The gut bile acid pool is millimolar in concentration, varies widely in composition among individuals and is linked to metabolic disease and cancer. Although these molecules are derived almost ...exclusively from the microbiota, remarkably little is known about which bacterial species and genes are responsible for their biosynthesis. Here we report a biosynthetic pathway for the second most abundant class in the gut, 3β-hydroxy(iso)-bile acids, whose levels exceed 300 μM in some humans and are absent in others. We show, for the first time, that iso-bile acids are produced by Ruminococcus gnavus, a far more abundant commensal than previously known producers, and that the iso-bile acid pathway detoxifies deoxycholic acid and thus favors the growth of the keystone genus Bacteroides. By revealing the biosynthetic genes for an abundant class of bile acids, our work sets the stage for predicting and rationally altering the composition of the bile acid pool.
Adolescence is a vulnerable period for experiencing poor sleep health. Growing studies have demonstrated lifestyle behaviors including physical activity (PA), screen time (SCT), and sedentary ...behaviors (SED) as the potential factors associated with sleep health in adolescents; yet, the evidence is inconclusive and the directionality of temporal associations across school days are not well understood. This study examined the day-to-day bidirectional associations of lifestyle behaviors with sleep health parameters in adolescents.
A total of 263 adolescents (58% boys) in 6th - 8th grades wore an accelerometer for 24-hour across the three consecutive school days and completed recording SCT in time-diary and answering sleep quality (SQ) questions for each day. Sleep-wake patterns as well as time spent in moderate- and vigorous-intensity PA (MVPA) and SED were objectively quantified from the wrist-worn accelerometry data across the two segments of the day (during and after school hours). Mixed model analyses were conducted to test bidirectional associations between lifestyle factors and sleep health parameters in each temporal direction across the days. Additionally, indirect associations across the days were tested using an autoregressive cross-lagged model analysis in the framework of path analysis.
MVPA minutes in a day did not predict sleep health parameters that night. The bidirectional associations were partially observed between SED and sleep health, but the significance and direction of the associations largely varied by the time segment of a day as well as types of sleep health parameters. Additionally, greater SCT during the day was associated with lower SQ that night (b = -0.010; P = .018), and greater SQ was associated with greater MVPA during school hours (b = 6.45; P = .028) and lower SED after school hours (b = -39.85; P = .029) the next day. Lastly, there were significant indirect associations of SCT with sleep health parameters across the days indicating multi-day lagged effects of SCT on sleep health the later nights.
This study highlights the importance of lowering SCT for better sleep health in adolescents during school days. Additionally, perceived SQ is shown to be a potential significant predictor promoting healthy behaviors the next day independent of sleep-wake patterns. Further studies are warranted to confirm the observed temporal associations between SCT, SQ, and behavioral outcomes in this vulnerable population.
To longitudinally evaluate the relationship between burnout and professional satisfaction with changes in physicians' professional effort.
Administrative/payroll records were used to longitudinally ...evaluate the professional work effort of faculty physicians working for Mayo Clinic from October 1, 2008, to October 1, 2014. Professional effort was measured in full-time equivalent (FTE) units. Physicians were longitudinally surveyed in October 2011 and October 2013 with standardized tools to assess burnout and satisfaction.
Between 2008 and 2014, the proportion of physicians working less than full-time at our organization increased from 13.5% to 16.0% (P=.05). Of the 2663 physicians surveyed in 2011 and 2776 physicians surveyed in 2013, 1856 (69.7%) and 2132 (76.9%), respectively, returned surveys. Burnout and satisfaction scores in 2011 correlated with actual reductions in FTE over the following 24 months as independently measured by administrative/payroll records. After controlling for age, sex, site, and specialty, each 1-point increase in the 7-point emotional exhaustion scale was associated with a greater likelihood of reducing FTE (odds ratio OR, 1.43; 95% CI, 1.23-1.67; P<.001) over the following 24 months, and each 1-point decrease in the 5-point satisfaction score was associated with greater likelihood of reducing FTE (OR, 1.34; 95% CI, 1.03-1.74; P=.03). On longitudinal analysis at the individual physician level, each 1-point increase in emotional exhaustion (OR, 1.28; 95% CI, 1.05-1.55; P=.01) or 1-point decrease in satisfaction (OR, 1.67; 95% CI, 1.19-2.35; P=.003) between 2011 and 2013 was associated with a greater likelihood of reducing FTE over the following 12 months.
Among physicians in a large health care organization, burnout and declining satisfaction were strongly associated with actual reductions in professional work effort over the following 24 months.
The microbiota modulatesgut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (TH17 cells). We previously ...reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. Although it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory bile acids are associated with inflammatory pathologies in humans. Here we identify human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well asthe abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-yt, a key TH17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3a-hydroxysteroid dehydrogenase genesthat are required fortheir biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of TH17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit TH17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.
Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut ...microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.
Human-associated microorganisms play a vital role in human health, and microbial imbalance has been linked to a wide range of disease states. In this Review, we explore recent efforts to progress ...from correlative studies that identify microorganisms associated with human disease to experiments that establish causal relationships between microbial products and host phenotypes. We propose that successful efforts to uncover phenotypes often follow a chain of evidence that proceeds from (1) association studies; to (2) observations in germ-free animals and antibiotic-treated animals and humans; to (3) fecal microbiota transplants (FMTs); to (4) identification of strains; and then (5) molecules that elicit a phenotype. Using this experimental 'funnel' as our guide, we explore how the microbiota contributes to metabolic disorders and hypertension, infections, and neurological conditions. We discuss the potential to use FMTs and microbiota-inspired therapies to treat human disease as well as the limitations of these approaches.
To evaluate the impact of organizational leadership on the professional satisfaction and burnout of individual physicians working for a large health care organization.
We surveyed physicians and ...scientists working for a large health care organization in October 2013. Validated tools were used to assess burnout. Physicians also rated the leadership qualities of their immediate supervisor in 12 specific dimensions on a 5-point Likert scale. All supervisors were themselves physicians/scientists. A composite leadership score was calculated by summing scores for the 12 individual items (range, 12-60; higher scores indicate more effective leadership).
Of the 3896 physicians surveyed, 2813 (72.2%) responded. Supervisor scores in each of the 12 leadership dimensions and composite leadership score strongly correlated with the burnout and satisfaction scores of individual physicians (all P<.001). On multivariate analysis adjusting for age, sex, duration of employment at Mayo Clinic, and specialty, each 1-point increase in composite leadership score was associated with a 3.3% decrease in the likelihood of burnout (P<.001) and a 9.0% increase in the likelihood of satisfaction (P<.001) of the physicians supervised. The mean composite leadership rating of each division/department chair (n=128) also correlated with the prevalence of burnout (correlation=-0.330; r(2)=0.11; P<.001) and satisfaction (correlation=0.684; r(2)=0.47; P<.001) at the division/department level.
The leadership qualities of physician supervisors appear to impact the well-being and satisfaction of individual physicians working in health care organizations. These findings have important implications for the selection and training of physician leaders and provide new insights into organizational factors that affect physician well-being.
Investigating human oligodendrogenesis and the interaction of oligodendrocytes with neurons and astrocytes would accelerate our understanding of the mechanisms underlying white matter disorders. ...However, this is challenging because of the limited accessibility of functional human brain tissue. Here, we developed a new differentiation method of human induced pluripotent stem cells to generate three-dimensional brain organoids that contain oligodendrocytes as well as neurons and astrocytes, called human oligodendrocyte spheroids. We found that oligodendrocyte lineage cells derived in human oligodendrocyte spheroids transitioned through developmental stages similar to primary human oligodendrocytes and that the migration of oligodendrocyte lineage cells and their susceptibility to lysolecithin exposure could be captured by live imaging. Moreover, their morphology changed as they matured over time in vitro and started myelinating neurons. We anticipate that this method can be used to study oligodendrocyte development, myelination, and interactions with other major cell types in the CNS.
Abstract Objective To explore the work lives, professional satisfaction, and burnout of US physicians by career stage and differences across sexes, specialties, and practice setting. Participants and ...Methods We conducted a cross-sectional study that involved a large sample of US physicians from all specialty disciplines in June 2011. The survey included the Maslach Burnout Inventory and items that explored professional life and career satisfaction. Physicians who had been in practice 10 years or less, 11 to 20 years, and 21 years or more were considered to be in early, middle, and late career, respectively. Results Early career physicians had the lowest satisfaction with overall career choice (being a physician), the highest frequency of work-home conflicts, and the highest rates of depersonalization (all P <.001). Physicians in middle career worked more hours, took more overnight calls, had the lowest satisfaction with their specialty choice and their work-life balance, and had the highest rates of emotional exhaustion and burnout (all P <.001). Middle career physicians were most likely to plan to leave the practice of medicine for reasons other than retirement in the next 24 months (4.8%, 12.5%, and 5.2% for early, middle, and late career, respectively). The challenges of middle career were observed in both men and women and across specialties and practice types. Conclusion Burnout, satisfaction, and other professional challenges for physicians vary by career stage. Middle career appears to be a particularly challenging time for physicians. Efforts to promote career satisfaction, reduce burnout, and facilitate retention need to be expanded beyond early career interventions and may need to be tailored by career stage.
Renal disease is growing in prevalence and has striking co-morbidities with metabolic and cardiovascular disease. Indoxyl sulfate (IS) is a toxin that accumulates in plasma when kidney function ...declines and contributes to the progression of chronic kidney disease. IS derives exclusively from the gut microbiota. Bacterial tryptophanases convert tryptophan to indole, which is absorbed and modified by the host to produce IS. Here, we identify a widely distributed family of tryptophanases in the gut commensal Bacteroides and find that deleting this gene eliminates the production of indole in vitro. By altering the status or abundance of the Bacteroides tryptophanase, we can modulate IS levels in gnotobiotic mice and in the background of a conventional murine gut community. Our results demonstrate that it is possible to control host IS levels by targeting the microbiota and suggest a possible strategy for treating renal disease.
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•Indole-producing tryptophanases (Tnases) in Bacteroides are identified computationally•Tnase activity and its control of indoxyl sulfate (IS) levels in vivo are established•Rational diet alteration in gnotobiotic mice with a synthetic community controls IS level•Colonization with Tnase-deficient Bacteroides lowers IS in conventional mice
Devlin et al. identify a widely distributed family of indole-producing tryptophanases in commensal gut bacteria. Using this information, they engineer bacteria to control in vivo production of the downstream product, the uremic toxin indoxyl sulfate. These results suggest a new strategy for treating chronic kidney disease by targeting the microbiome.
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