Gut microbiome variation modulates the effects of dietary fiber on host metabolism

Background: There is general consensus that consumption of dietary fermentable fiber improves cardiometabolic health, in part by promoting mutualistic microbes and by increasing production of beneficial metabolites in the distal gut. However, human studies have reported variations in the observed benefits among individuals consuming the same fiber. Several factors likely contribute to this variation, including host genetic and gut microbial differences. We hypothesized that gut microbial metabolism of dietary fiber represents an important and differential factor that modulates how dietary fiber impacts the host. Results: We examined genetically identical gnotobiotic mice harboring two distinct complex gut microbial communities and exposed to four isocaloric diets, each containing different fibers: (i) cellulose, (ii) inulin, (iii) pectin, (iv) a mix of 5 fermentable fibers (assorted fiber). Gut microbiome analysis showed that each transplanted community preserved a core of common taxa across diets that differentiated it from the other community, but there were variations in richness and bacterial taxa abundance within each community among the different diet treatments. Host epigenetic, transcriptional, and metabolomic analyses revealed diet-directed differences between animals colonized with the two communities, including variation in amino acids and lipid pathways that were associated with divergent health outcomes. Conclusion: This study demonstrates that interindividual variation in the gut microbiome is causally linked to differential effects of dietary fiber on host metabolic phenotypes and suggests that a one-fits-all fiber supplementation approach to promote health is unlikely to elicit consistent effects across individuals. Overall, the presented results underscore the importance of microbe-diet interactions on host metabolism and suggest that gut microbes modulate dietary fiber efficacy. [MediaObject not available: see fulltext.]Fil: Murga Garrido, Sofia M.. Universidad Nacional Autónoma de México; México. University of Wisconsin; Estados UnidosFil: Hong, Qilin. University of Wisconsin; Estados UnidosFil: Cross, Tzu Wen L.. University of Wisconsin; Estados Unidos. Purdue University; Estados UnidosFil: Hutchison, Evan R.. University of Wisconsin; Estados UnidosFil: Han, Jessica. Wisconsin Institute for Discovery; Estados UnidosFil: Thomas, Sydney P.. Wisconsin Institute for Discovery; Estados UnidosFil: Vivas, Eugenio I.. University of Wisconsin; Estados UnidosFil: Denu, John. Wisconsin Institute for Discovery; Estados UnidosFil: Ceschin, Danilo Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; ArgentinaFil: Tang, Zheng Zheng. University of Wisconsin; Estados Unidos. Wisconsin Institute for Discovery; Estados UnidosFil: Rey, Federico E.. University of Wisconsin; Estados Unido

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Rotenone Decreases Hatching Success in Brine Shrimp Embryos by Blocking Development: Implications for Zooplankton Egg Banks

<div><p>While many zooplankton species recover quickly after the treatment of water resources with the piscicide, rotenone, some fail to reach pretreatment population density or, in rare cases, do not reappear at all. The variable impact of rotenone on zooplankton populations could stem from differences in the capacity of species to switch entirely to anaerobic catabolic pathways in the presence of rotenone, which blocks mitochondrial electron transport. Alternatively, variable responses among species could originate from differences in permeability of dormant life-stages to lipophilic chemicals like rotenone. The purpose of the present study was to determine the effects of rotenone on development, emergence and hatching of zooplankton embryos that lack both the anaerobic capacity to develop in the presence of rotenone and a permeability barrier to prevent the entry of rotenone during dormancy. Post-diapause embryos of the brine shrimp, <i>Artemia franciscana</i>, were employed as a model system, because they are permeable to lipophilic compounds when dechorionated and require aerobic conditions to support development. Early development in this species is also well characterized in the literature. Brine shrimp embryos were exposed to rotenone while development was either slowed by chilling or suspended by anoxia. Development, emergence and hatching were then observed in rotenone-free artificial seawater. The data presented demonstrate that rotenone freely diffuses across the embryonic cuticle in a matter of hours, and prevents development and emergence after brief exposures to ecologically relevant concentrations (0.025–0.5 mg L^-1) of the piscicide. Neither the removal of rotenone from the environment, nor the removal of embryonic water with a hypertonic solution, are sufficient to reverse this block on development and emergence. These data indicate that rotenone could impair recruitment from egg banks for species of zooplankton that lack both an embryonic barrier to the entry of lipophilic compounds and the anaerobic capacity to develop when NADH:ubiquinone oxidoreductase activity is inhibited by rotenone.</p></div

Dissecting the impact of dietary fiber type on atherosclerosis in mice colonized with different gut microbial communities

Dietary fiber consumption has been linked with improved cardiometabolic health, however, human studies have reported large interindividual variations in the observed benefits. We tested whether the effects of dietary fiber on atherosclerosis are influenced by the gut microbiome. We colonized germ-free ApoE-/- mice with fecal samples from three human donors (DonA, DonB, and DonC) and fed them diets supplemented with either a mix of 5 fermentable fibers (FF) or non-fermentable cellulose control (CC) diet. We found that DonA-colonized mice had reduced atherosclerosis burden with FF feeding compared to their CC-fed counterparts, whereas the type of fiber did not affect atherosclerosis in mice colonized with microbiota from the other donors. Microbial shifts associated with FF feeding in DonA mice were characterized by higher relative abundances of butyrate-producing taxa, higher butyrate levels, and enrichment of genes involved in synthesis of B vitamins. Our results suggest that atheroprotection in response to FF is not universal and is influenced by the gut microbiome.Published versionThis work was partly supported by grants from NIH HL144651 (F.E.R.), HL148577 (F.E.R.), and EB030340 (F.E.R.). This work was also supported by a grant from a Transatlantic Networks of Excellence Award from the Leducq Foundation (17CVD01). ERH was supported in part by the Metabolism and Nutrition Training Program NIH T32 (DK007665) and by the University of Wisconsin–Madison Food Research Institute (Robert H. and Carol L. Deibel Distinguished Graduate Fellowship in Probiotic Research). T.-W.L.C. was supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL007936 from the National Heart Lung and Blood Institute to the University of Wisconsin–Madison Cardiovascular Research Center

Washing embryos, and removing bulk embryonic water by a cycle of dehydration and rehydration, fails to reverse the effects of rotenone pre-exposure on emergence and hatching.

<p>Relative abundance of three developmental stages at 43 h is displayed: black for embryo, grey for emergence stages, and white for larvae. Control lacked rotenone; percent values calculated from evaluation of 162 or 183 individuals for control and rotenone treatments, respectively.</p

Concentration-dependent effect of pre-exposure with rotenone (method No. 2).

<p>Early development, emergence and hatching in <i>A</i>. <i>franciscana</i> were assessed by periodic observation over 68 h in static 12-well plates containing rotenone-free ASW, and maintained under constant darkness. Concentration of rotenone during 24 h preincubation at 0°C was varied. Hatching success was assessed after 68 h at 22°C (A). Development, emergence and hatching were also assessed at 2 h intervals for encysted embryonic (B), emergence 1 (C,D), emergence 2 (E-G) or larval (H) stages according to nomenclature of Neumeyer, Gerlach (27). Data plotted as mean±s.e.m.; n = 3 with 123±2 embryos per treatment replicate; ANOVA followed by Tukey’s post-hoc test used to compare means for treatment types at each time point; shared letters indicate no significant difference; open arrows identify time-point when 0.025 μg ml^-1 rotenone treatment first significantly altered abundance relative to the control; †, mean values for 0.025 μg ml^-1 and 0.05 μg ml^-1 treatments significantly greater than all other treatments; ‡, mean for 0.025 μg ml^-1 significantly greater than control treatment while 0.05μg ml^-1 treatment is significantly greater than all other treatments at the same time point; *, mean value at 68 h significantly different from 36 h as determined by two-tailed Student’s t-test; solid arrow indicates statistically supported peak shift for rotenone treatments, relative to the control.</p

Concentration-dependent effect of pre-exposure with rotenone (method No. 1).

<p>Hatching success for <i>A</i>. <i>franciscana</i> was assessed by end-point assay after 64–67 h in rotenone-free ASW under room lighting with aeration by orbital shaking. Concentration of rotenone during 24 h preincubation at 0°C was varied. Relative abundance of larvae plotted as mean±s.e.m.; n = 3 with 185±12 embryos per treatment replicate; ANOVA and Tukey’s post-hoc test used to compare means; shared letters indicate no significant difference.</p

Time-dependent effects of pre-exposure to rotenone.

<p>Emergence and hatching of <i>A</i>. <i>franciscana</i> were assessed by endpoint assay after 43 h of development in rotenone-free ASW. Duration of pre-exposure to 0.5 μg ml^-1 rotenone during preceding 24 h was varied. Relative abundance of three developmental stages plotted as mean±s.e.m. with percent values calculated from evaluation of 349±28 embryos per treatment replicate, n = 3; ANOVA and Tukey’s post-hoc test used to compare three treatment types for each developmental stage; shared letters indicate no significant difference among means with upper case used for encysted embryos and lower case for larvae. No significant differences identified for emerging embryos.</p

Increasing temperature does not increase the sensitivity of hatching to pre-incubation with rotenone for 5 d under anoxia.

<p>Hatching success was assessed in rotenone-free ASW under normoxic conditions at 22°C after anoxic pre-incubation for 5 d at 22°C (grey bars) or 4°C (black bars) in the presence or absence of rotenone. Data plotted as mean±s.e.m.; percent hatch calculated from evaluation of 247±30 embryos per individual replicate, n = 3; p-values for Bonferroni multiple comparison test are displayed.</p