The effect of selected synbiotics on microbial composition and short-chain Fatty Acid production in a model system of the human colon.

Prebiotics, probiotics and synbiotics can be used to modulate both the composition and activity of the gut microbiota and thereby potentially affecting host health beneficially. The aim of this study was to investigate the effects of eight synbiotic combinations on the composition and activity of human fecal microbiota using a four-stage semicontinuous model system of the human colon.Carbohydrates were selected by their ability to enhance growth of the probiotic bacteria Lactobacillus acidophilus NCFM (NCFM) and Bifidobacterium animalis subsp. lactis Bl-04 (Bl-04) under laboratory conditions. The most effective carbohydrates for each probiotic were further investigated, using the colonic model, for the ability to support growth of the probiotic bacteria, influence the composition of the microbiota and stimulate formation of short-chain fatty acids (SCFA).The following combinations were studied: NCFM with isomaltulose, cellobiose, raffinose and an oat β-glucan hydrolysate (OBGH) and Bl-04 with melibiose, xylobiose, raffinose and maltotriose. All carbohydrates showed capable of increasing levels of NCFM and Bl-04 during fermentations in the colonic model by 10(3)-10(4) fold and 10-10(2) fold, respectively. Also the synbiotic combinations decreased the modified ratio of Bacteroidetes/Firmicutes (calculated using qPCR results for Bacteroides-Prevotella-Porphyromonas group, Clostridium perfringens cluster I, Clostridium coccoides - Eubacterium rectale group and Clostridial cluster XIV) as well as significantly increasing SCFA levels, especially acetic and butyric acid, by three to eight fold, as compared to the controls. The decreases in the modified ratio of Bacteroidetes/Firmicutes were found to be correlated to increases in acetic and butyric acid (p=0.04 and p=0.03, respectively).The results of this study show that all synbiotic combinations investigated are able to shift the predominant bacteria and the production of SCFA of fecal microbiota in a model system of the human colon, thereby potentially being able to manipulate the microbiota in a way connected to human health

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Correlation between Bacteroidetes/Firmicutes ratios and concentrations of SCFA.

<p>Correlation between concentrations of acetic acid (○) and butyric acid (□) and <i>Bacteroidetes/Firmicutes</i> ratios (<i>Bacteroides-Prevotella-Porphyromonas</i> group/<i>Clostridium perfringens</i> cluster I, <i>Clostridium coccoides - Eubacterium rectale</i> group and Clostridial cluster XIV) for synbiotic combinations with <i>Lactobacillus acidophilus</i> NCFM (A) and <i>Bifidobacterium animalis</i> subsp. <i>lactis</i> Bl-04 (B). Concentrations of acetic and butyric acid in control fermentations are denoted by grey circles and squares, respectively. The Spearman Rank probabilities (p) and correlations (R) are shown in the graphs.</p

Concentrations of short-chain fatty acids as determined by gas chromatography; acetic acid (A), propionic acid (B) and butyric acid (C) in vessels V1–V4 of the colonic model after control and synbiotic fermentations.

<p>Synbiotic fermentations are denoted as follows: <i>Lactobacillus acidophilus</i> NCFM in combination with; isomaltulose (•)(n = 2), cellobiose (▴)(n = 2), raffinose (♦)(n = 2) and OBGH (▪)(n = 2) and <i>Bifidobacterium animalis</i> subsp. <i>lactis</i> Bl-04 in combination with; melibiose (○)(n = 2), xylobiose (Δ) (n = 2), raffinose (◊)(n = 2) and maltotriose (□)(n = 3). Control fermentations (n = 3) are denoted by crosses and dotted lines and results are shown as mean concentrations (mmol/L) for each vessel ± standard error of mean. *p<0.05, **p<0.005.</p

Ratios of <i>Bacteroidetes/Firmicutes</i> as determined by qPCR.

<p>Ratios of <i>Bacteroidetes/Firmicutes</i> (<i>Bacteroides-Prevotella-Porphyromonas</i> group/<i>Clostridium perfringens</i> cluster I, <i>Clostridium coccoides - Eubacterium rectale</i> group and Clostridial cluster XIV) for fermentations with <i>Lactobacillus acidophilus</i> NCFM (A) in combination with isomaltulose (•) (n = 2), cellobiose (▴)(n = 2), raffinose (♦)(n = 2) and OBGH (▪)(n = 2); <i>Bifidobacterium animalis</i> subsp. <i>lactis</i> Bl-04 (B) in combination with melibiose (<b>○</b>)(n = 2), xylobiose (Δ) (n = 2), raffinose (◊)(n = 2) and maltotriose (□)(n = 3). Control fermentations (n = 3) are denoted by crosses and dotted lines and results are shown as mean values for each vessel, V1–V4, ± standard error of mean. *p<0.05.</p

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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