Effect of daily ingestion of Bifidobacterium and dietary fiber on vascular endothelial function: a randomized, double-blind, placebo-controlled, parallel-group comparison study.

Bifidobacterium animalis subsp. lactis GCL2505 (GCL2505) improves the intestinal microbiota and reduces human visceral fat. This randomized, double-blind, placebo-controlled, parallel-group study was conducted to examine the effects of inulin, a prebiotic dietary fiber, and GCL2505 on vascular endothelial function in healthy subjects (n = 60). The test drink contained 2.0 g/100 g inulin and 1.0 × 1010 colony-forming units/100 g GCL2505 and was consumed daily for 12 weeks. Flow-mediated dilation was set as the primary endpoint. Subgroup analysis of vascular endothelial function demonstrated a significant increase in the change of flow-mediated dilation (%) from weeks 0 to 12 in the GCL2505 and inulin group (n = 24) compared with the placebo group (n = 23), while an improving trend in low-density lipoprotein cholesterol and plasminogen activator inhibitor-1 were confirmed. Our results indicated that the test drink had a positive effect on vascular endothelial function and related blood parameters.

Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications.

BACKGROUND & AIMS: We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, the Japanese 4D (Disease, Drug, Diet, Daily Life) microbiome cohort, and non-Japanese data sets. METHODS: We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 control individuals matched by important confounders. RESULTS: Multiple correlations were found between COVID-19-related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan. CONCLUSIONS: Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.

Bifidobacterium animalis subsp. lactis GCL2505 modulates host energy metabolism via the short-chain fatty acid receptor GPR43.

Short-chain fatty acids (SCFAs), which are metabolites derived from the fermentation of dietary fibre by the gut microbiota, are important for host metabolic health. There is interest in probiotics for their beneficial effects on metabolic disorders, such as obesity, but the underlying mechanisms remain largely unknown. In this study, we evaluated whether Bifidobacterium animalis subsp. lactis GCL2505 (GCL2505), a probiotic strain capable of proliferating and increasing SCFA levels in the gut, exerts anti-metabolic syndrome effects via the SCFA receptor G protein-coupled receptor 43 (GPR43). A GCL2505 treatment suppressed body fat accumulation, improved glucose tolerance, and enhanced systemic fatty acid oxidation in high-fat diet (HFD)-fed wild type (WT) mice, whereas these effects were not observed in HFD-fed Gpr43 knockout (Gpr43-/-) mice. Caecal and plasma acetate levels were elevated by GCL2505 in WT and Gpr43-/- mice, but the negative correlation between plasma acetate levels and body fat accumulation was observed only in WT mice. We further demonstrated that GCL2505 suppressed insulin signalling in the adipose tissue via GPR43. These results suggested that increases in SCFA levels in response to GCL2505 enhance host energy expenditure, which decreases fat accumulation via activated GPR43.

Effects of synbiotics containing Bifidobacterium animalis subsp. lactis GCL2505 and inulin on intestinal bifidobacteria: A randomized, placebo-controlled, crossover study.

A number of studies have shown the bifidogenic effects of either probiotic bifidobacteria or inulin, and this bifidogenic shift in the composition of the colonic microbiota is likely the basis for their positive impact on human health. This study aimed to evaluate the effects of synbiotics containing the probiotic bacterium Bifidobacterium animalis subsp. lactis (B. lactis) GCL2505 and inulin on the levels of intestinal bifidobacteria compared with B. lactis GCL2505 alone. A randomized, double-blind, placebo-controlled, crossover trial was carried out involving 60 healthy subjects with a tendency for constipation using fermented milk containing B. lactis GCL2505 and inulin (synbiotic), only B. lactis GCL2505 (probiotic), and placebo. Fecal samples were collected at the end of each 2-week intervention period, and the bifidobacterial count was analyzed by quantitative real-time PCR. The numbers of total bifidobacteria and B. lactis in feces were significantly increased during the probiotic and synbiotic intake periods compared with the placebo intake period. Furthermore, the numbers of total bifidobacteria and endogenous bifidobacteria were significantly higher in the synbiotic intake period compared with the probiotic intake period, while there was no difference in the number of B. lactis. These results suggested that the synbiotics containing B. lactis GCL2505 and inulin had a greater effect on the number of bifidobacteria than a drink containing probiotics alone and could be useful for the improvement of the intestinal environment.

Effect of Bifidobacterium animalis subsp. lactis GCL2505 on the physiological function of intestine in a rat model.

Bifidobacterium animalis ssp. lactis GCL2505 has been shown to proliferate in the human intestine. The intestinal dynamics and physiological effects of GCL2505 as well as the mechanism underlying proliferation in the gut were investigated. GCL2505 showed markedly higher resistance to free bile acids (cholic and deoxycholic acids) than other bifidobacterial species. The intestinal dynamics of GCL2505 and B. longum ssp. longum JCM1217T was compared. The level of B. animalis ssp. lactis in the GCL2505-administered group was remarkably higher than that of B. longum in the JCM1217T-administered group. The distribution of B. animalis ssp. lactis through the intestine of the GCL2505-administered group revealed that GCL2505 proliferated in the cecum. The physiological effects of GCL2505 and JCM 1217T were investigated. The cecal IgA level in the GCL2505-administered group was significantly higher than that in the nontreated control group. In contrast, the JCM 1217T-administered group did not manifest any change in the cecal IgA level. Mucin excretion in the GCL2505-administered group was significantly higher than that in the JCM 1217T-administered group. The thickness of the sulfomucin layer of the colon in the GCL2505-administered group tended to be higher than that in the JCM 1217T-administered group. In a loperamide-induced constipation model, fecal excretion in the GCL2505-administered group was significantly increased compared with that in the loperamide-treated control group. Short-chain fatty acid concentration in the GCL2505-administered group was significantly higher than that in the loperamide-treated control group. These results indicate that the level of proliferation of probiotics in the intestine correlates with the magnitude of host physiological responses, such as IgA production and mucin secretion, which possibly affect gastrointestinal functions such as bowel movement to counteract constipation. GCL2505 exhibits high tolerance to secondary bile acids, which partially explains its higher rate of proliferation in the large intestine.

Effect of Bifidobacterium animalis ssp. lactis GCL2505 on visceral fat accumulation in healthy Japanese adults: a randomized controlled trial.

Bifidobacterium animalis ssp. lactis GCL2505 (B. lactis GCL2505) is able to survive passage through the intestine and then proliferate, leading to an increase in the amount of gut bifidobacteria. In the present study, we evaluated the impact of B. lactis GCL2505 on abdominal visceral fat storage in overweight and mildly obese Japanese adults. This clinical study was a double-blind, randomized, placebo-controlled, parallel-group comparative trial performed for 12 weeks. Healthy Japanese subjects (N=137) with body mass indices ranging from 23 to 30 kg/m2 consumed either fermented milk containing B. lactis GCL2505 or a placebo every day, and then visceral and subcutaneous abdominal fat areas were measured by computed tomography as the primary endpoints. The number of fecal bifidobacteria was also measured. Visceral fat area, but not subcutaneous fat area, was significantly reduced from baseline at 8 and 12 weeks in the GCL2505 group, compared with the placebo group. The total number of fecal bifidobacteria was significantly increased in the GCL2505 group. These results indicate that B. lactis GCL2505 reduces abdominal visceral fat, a key factor associated with metabolic disorders. This finding suggests that this probiotic strain can potentially serve as a specific functional food to achieve visceral fat reduction in overweight or mildly obese individuals.

Short- and long-term dynamics in the intestinal microbiota following ingestion of Bifidobacterium animalis subsp. lactis GCL2505.

Bifidobacterium animalis subsp. lactis GCL2505 (B. lactis GCL2505) is able to survive passage through the intestines and proliferate. The daily dynamics of the intestinal bifidobacteria following ingestion of probiotics are not yet clear. Moreover, the effects of long-term ingestion of probiotics on the intestinal microbiota have not been well studied. Two experiments were performed in the present study. In Experiment 1, 53 healthy female volunteers received B. lactis GCL2505; B. bifidum GCL2080, which can survive but not proliferate in the intestine; or yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus for 2 weeks, and the daily dynamics of intestinal bifidobacteria were investigated. The number of fecal bifidobacteria significantly increased on day 1, and this was maintained until day 14 in the B. lactis GCL2505 ingestion group. However, no significant change in the number of fecal bifidobacteria was observed in the other groups throughout the ingestion period. In Experiment 2, 38 constipated volunteers received either B. lactis GCL2505 or a placebo for 8 weeks. Both the number of fecal bifidobacteria and the frequency of defecation significantly increased throughout the ingestion period in the B. lactis GCL2505 ingestion group. These results suggested that the proliferation of ingested bifidobacteria within the intestine contributed to a rapid increase in the amount of intestinal bifidobacteria and subsequent maintenance of these levels. Moreover, B. lactis GCL2505 improved the intestinal microbiota more effectively than non-proliferating bifidobacteria and lactic acid bacteria.

Simultaneous ingestion of high-methoxy pectin from apple can enhance absorption of quercetin in human subjects.

Chronic ingestion of apple pectin has been shown to increase the absorption of quercetin in rats. The present study was designed to elucidate whether the simultaneous ingestion of quercetin with apple pectin could enhance the absorption of quercetin in humans, and the effects of dose dependency and degree of pectin methylation on quercetin absorption were also investigated. Healthy volunteers (n 19) received 200 ml of 0.5 mg/ml of quercetin drinks with or without 10 mg/ml of pectin each in a randomised cross-over design study with over 1-week intervals; urine samples from all the subjects were collected within 24 h after ingestion of the test drinks, and urinary deconjugated quercetin and its metabolites were determined using HPLC. The sum of urinary quercetin and its metabolites excreted was increased by 2.5-fold by the simultaneous ingestion of pectin. The metabolism of methylated quercetin (isorhamnetin and tamarixetin) was not affected by pectin ingestion. In six volunteers, who received quercetin drinks containing 0, 3 and 10 mg/ml of pectin, the sum of urinary quercetin and its metabolites excreted also increased in a pectin dose-dependent manner. Furthermore, the simultaneous ingestion of quercetin with low-methoxy and high-methoxy pectin, respectively, increased the sum of urinary excretion of quercetin and its metabolites by 1.69-fold and significantly by 2.13-fold compared with the ingestion of quercetin without pectin. These results elucidated that apple pectin immediately enhanced quercetin absorption in human subjects, and that its enhancing effect was dependent on the dose and degree of pectin methylation. The results also suggested that the viscosity of pectin may play a role in the enhancement of quercetin absorption.

Effects of administration of Bifidobacterium animalis subsp. lactis GCL2505 on defecation frequency and bifidobacterial microbiota composition in humans.

The aim of this study was to evaluate the changes in endogenous bifidobacteria and administered Bifidobacterium animalis subsp. lactis (B. lactis) GCL2505 (GCL2505) in the intestine after administration of GCL2505 by means of a randomized, placebo-controlled double-blind, cross-over study. An increase in the number of total bifidobacteria (the sum of B. bifidum, B. breve, B. longum subsp. longum, B. adolescentis, B. anglatum, B. catenulatum, B. pseudocatenulatum, B. dentium, B. longum subsp. infantis and B. lactis) in the feces were observed after administration of GCL2505 using species- and subspecies-specific real-time polymerase chain reaction analysis. However, the number of endogenous bifidobacteria species (excluding B. lactis) remained unchanged. B. lactis also became the predominant bifidobacterial species. Taking into account the number of GCL2505 administered, the findings further suggested that GCL2505 proliferated in the intestine. In addition, the defecation frequency increased during GCL2505 administration compared with the placebo. Moreover, a single administration study (n=17) clearly demonstrated that GCL2505 successfully reached the intestine before proliferating at least 10-fold. This is the first report to show an increase in intestinal bifidobacteria, with no changes to the endogenous species, and improvements in constipation following proliferation of administered bifidobacteria.

Chronic ingestion of apple pectin can enhance the absorption of quercetin.

The effect of apple pectin (AP) on quercetin and rutin bioavailability was investigated. Rats received a basal (control) or AP-containing diet for 6 weeks followed by orally administered quercetin or rutin. With quercetin administration, the maximum concentration and area under the curve of concentration-time from 0 to 24 h for the sum of quercetin metabolites in the plasma were significantly higher in AP-fed rats than in the control group. However, AP did not significantly affect rutin bioavailability. The crypt depth of the jejunum and ileum and the villus thickness of the ileum of AP-fed rats were significantly greater than those of control rats. These results demonstrate that chronic AP ingestion enhances intestinal absorption of quercetin. This increase in quercetin absorption might be attributed to alteration of the absorptive capacity of the small intestine through AP-induced improvement of its morphological and physiological properties.