Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Reduced gut microbial diversity in familial hypercholesterolemia with no effect of omega-3 polyunsaturated fatty acids intervention - a pilot trial.

Individuals with familial hypercholesterolemia (FH) undergo an aggressive treatment with cholesterol-lowering drugs to prevent coronary heart disease. Recent evidence suggests an interplay between the gut microbiota, blood lipid levels and lipid-lowering drugs, but this has yet to be studied in individuals with FH. The objective of the study was to characterize the gut microbiota of individuals with familial hypercholesterolemia and examine if effects of omega-3 polyunsaturated fatty acids (PUFAs) on blood lipids act through modification of the gut microbiome. The gut microbiota composition of individuals with FH (N = 21) and healthy controls (N = 144) was analyzed by extracting DNA from stool samples and sequencing of the V3-V4 region of the 16S rRNA gene. A subgroup (n = 15) of the participants received omega-3 polyunsaturated fatty acids (PUFAs) supplementation or placebo in a crossover manner, and the effect of PUFAs on the gut microbiota was also investigated. Individuals with FH had a different gut microbiota composition compared to healthy controls, characterized by reduced richness (p = .001) and reduction of several genera belonging to Clostridia and Coriobacteriia. Patients using ezetimibe in addition to statins appeared to have lower richness compared to those only using statins (p = .01). Intervention with omega-3 PUFAs had negligible impact on the microbiota composition. Positive effects on blood lipids after intervention with omega-3 PUFA were not associated with baseline gut microbiota composition or gut microbial changes during treatment. Further, patients with FH have an altered gut microbiota compared to healthy controls, possibly driven by the use of ezetimibe.

Cycling-related injuries at Sørlandet Hospital, Kristiansand. / Sykkelrelaterte skader på Sørlandet sykehus Kristiansand.

BACKGROUND: It is a policy objective to increase the percentage of journeys made by bicycle in Norway from the current 5 % to 10 %. Kristiansand is one of the most active cities in Norway in terms of cycling. We wished to identify the extent of injuries among cyclists admitted to the hospital. MATERIAL AND METHOD: We reviewed the medical records of patients with cycling-related injuries who were admitted to Sørlandet Hospital, Kristiansand in the period 1 January 2012 to 31 December 2015. Patient, accident, injury and treatment characteristics were recorded, as well as any sequelae after 12 months. RESULTS: Altogether 224 adults and 53 children (<16 years) were registered with cycling-related injuries, most of which (n=192, 69 %) were mild/moderate. Very severe and critical injuries were recorded in 6 (11 %) children and 22 (10 %) adults. Fractures (n=179, 65 %) and minor head injuries (n= 78, 28 %) dominated the injury panorama. Surgical treatment was undertaken in 107 (48 %) adults and 19 (36 %) children. A total of 12 (4 %) patients were transferred to the trauma centre at Oslo University Hospital Ullevål. Four adults had significant sequelae after 12 months, all related to severe head/neck injury. INTERPRETATION: A considerable proportion of serious and complex injuries require that the national guidelines for use of a trauma team be followed. Systematic and ongoing registration of cyclists' injuries in the form of a national registry could help increase our insight into the circumstances surrounding accidents and the extent of injuries related to these.

Rosuvastatin alters the genetic composition of the human gut microbiome.

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.

Low fibre intake is associated with gut microbiota alterations in chronic heart failure.

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.

Microbial translocation revisited: targeting the endotoxic potential of gut microbes in HIV-infected individuals.

OBJECTIVE: Translocation of microbial products such as lipopolysaccharides (LPS) from the gut may contribute to chronic inflammation in HIV-infected individuals. Recent studies indicate that differences in degree of acylation of gut-bacterial-derived LPS may explain variable immune effects, with hexa-acylated rather than penta-acylated LPS having proinflammatory capacity. We investigated whether the degree of acylation of gut-derived LPS associates with systemic inflammation, and the potential effect of probiotic intervention. METHODS: Gut microbiota profiles from a probiotics intervention were investigated and validated in a cohort of HIV-infected individuals commencing antiretroviral therapy. The PiCRUSt software was used to predict overall functional capacity of the microbiota and in-house bioinformatics to distinguish between bacteria producing hexa-acylated and penta-acylated LPS. RESULTS AND CONCLUSION: HIV-infected individuals with the highest ratio of proinflammatory hexa-acylated LPS to noninflammatory penta-acylated LPS-producing bacteria exhibited increased levels of systemic inflammation (neopterin, P < 0.001) and tryptophan catabolism (kynurenine/tryptophan ratio, P = 0.01), indicating a link between proinflammatory LPS, tryptophan catabolism and inflammation. After probiotics for 8 weeks, there was a decrease in Gram-negative bacteria (P = 0.01), related primarily to a reduction in bacteria producing penta-acylated LPS (P = 0.01), but not hexa-acylated LPS. The reduction in Gram-negative bacteria correlated positively with decreased plasma LPS (r = 0.72), mainly related to a reduction in bacteria producing noninflammatory penta-acylated LPS (r = 0.58). Notably, gut bacteria producing hexa-acylated LPS were outnumbered by penta-acylated LPS with a factor of 25 in HIV-infected individuals. Further studies are warranted to determine whether microbes producing hexa-acylated LPS might be a more relevant trigger of systemic inflammation compared with plasma LPS captured by the existing limulus assay.