Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms.

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.

Alcohol-Induced Immune Dysregulation in the Colon Is Diurnally Variable.

INTRODUCTION: Alcohol increases the risk of colon cancer. Colonic inflammation mediates the effects of alcohol on colon carcinogenesis. Circadian rhythm disruption enhances the alcohol's effect on colonic inflammation and cancer. OBJECTIVE: Here, we investigate the diurnal variation of lymphocyte infiltration in the colonic mucosa in response to alcohol. METHODS: Sixty C57BL6/J mice were fed a chow diet, and gavaged with alcohol at a specific time once per day for 3 consecutive days. Immunohistochemistry and immunofluorescence staining were used to quantify total, effector, and regulatory T cells in the colon. Student's t test, one-way ANOVA, and two-way ANOVA were used to determine significance. RESULTS: Following the alcohol binge, the composition of immune T cell subsets in the mouse colon was time-dependent. Alcohol did not alter the total number of CD3+ T cells. However, upon alcohol treatment, T-bet+ T helper 1 (Th1) cells appeared to dominate the T cell population following a reduction in Foxp3+ regulatory T cell (Treg) numbers. Depletion of Tregs was time-dependent, and their numbers were dramatically reduced when alcohol was administered during the rest phase. A reduction in Tregs significantly increased the Th1/Treg ratio, resulting in a more proinflammatory milieu. CONCLUSIONS: Alcohol enhanced the proinflammatory profile in the colon mucosa, as demonstrated by a higher T-bet+/Foxp3+ ratio, especially during the rest phase. These findings may partly account for the interaction of circadian rhythm disruption with alcohol in colon inflammation and cancer.

Alcohol Effects on Colon Epithelium are Time-Dependent.

BACKGROUND: Alcohol intake increases the risk of developing colon cancer. Circadian disruption promotes alcohol's effect on colon carcinogenesis through unknown mechanisms. Alcohol's metabolites induce DNA damage, an early step in carcinogenesis. We assessed the effect of time of alcohol consumption on markers of tissue damage in the colonic epithelium. METHODS: Mice were treated by alcohol or phosphate-buffered saline (PBS), at 4-hour intervals for 3 days, and their colons were analyzed for (i) proliferation (Ki67) and antiapoptosis (Bcl-2) markers, (ii) DNA damage (γ-H2AX), and (iii) the major acetaldehyde (AcH)-DNA adduct, N2 -ethylidene-dG. To model circadian disruption, mice were shifted once weekly for 12 h and then were sacrificed at 4-hour intervals. Samples of mice with a dysfunctional molecular clock were analyzed. The dynamics of DNA damage repair from AcH treatment as well as role of xeroderma pigmentosum, complementation group A (XPA) in their repair were studied in vitro. RESULTS: Proliferation and survival of colonic epithelium have daily rhythmicity. Alcohol induced colonic epithelium proliferation in a time-dependent manner, with a stronger effect during the light/rest period. Alcohol-associated DNA damage also occurred more when alcohol was given at light. Levels of DNA adduct did not vary by time, suggesting rather lower repair efficiency during the light versus dark. XPA gene expression, a key excision repair gene, was time-dependent, peaking at the beginning of the dark. XPA knockout colon epithelial cells were inefficient in repair of the DNA damage induced by alcohol's metabolite. CONCLUSIONS: Time of day of alcohol intake may be an important determinant of colon tissue damage and carcinogenicity.

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus.

Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-ß, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.

A reduced factor structure for the PROQOL-HIV questionnaire provided reliable indicators of health-related quality of life.

OBJECTIVES: To identify a simplified factor structure for the PROQOL-human immunodeficiency virus (HIV) questionnaire to improve the measurement of the health-related quality of life (HRQL) of HIV-positive patients in clinical care and research settings. STUDY DESIGN AND SETTING: HRQL data were collected using the eight-dimension PROQOL-HIV questionnaire from 2,537 patients (VESPA2 study). Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) validated a simpler four-factor structure and assessed measurement invariance (MI). Multigroup analysis assessed the effect of sex, age, and antiretroviral therapy (ART) on the resulting factor scores. Correlations with symptom and Short Form (SF)-12 self-reports assessed convergent validity. RESULTS: Item analysis, EFA, and CFAs confirmed the validity [comparative fit index (CFI), 0.948; root mean square error of approximation, 0.064] and reliability (α's ≥ 0.8) of four dimensions: physical health and symptoms, health concerns and mental distress, social and intimate relationships, and treatment-related impact. Strong MI was demonstrated across sex and age (decrease in CFI <0.01). A multiple-cause multiple-indicator model indicated that HRQL correlated as expected with sex, age, and the ART status. Correlations of HRQL, symptom reports, and SF-12 scores evidenced convergent validity criterion. CONCLUSION: The simplified factor structure and scoring scheme for PROQOL-HIV will allow clinicians to monitor with greater reliability the HRQL of patients in clinical care and research settings.

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Psychometric assessment of health-related quality of life and symptom experience in HIV patients treated with antiretroviral therapy.

PURPOSE: Symptoms which are found to cluster consistently can have synergistic effects on patient outcomes and therefore may serve to predict morbidity or disentangle disease progression from comorbid conditions. Self-report HIV-specific symptom and HRQL measures were jointly analyzed in HIV-positive patients under different antiretroviral treatment regimens. METHODS: The responses of N = 365 patients from four countries to the 9-item Physical Health and Symptom dimension of the PROOQL-HIV questionnaire and an HIV Symptom checklist were analyzed. Item response modeling and multidimensional scaling were used to derive HRQL scores free of any differential item functioning related to gender and target language and to summarize symptom co-expression in patients under protease inhibitor treatment(PI, N = 164, 45%) versus other medication (Non-PI). RESULTS: Women reported poorer HRQL (p = 0:037), and HRQL did not differ between the target languages of French, English, and Thai. Fatigue, muscular pain, or difficulties falling asleep was the most frequently reported symptoms [35%). PI versus Non-PI patients exhibited different pattern of symptoms with lipodystrophy-related and gastrointestinal symptoms forming well-separated clusters in the PI group. A higher number of symptoms were associated with lower HRQL (p < 0:001), and patients taking PIs reported lower HRQL (p = 0:003). Patients in both groups who reported fatigue, sexual dysfunction, or several lipodystrophy-related symptoms had poorer quality of life.

The development of PROQOL-HIV: an international instrument to assess the health-related quality of life of persons living with HIV/AIDS.

OBJECTIVES: Health-related quality of life (HRQL) is an important outcome in HIV/AIDS infection and treatment. However, most existing HIV-HRQL instruments miss important issues (eg, sleeping problems, lipodystrophy). They were developed before highly active antiretroviral therapy (pre-HAART), and in a single language. We sought to develop a contemporary HIV-HRQL instrument (PROQOL-HIV) in multiple languages that accounts for HAART treatment and side effects. This article details the 3-stage content validation phase of PROQOL-HIV. METHODS: In stage 1, we developed a conceptual model of HIV-HRQL and questionnaire item bank from thematic analysis of 152 patient interviews conducted simultaneously across 9 countries. In stage 2, pilot items were selected by an expert panel to form the pilot instrument. Stage 3 involved linguistic validation and harmonization of selected items to form an equivalent instrument in 9 target languages. RESULTS: Analysis of 3375 pages of interview text revealed 11 underlying themes: general health perception, social relationships, emotions, energy/fatigue, sleep, cognitive functioning, physical and daily activity, coping, future, symptoms, and treatment. Seven issues new to HIV-HRQL measurement were subsumed by these themes: infection fears, future concerns, satisfaction with care, self-esteem problems, sleep problems, work disruption, and treatment issues. Of the 442 theme-related items banked, 70 items met the retention criteria and formed the pilot PROQOL-HIV instrument. CONCLUSIONS: HIV patients across 11 countries attributed a wide range of physical, mental, and social issues to their condition, many of which were not measured by existing HIV-HRQL instruments. The pilot PROQOL-HIV instrument captures these issues, is sensitive to sociocultural context, disease stage, and HAART.

Australian adults use complementary and alternative medicine in the treatment of chronic illness: a national study.

OBJECTIVES: The objectives of this study were to identify the prevalence of the use of vitamin/mineral supplements or natural/herbal remedies, concurrent use of pharmaceutical medication, and to profile those most likely to use these complementary and alternative medicines (CAM) in the treatment of five chronic conditions identified as national health priorities (asthma, diabetes, arthritis, osteoporosis, heart or circulatory condition) within the Australian adult population. METHODS: Analysis of the Australian National Health Survey database, 2004-05. RESULTS: Approximately 24% (1.3 million) of Australian adults with a chronic condition regularly applied CAM to treatment. CAM was most often used exclusively or in combination with pharmaceutical medicine in the treatment of arthritis and osteoporosis. Fewer than 10% of adults with asthma, diabetes or a heart or circulatory condition used CAM, most preferring pharmaceutical medicine. Regular CAM users were more likely to be aged ≥60, female, have a secondary school education and live in households with lower incomes than non-users. Non-users were more likely to be 30-59 years old and tertiary educated. CONCLUSION AND IMPLICATIONS: Arthritis, osteoporosis and, to a lesser extent, heart or circulatory conditions are illnesses for which doctors should advise, and patients need to be most aware about the full effects of CAM and possible interactive effects with prescribed medicine. They are also conditions for which research into the interactive effects of CAM and pharmaceutical medication would seem of most immediate benefit.