The pharmacokinetics of adriamycin given as free and in DNA-complexed form was compared in six children with malignant disease. The two types of adriamycin were given to the same child at 3--4-week ...intervals, thereby excluding genetic variations when comparing the results. Plasma and urine were collected during and after the drug infusion, and the drug concentrations were measured by means of a sensitive fluorimetric procedure. The study shows that one obtains: 1. a much higher plasma concentration of adriamycin when it is given in the complexed form. 2. a lower urine excretion of adriamycin and fluorescent metabolites when adriamycin is administered as the DNA-complex.
To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional ...changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD).
Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses.
Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation–free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD.
The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
Aims
Recent reports have suggested that patients with heart failure (HF) have an altered gut microbiota composition; however, associations with diet remain largely uninvestigated. We aimed to explore ...differences in the gut microbiota between patients with HF with reduced ejection fraction and healthy controls, focusing on associations with diet and disease severity.
Methods and results
The microbiota composition of two cross‐sectional cohorts (discovery, n = 40 and validation, n = 44) of patients with systolic HF and healthy controls (n = 266) was characterized by sequencing of the bacterial 16S rRNA gene. The overall microbial community (beta diversity) differed between patients with HF and healthy controls in both cohorts (P < 0.05). Patients with HF had shifts in the major bacterial phyla, resulting in a lower Firmicutes/Bacteroidetes (F/B) ratio than controls (P = 0.005). Patients reaching a clinical endpoint (listing for heart transplant or death) had lower bacterial richness and lower F/B ratio than controls (P < 0.01). Circulating levels of trimethylamine‐N‐oxide were associated with meat intake (P = 0.016), but not with gut microbiota alterations in HF. Low bacterial richness and low abundance of several genera in the Firmicutes phylum were associated with low fibre intake.
Conclusions
The gut microbiota in HF was characterized by decreased F/B ratio and reduced bacterial diversity associated with clinical outcome. The gut microbiota alterations in HF were partly related to low fibre intake, emphasizing the importance of diet as a covariate in future studies. Our data could provide a rationale for targeting the gut microbiota in HF with high‐fibre diet.
The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common ...drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.
TA‐TMA is a post‐hematopoietic stem cell transplant complication with clinical features of hemolytic anemia and thrombocytopenia. A 26‐month‐old child who had had an allogeneic transplant for ...treatment of DBA developed severe TA‐TMA with heavy red blood cell and platelet transfusion dependence. Incidentally, he was found to have a lung sequestration. TA‐TMA resolved and transfusion dependence resolved after resection of the sequestration. The finding suggests the malformation vasculature was selectively vulnerable to the trigger of TA‐TMA—raising perhaps a clue to basic pathophysiology of TA‐TMA and/or vascular malformations.
Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one ...discovery panel (n = 165) and one validation panel (n = 87). Serum activity of autotaxin was measured in diluted sera by a fluorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n = 118 71.5%; validation panel: n = 35 40.2%), showed higher autotaxin activity compared with the other patients, P < 0.001 and P = 0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P < 0.001, validation panel: P = 0.001). There was no relationship between autotaxin activity and the presence of inflammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confidence interval 1.21-3.40), P < 0.01), independent from Mayo risk score, an in-house enhanced liver fibrosis score and interleukin-8 in serum. In conclusion, increased serum autotaxin activity is associated with reduced liver transplant-free survival independent from Mayo risk score and markers of inflammation and fibrosis.
The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common ...drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.
Artificial insemination (AI) in sheep is currently limited by the poor fertility obtained following non-surgical intracervical insemination of frozen–thawed semen. An exception to this general ...finding is the non-return rate of around 58% reported for large scale on-farm AI in Norway. The objective of the present study was to determine if similar results could be obtained under Irish conditions. Comparisons were made between semen collected, and frozen, from rams in Norway (NOR) and Ireland (IRL). The effects of synchronisation and inseminator were also examined. Parous ewes (
n=297) of various breed types were inseminated to a natural (N) or synchronised (S) oestrus with either fresh (from Irish rams) or frozen–thawed (IRL and NOR) semen. Ewes were randomly assigned, within breed, to the following treatment groups: (i) Fresh-N:
n=28, (ii) Fresh-S:
n=30, (iii) IRL-N:
n=62, (iv) IRL-S:
n=50, (v) NOR-N:
n=68, (vi) NOR-S:
n=59. Within each group, ewes were inseminated by an experienced Norwegian or by an Irish inseminator. Pregnancy rate did not differ significantly between ewes inseminated to a natural or synchronised oestrus nor between Norwegian and Irish frozen semen. The proportion of ewes pregnant after insemination with fresh semen was 0.82 and 0.70 (treatments i and ii) compared with 0.40, 0.52, 0.34 and 0.37 (treatments (iii)–(vi)) for frozen semen (
P<0.001). Corresponding litter sizes (±S.E.), adjusted for ovulation rate, were 2.9±0.22, 3.3±0.23, 2.2±0.21, 1.7±0.21, 2.2±0.21 and 2.1±0.21 (fresh versus frozen;
P<0.001). There was an interaction between semen type (fresh or frozen) and oestrus type (N or S) for litter size due to an increased adverse effect of frozen semen on litter size in synchronised ewes (
P<0.05). Pregnancy rate was significantly influenced by breed of ewe (
P<0.01) and inseminator (
P<0.05). These results suggest that ewe breed may be a critical determinant of the potential for the exploitation of cervical insemination of frozen–thawed semen in sheep breeding programmes.
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