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Human gut bacteria metabolize dietary components such as choline and carnitine to trimethylamine (TMA) that is subsequently oxidized to trimethylamine- N -oxide (TMAO) by hepatic enzymes. Increased plasma levels of TMAO are associated with the development of cardiovascular and renal disease. In this study, we applied gene-targeted assays in order to quantify (qPCR) and characterize (MiSeq) bacterial genes encoding enzymes responsible for TMA production, namely choline-TMA lyase ( CutC ), carnitine oxygenase ( CntA ) and betaine reductase ( GrdH ) in 89 fecal samples derived from various mammals spanning three dietary groups (carnivores, omnivores and herbivores) and four host orders (Carnivora, Primates, Artiodactyla and Perissodactyla). All samples contained potential TMA-producing bacteria, however, at low abundances (<1.2% of total community). The cutC gene was more abundant in omnivores and carnivores compared with herbivores. C ntA was almost absent from herbivores and grdH showed lowest average abundance of all three genes. Bacteria harboring cutC and grdH displayed high diversities where sequence types affiliated with various taxa within Firmicutes dominated, whereas cntA comprised sequences primarily linked to Escherichia . Composition of TMA-forming communities was strongly influenced by diet and host taxonomy and despite their high correlation, both factors contributed uniquely to community structure. Furthermore, Random Forest (RF) models could differentiate between groups at high accuracies. This study gives a comprehensive overview of potential TMA-producing bacteria in the mammalian gut demonstrating that both diet and host taxonomy govern their abundance and composition. It highlights the role of functional redundancy sustaining potential TMA formation in distinct gut environments., (Copyright © 2020 Rath, Rud, Pieper and Vital.)

The secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), formed by gut microbiota from primary bile acids via a multi-step 7α-dehydroxylation reaction, have wide-ranging effects on host metabolism and play an important role in health and disease. A few 7α-dehydroxylating strains have been isolated, where bile acid-inducible ( bai ) genes were organized in a gene cluster and encoded major enzymes involved. However, only little is known on diversity and abundance of intestinal bacteria catalysing DCA/LCA formation in the human gut in situ . In this study, we took the opportunity to screen metagenome-assembled genomes (MAGs) from sequence data of stool samples provided by two recent studies along with newly available gut-derived isolates for the presence of the bai gene cluster. We revealed in total 765 and 620 MAGs encoding the potential to form DCA/LCA that grouped into 21 and 26 metagenomic species, respectively. The majority of MAGs (92.4 and 90.3%) were associated with a Ruminococcaceae clade that still lacks an isolate, whereas less MAGs belonged to Lachnospiraceae along with eight new isolates (n total = 11) that contained the bai genes. Only a few MAGs were linked to Peptostreptococcaceae . Signatures for horizontal transfer of bai genes were observed. This study gives a comprehensive overview of the diversity of bai -exhibiting bacteria in the human gut highlighting the application of metagenomics to unravel potential functions hidden from current isolates. Eventually, isolates of the identified main MAG clade are required in order to prove their capability of 7α-dehydroxylating primary bile acids., Competing Interests: There is no conflict of interest.

Background: It is becoming evident that certain features of human microbiota, encoded by distinct autochthonous taxa, promote disease. As a result, borders between the so-called opportunistic pathogens, pathobionts, and commensals are increasingly blurred, and specific targets for manipulating microbiota to improve host health are becoming elusive., Results: In this study, we focus on the functions of host bacterial communities that have the potential to cause disease, proposing the term "pathogenic function (pathofunction)". The concept is presented via three distinct examples, namely, the formation of (i) trimethylamine, (ii) secondary bile acids, and (iii) hydrogen sulfide, which represent metabolites of the gut microbiota linked to the development of non-communicable diseases. Using publicly available metagenomic and metatranscriptomic data (n = 2975), we quantified those pathofunctions in health and disease and exposed the key players. Pathofunctions were ubiquitously present with increased abundances in patient groups. Overall, the three pathofunctions were detected at low mean concentrations (< 1% of total bacteria carried respective genes) and encompassed various taxa, including uncultured members., Conclusions: We outline how this function-centric approach, where all members of a community exhibiting a particular pathofunction are redundant, can contribute to risk assessment and the development of precision treatment directing gut microbiota to increase host health.

Objective: To compare the effects of two postmenopausal regimens on menopausal symptoms, bleeding episodes, side effects and acceptability., Design: Double-blind, randomised controlled trial., Setting: Twenty-nine sites in Denmark, nine in Norway and six in Sweden., Participants: Four hundred and thirty-seven postmenopausal women with menopausal complaints. None of these women had had a hysterectomy., Interventions: Daily treatment with tibolone 2.5 mg (n = 218) or 17beta-oestradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA) (n = 219)., Main Outcome Measures: Hot flushes, sweating episodes, vaginal dryness, assessment of sexual life and bleeding patterns; at baseline and after 4, 12, 24 and 48 weeks., Results: Treatment with either preparation significantly reduced mean scores for hot flushes, sweating episodes and vaginal dryness. The overall discontinuation rate was 28% (tibolone 25%, E2/NETA 31%; P = 0.14), mostly during the first six months. There was a markedly lower cumulative incidence of bleeding or spotting episodes with tibolone compared with E2/NETA (P < 0.0001), mainly during the first six treatment cycles., Conclusions: Both tibolone and E2/NETA effectively alleviate menopausal symptoms. However, tibolone caused significantly fewer bleeding or spotting episodes, which were reflected by lower overall rates of bleeding, as well as lower drop-out rates due to bleeding.

Of continent women undergoing the Manchester procedure for genito-urinary prolapse, about 25% develop urinary stress-incontinence. In order to study whether this is due to pre-existing anatomical factors or to the surgical procedure itself, a prospective study was set up. Fifty-eight continent women operated on for genito-urinary prolapse, underwent urethrocystography prior to and 3 months following surgery. Sixteen of the 58 (28%) developed stress-incontinence following the operation. Radiological parameters preoperatively were of little help in distinguishing the patients developing incontinence from those remaining continent. The stress-incontinence following a Manchester procedure for genital prolapse seems to depend on two surgical factors: an insufficient elevation of the bladder-neck and a radical reduction of the cystocele. A parameter combining the two factors: the percentage reduction of the cystocele minus the percentage elevation of the bladder-neck, was significantly lower in women remaining continent than in those who developed stress-incontinence.

To determine the components of the intraurethral pressure at rest, five continent women were studied with simultaneous urethrocystometry, including urethral pressure profile measurements, before, during and after curarization, as well as after clamping of the arterial blood supply to the urethra. The results showed that the striated muscle component in the urethra and pelvic floor is responsible for one-third of the total intraurethral pressure. Another one-third is exerted by the urethral vascular bed. The remaining one-third is most probably attributable to the smooth musculature and connective tissues in the urethra and the periurethral tissues.

Urethral pressure is made up of three components, equal in size: the striated muscle component, the smooth muscle component, and the vascular component. Anti-embolism stockings have been helpful in bringing about significant improvement in blood flow through the lower extremities. A pilot study was undertaken with 15 women to find out whether or not the same approach led to increase in urethral pressure. Simultaneous urethrocystometry was applied to women with and without stockings. Significant rise in urethral pressure was recorded from women with urinary stress incontinence who used stockings. Four of eight incontinent women were improved to continence by means of stockings.

A study was performed to find out how often continent women develop urinary stress-incontinence after a Manchester operation for genito-urinary prolapse, and to ascertain whether factors in the selection of patients, or steps in the surgical procedure are responsible for producing stress-incontinence postoperatively. Seventy-three of 102 consecutive patients were continent before operation. Sixteen of the 73 women (22%) became stress incontinent. Advanced age increased the risk of developing urinary stress-incontinence. Twenty-five per cent of the women more than 60 years old developed stress-incontinence, but only 1 of 13 below the age of 60. Preoperative urethral closure pressure was significantly lower in those developing urinary stress-incontinence, and closure pressure was further reduced by surgery in this group, significantly more than in the women remaining continent. Surgery significantly reduced the pressure transmission ratio in the patients who developed urinary stress-incontinence, and less in the continent ones. The preoperative pressure transmission ratio, however, was not related to the risk of developing urinary stress-incontinence after the operation. The urodynamic examinations pre- and postoperatively demonstrated important changes in the urodynamic parameters produced by the Manchester procedure, but did not prove useful in determining which patients will develop urinary stress-incontinence.