanisms involved in controlling intestinal colonization with commensal bacteria are poorly understood. We observed that under specific pathogen-free or germ-free conditions, intragastric administration of Pseudomonas aeruginosa, E. coli, Staphylococcus aureus, or Lactobacillus gasseri resulted in increased colonization of the small intestine and bacterial translocation in mice lacking Cd1d, an MHC class I-like molecule, compared with WT mice. In contrast, activation of Cd1d-restricted T cells (NKT cells) with alpha-galactosylceramide caused diminished intestinal colonization with the same bacterial strains. We also found prominent differences in the composition of intestinal microbiota, including increased adherent bacteria, in Cd1d-/- mice in comparison to WT mice under specific pathogen-free conditions. Germ-free Cd1d-/- mice exhibited a defect in Paneth cell granule ultrastructure and ability to degranulate after bacterial colonization. In vitro, NKT cells were shown to induce the release of lysozyme from intestinal crypts. Together, these data support a role for Cd1d in regulating intestinal colonization through mechanisms that include the control of Paneth cell function.

Background: Kawasaki disease is a common systemic vasculitis that leads to coronary artery lesions. Besides its antihypertensive effects, losartan can modulate inflammation in cardiovascular disease. We examined whether losartan can attenuate coronary inflammation in a murine model of Kawasaki disease. Methods and Results: Five-wk-old C57/BL6J male mice were intraperitoneally injected with Lactobacillus casei cell wall extract to induce coronary inflammation and divided into four groups: placebo, intravenous immunoglobulin (IVIG), losartan, and IVIG+losartan. After 2 wk, mice were harvested. The coronary perivasculitis was significantly attenuated by losartan but not by IVIG alone, and further dramatic attenuation by IVIG+losartan was observed. The frequency of Lactobacillus casei cell wall extract-induced myocarditis (80%) was markedly lowered by losartan (22%) and IVIG+losartan (0%). Furthermore, interleukin (IL)-6 mRNA was markedly attenuated by IVIG+losartan. Serum levels of IL-6, TNF-α, MCP-1, and IL-10 after Lactobacillus casei cell wall extract injection were slightly decreased by IVIG or losartan. Moreover, IL-1β, IL-10, and MCP-1 levels were significantly decreased by IVIG+losartan. Conclusion: The addition of losartan to IVIG strongly attenuated the severity of coronary perivasculitis and the incidence of myocarditis, along with suppressing systemic/local cytokines as well as the activated macrophage infiltration. Therefore, losartan may be a potentially useful additive drug for the acute phase of Kawasaki disease to minimize coronary artery lesions.

A novel strain of Lactobacillus johnsonii No. 1088 was isolated from the gastric juice of a healthy Japanese male volunteer, and characterized for its effectiveness in the stomach environment. Lactobacillus johnsonii No. 1088 was found to have the strongest acid resistance among several lactobacilli examined (>10% of cells survived at pH 1.0 after 2 h), and such a high acid resistance property was a specific characteristic of this strain of L. johnsonii. When cultured with various virulent bacteria, L. johnsonii No. 1088 inhibited the growth of Helicobacter pylori, Escherichia coli O‐157, Salmonella Typhimurium, and Clostridium difficile, in which case its effectiveness was more potent than that of a type strain of L. johnsonii, JCM2012. In addition to its effect in vitro, L. johnsonii No. 1088 inhibited the growth of H. pylori in human intestinal microbiota‐associated mice in both its live and lyophilized forms. Moreover, L. johnsonii No. 1088 suppressed gastric acid secretion in mice via decreasing the number of gastrin‐positive cells in the stomach. These results taken together suggest that L. johnsonii No. 1088 is a unique lactobacillus having properties beneficial for supporting H. pylori eradication by triple therapy including the use of a proton pump inhibitor (PPI) and also for prophylaxis of gastroesophageal reflux disease possibly caused after H. pylori eradication as a side effect of PPI. Effect of proton pump inhibitor and Lactobacillus johnsonii No. 1088 on the number of gastrin‐positive cells and stomach weight. Preadministration with L. johnsonii No. 1088 significantly prevented the increase in the number of gastrin‐positive cells (Fig. 5A, closed bars) and also that in stomach weight (Fig. 5B, closed bars).

Background: Intestinal microbiota are known to play an important role in the establishment of oral tolerance, thereby protecting the organism from food allergies. Dietary intake of nucleic acid (NA) is also reported to have such an anti-allergic effect; however, one unsolved question is whether or not dietary NA would act through a process of toll-like receptor 9 signaling activated by DNA containing a CpG motif, a well-known sequence leading to immunostimulatory activity. In this study, we focused on the question of whether the addition of dietary NA lacking CpG motifs would allow continued modulation of the Th1/Th2 balance. Methods: Germ free (GF) and Bifidobacterium-infantis-monoassociated BALB/c mice were maintained on either an NA-free casein diet or on an NA-supplemented casein diet for 4 weeks. Thereafter, both the in vivo anti-casein antibody levels and in vitro splenocyte cytokine secretion pattern were evaluated. Results: Feeding with a casein diet elicited a substantial increase in the serum anti-casein-specific IgG1, IgG2a, and IgE levels of GF mice fed the NA free-diet. The in vitro cytokine production profile showed that enhanced IL-4 production in the GF mice fed the NA free-diet was markedly reduced by the supplementation with dietary NA in both the GF and B.-infantis-monoassociated mice. In addition, IFN-γ secretion increased in the B.-infantis-reconstituted mice fed the diet containing NA. Conclusions: These results suggest that dietary intake of NA devoid of CpG motifs may prevent the development of allergies via acceleration of Th1-dominant immunity.

Background. Phenols and indoles are fermentation products and putrefactants of intestinal bacterial origin. They present a problem in chronic renal failure and hemodialysis patients because they accumulate in the body as uremic toxins. Methods. A comparative study was performed in groups of patients with chronic renal failure (CRF) before the initiation of dialysis, hemodialysis patients (HD), and healthy adults to investigate changes in intestinal flora and to measure the blood levels of uremic toxins. Results. The level of Escherichia coli was significantly increased in the CRF and HD groups compared with the healthy controls (P= 0.02, controls vs CRF before dialysis; P= 0.0014, controls vs HD). Fecal concentrations of phenol and scatole were most highly elevated in the HD group, and the difference between the CRF and HD groups was significant (P= 0.02 for phenol; P= 0.01 for scatole). Serum concentrations of phenol, p-cresol, and indican were significantly elevated in the CRF group (P= 0.01; P= 0.008; and P < 0.0001 vs controls, respectively). For indican, a correlation was found between fecal and serum concentrations only in the HD group (correlation coefficient of 0.821; P= 0.04). In the CRF group, a correlation was obtained between the urine and serum concentrations of phenol and p-cresol (0.852, P= 0.01; 0.758, P= 0.02, respectively). A correlation was also found between the serum concentrations of indican and serum creatinine (SCr) (0.610; P= 0.004) and [beta]2-microglobulin ([beta]2-MG) (0.739; P= 0.005). Conclusions. An abnormal balance of intestinal bacterial flora and increased intestinal bacteria-derived putrefactants were observed in the CRF group. The increased concentration of toxins with renal sclerosing effects, such as indican, may contribute to further deterioration of renal function.