Adlercreutzia equolifaciens Is an Anti-Inflammatory Commensal Bacterium with Decreased Abundance in Gut Microbiota of Patients with Metabolic Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) affects about 20-40% of the adult population in high-income countries and is now a leading indication for liver transplantation and can lead to hepatocellular carcinoma. The link between gut microbiota dysbiosis and NAFLD is now clearly established. Through analyses of the gut microbiota with shotgun metagenomics, we observe that compared to healthy controls, Adlercreutzia equolifaciens is depleted in patients with liver diseases such as NAFLD. Its abundance also decreases as the disease progresses and eventually disappears in the last stages indicating a strong association with disease severity. Moreover, we show that A. equolifaciens possesses anti-inflammatory properties, both in vitro and in vivo in a humanized mouse model of NAFLD. Therefore, our results demonstrate a link between NAFLD and the severity of liver disease and the presence of A. equolifaciens and its anti-inflammatory actions. Counterbalancing dysbiosis with this bacterium may be a promising live biotherapeutic strategy for liver diseases.

Risk Factors Associated With Femorotomy or Fracture During Cementless Stem Removal and Generation of an Individual Predictive Risk Score.

BACKGROUND: Femorotomy is a commonly used technique during cementless stem removal but should be preferred in selective revision cases to prevent intraoperative femoral fracture associated with deteriorated clinical outcome. Our aim was to assess the risk factors for fracture or femorotomy and develop a predictive risk stratification score. METHODS: A monocentric retrospective cohort including 202 patients was analyzed. Thirty six candidate prognostic factors were assessed. RESULTS: The following independent predictors of fracture or femorotomy were identified: presence of a "bracket sign" (Odds Ratio [OR]: 10.857; 95% Confidence interval [CI]: 2.613-45.115; P = .001) defined as a distal spot weld between the surface of the implant and closest endosteum, bone contact in zone 2 (OR: 4.700; 95% CI: 1.827-12.089; P = .001), 6 (OR: 4.966; 95% CI: 1.823-13.530; P = .002), 12 (OR: 9.660; 95% CI: 3.715-25.116; P < .0001), 13 (OR: 2.958; 95% CI: 1.009-8.021; P = .033), and global hypertrophy (OR: 0.170; 95% CI: 0.036-0.806; P = .026). The prognostic score, named Femorotomy INcidence Numeric scoring system, had good performance and discriminability; the area under the curve of the model was 0.924 (95% CI: 0.878-0.969). CONCLUSION: The only independent risk factors were those assessed on X-ray (eg, bracket sign, bone contact in zones 2, 6, 12, and 13), while global hypertrophy was protective. We noticed the importance of differentiating pedestals and "bracket signs"; the latter is an indicator of fixation of the stem. We developed a risk prediction score (Femorotomy INcidence Numeric score) of fracture or femorotomy that can be used as a companion tool to assess the risk for doing an early osteotomy of the femur.

Alteration of microbiota antibody-mediated immune selection contributes to dysbiosis in inflammatory bowel diseases.

Human secretory immunoglobulins (SIg) A1 and SIgA2 guide mucosal responses toward tolerance or inflammation, notably through reverse-transcytosis, the apical-to-basal transport of IgA2 immune complexes via M cells of gut Peyer's patches. As such, the maintenance of a diverse gut microbiota requires broad affinity IgA and glycan-glycan interaction. Here, we asked whether IgA1 and IgA2-microbiota interactions might be involved in dysbiosis induction during inflammatory bowel diseases. Using stool HPLC-purified IgA, we show that reverse-transcytosis is abrogated in ulcerative colitis (UC) while it is extended to IgA1 in Crohn's disease (CD). 16S RNA sequencing of IgA-bound microbiota in CD and UC showed distinct IgA1- and IgA2-associated microbiota; the IgA1+ fraction of CD microbiota was notably enriched in beneficial commensals. These features were associated with increased IgA anti-glycan reactivity in CD and an opposite loss of reactivity in UC. Our results highlight previously unknown pathogenic properties of IgA in IBD that could support dysbiosis.

Fecal microbiome as determinant of the effect of diet on colorectal cancer risk: comparison of meat-based versus pesco-vegetarian diets (the MeaTIc study).

BACKGROUND: Convincing evidence suggests that the risk of colorectal cancer (CRC) is increased by the typical Western diet characterized by high consumption of red and processed meat. In addition, some epidemiological studies suggest a reduction in the risk of CRC associated with fish consumption. The role of the gut microbiome in this diet-associated risk is not well understood. METHODS/DESIGN: This is a randomized parallel open clinical trial comprising a total of 150 clinically healthy subjects randomly assigned to three groups: a meat-based diet of which 4 portions per week are red meat (1 portion = 150 g), 3 portions per week are processed meat (1 portion = 50 g), and 1 portion per week is poultry (1 portion = 150 g), for a total amount of 900 g per week of meat and derivatives; a meat-based diet supplemented with alpha-tocopherol; and a pesco-vegetarian diet excluding fresh and processed meat and poultry, but which includes 3 portions per week of fish for a total amount of 450 g per week. Each intervention will last 3 months. The three diets will be isocaloric and of three different sizes according to specific energy requirements. Anthropometric measurements, body composition, and blood and fecal samples will be obtained from each participant at the beginning and end of each intervention phase. The measure of the primary outcome will be the change from baseline in DNA damage induced by fecal water using the comet assay in a cellular model. Secondary outcome measures will be changes in the profile of fecal microbiomes, global fecal and urinary peroxidation markers, and neoplastic biomarkers. DISCUSSION: Although epidemiological data support the promoting role of meat and the possible protective role of fish in colon carcinogenesis, no study has directly compared dietary profiles characterized by the presence of these two food groups and the role of the gut microbiome in these diet-associated CRC risks. This study will test the effect of these dietary profiles on validated CRC risk biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03416777. Registered on 3 May 2018.

Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism.

Current fructose consumption levels often overwhelm the intestinal capacity to absorb fructose. We investigated the impact of fructose malabsorption on intestinal endocrine function and addressed the role of the microbiota in this process. To answer this question, a mouse model of moderate fructose malabsorption [ketohexokinase mutant (KHK)-/-] and wild-type (WT) littermate mice were used and received a 20%-fructose (KHK-F and WT-F) or 20%-glucose diet. Cholecystokinin (Cck) mRNA and protein expression in the ileum and cecum, as well as preproglucagon (Gcg) and neurotensin (Nts) mRNA expression in the cecum, increased in KHK-F mice. In KHK-F mice, triple-label immunohistochemistry showed major up-regulation of CCK in enteroendocrine cells (EECs) that were glucagon-like peptide-1 (GLP-1)+/Peptide YY (PYY-) in the ileum and colon and GLP-1-/PYY- in the cecum. The cecal microbiota composition was drastically modified in the KHK-F in association with an increase in glucose, propionate, succinate, and lactate concentrations. Antibiotic treatment abolished fructose malabsorption-dependent induction of cecal Cck mRNA expression and, in mouse GLUTag and human NCI-H716 cells, Cck mRNA expression levels increased in response to propionate, both suggesting a microbiota-dependent process. Fructose reaching the lower intestine can modify the composition and metabolism of the microbiota, thereby stimulating the production of CCK from the EECs possibly in response to propionate.-Zhang, X., Grosfeld, A., Williams, E., Vasiliauskas, D., Barretto, S., Smith, L., Mariadassou, M., Philippe, C., Devime, F., Melchior, C., Gourcerol, G., Dourmap, N., Lapaque, N., Larraufie, P., Blottière, H. M., Herberden, C., Gerard, P., Rehfeld, J. F., Ferraris, R. P., Fritton, J. C., Ellero-Simatos, S., Douard, V. Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism.

Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects.

BACKGROUND: The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms. OBJECTIVES: This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk. METHODS: We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings). RESULTS: The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk. CONCLUSIONS: The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.

Reduced obesity, diabetes, and steatosis upon cinnamon and grape pomace are associated with changes in gut microbiota and markers of gut barrier.

Increasing evidence suggests that polyphenols have a significant potential in the prevention and treatment of risk factors associated with metabolic syndrome. The objective of this study was to assess the metabolic outcomes of two polyphenol-containing extracts from cinnamon bark (CBE) and grape pomace (GPE) on C57BL/6J mice fed a high-fat diet (HFD) for 8 wk. Both CBE and GPE were able to decrease fat mass gain and adipose tissue inflammation in mice fed a HFD without reducing food intake. This was associated with reduced liver steatosis and lower plasma nonesterified fatty acid levels. We also observed a beneficial effect on glucose homeostasis, as evidenced by an improved glucose tolerance and a lower insulin resistance index. These ameliorations of the overall metabolic profile were associated with a significant impact on the microbial composition, which was more profound for the GPE than for the CBE. At the genus level, Peptococcus were decreased in the CBE group. In the GPE-treated group, several key genera that have been previously found to be linked with HFD, metabolic effects, and gut barrier integrity were affected: we observed a decrease of Desulfovibrio, Lactococcus, whereas Allobaculum and Roseburia were increased. In addition, the expression of several antimicrobial peptides and tight junction proteins was increased in response to both CBE and GPE supplementation, indicating an improvement of the gut barrier function. Collectively, these data suggest that CBE and GPE can ameliorate the overall metabolic profile of mice on a high-fat diet, partly by acting on the gut microbiota.

Microbiota, Liver Diseases, and Alcohol.

Being overweight and obesity are the leading causes of liver disease in Western countries. Liver damage induced by being overweight can range from steatosis, harmless in its simple form, to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol consumption is an additional major cause of liver disease. Not all individuals who are overweight or excessively consume alcohol develop nonalcoholic fatty liver diseases (NAFLD) or alcoholic liver disease (ALD) and advanced liver disease. The role of the intestinal microbiota (IM) in the susceptibility to liver disease in this context has been the subject of recent studies. ALD and NAFLD appear to be influenced by the composition of the IM, and dysbiosis is associated with ALD and NAFLD in rodent models and human patient cohorts. Several microbial metabolites, such as short-chain fatty acids and bile acids, are specifically associated with dysbiosis. Recent studies have highlighted the causal role of the IM in the development of liver diseases, and the use of probiotics or prebiotics improves some parameters associated with liver disease. Several studies have made progress in deciphering the mechanisms associated with the modulation of the IM. These data have demonstrated the intimate relationship between the IM and metabolic liver disease, suggesting that targeting the gut microbiota could be a new preventive or therapeutic strategy for these diseases.

Cystathionine ß-synthase genetic variant rs2124459 is associated with a reduced risk of cleft palate in French and Belgian populations.

BACKGROUND: Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B12 metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways. OBJECTIVE: We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism. METHODS: We performed a case-control discovery study on children with OFC (236 cases, 145 controls) and their related mothers (186 cases, 127 controls). We performed a replication study on the top significant genetic variant in an independent group from Belgium (248 cases, 225 controls). RESULTS: In the discovery study on 'mothers', the CBS locus reached array-wide significance (p=9.13×10-6; Bonferroni p=4.77×10-3; OR 0.47 (0.33 to 0.66)) among the 519 haplotypes tested for their association with OFC risk. Within the CBS haplotype block (rs2124459, rs6586282, rs4920037, rs234705, rs234709), the rs2124459 was the most significantly associated with a reduced risk of OFC (p=1.77×10-4; Bonferroni p=2.00×10-2; OR 0.53 (0.38 to 0.74), minor allele). The rs2124459 was associated with a reduced risk of cleft palate (CP) (p=6.78×10-5; Bonferroni p=7.80×10-3; OR 0.40 (0.25 to 0.63)). In the 'children' group, the rs2124459 was associated with a reduced risk of CP (p=0.02; OR 0.61 (0.40 to 0.93), minor allele). The association between rs2124459 and reduced risk of CP was replicated in an independent children population from Belgium (p=0.02; OR 0.64 (0.44 to 0.93), minor allele). CONCLUSIONS: The CBS rs2124459 was associated with a reduced risk of CP in both French and Belgian populations. These results highlight the prominent involvement of the vitamin B6-dependent transsulfuration pathway of homocysteine in OFC risk and the interest for evaluating vitamin B6 status in further population studies.

Association of IL1B polymorphism with left ventricular systolic dysfunction: a relation with the release of interleukin-1ß in stress condition.

OBJECTIVE: Proinflammatory cytokines play a major role in the pathomechanisms of heart failure. Besides this, the influence of mental stress on heart failure is poorly documented despite its effects on sympathetic stimulation of interleukin-1ß (IL-1ß) secretion. We examined whether the polymorphisms of proinflammatory cytokines are predictors of left ventricular systolic dysfunction (LVSD) and if so, whether such associations are related to the secretion of these cytokines, in 572 consecutive patients under mental stress produced by coronary angiography. METHODS: We examined IL-1RN (VNTR), IL1A-889 C>T, IL1B-511 C>T, IL6-174 G>C and TNFA-308 G>A, according to LVSD (left ventricular ejection fraction, <40%). Saliva IL-1ß, serum tumour necrosis factor-α and C-reactive protein were assayed in basal (T0 and T2, before and after coronary angiography) and stress (T1) conditions. MAIN RESULTS: The 42.1% of patients with LVSD had a 1.5-fold higher frequency of IL1B T allele (P<0.001). IL1B-511TT was associated with LVSD (P=0.008) and with a decrease in IL-1ß level in saliva at T1 (P=0.013). IL-1ß was the highest at T1 (P<0.001) and was associated with left ventricular ejection fraction (P=0.002). The IL1B TT genotype and the C-reactive protein were the two independent predictors of LVSD in multivariate analysis, with an odds ratio of 2.7 (95% confidence interval: 1.3-5.5; P=0.008) and 1.1 (95% confidence interval: 1.1-1.2; P<0.001), respectively. CONCLUSION: IL1B was a predictor of LVSD and of the decreased IL-1ß response to stress. This suggests that IL1B exerts an influence on LVSD through its effect on IL-1ß secretion.

Modeling of the angular tolerancing of an effective medium diffractive lens using combined finite difference time domain and radiation spectrum method algorithms.

A new rigorous vector-based design and analysis approach of diffractive lenses is presented. It combines the use of two methods: the Finite-Difference Time-Domain for the study in the near field, and the Radiation Spectrum Method for the propagation in the far field. This approach is proposed to design and optimize effective medium cylindrical diffractive lenses for high efficiency structured light illumination systems. These lenses are realised with binary subwavelength features that cannot be designed using the standard scalar theory. Furthermore, because of their finite and high frequencies characteristics, such devices prevent the use of coupled wave theory. The proposed approach is presented to determine the angular tolerance in the cases of binary subwavelength cylindrical lenses by calculating the diffraction efficiency as a function of the incidence angle.

Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: a multicenter case-control study.

Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6.

Effects of vitamin B12 and folate deficiencies on DNA methylation and carcinogenesis in rat liver.

Deficiencies of the major dietary sources of methyl groups, methionine and choline, lead to the formation of liver cancer in rodents. The most widely investigated hypothesis has been that dietary methyl insufficiency results in abnormal DNA methylation. Vitamin B12 and folate also play important roles in DNA methylation since these two coenzymes are required for the synthesis of methionine and S-adenosyl methionine, the common methyl donor required for the maintenance of methylation patterns in DNA. The aim of this study was to review the effects of methyl-deficient diets on DNA methylation and liver carcinogenesis in rats, and to evaluate the role of vitamin B12 status in defining carcinogenicity of a methyl-deficient diet. Several studies have shown that a methyl-deficient diet influences global DNA methylation. Evidence from in vivo studies has not clearly established a link between vitamin B12 and DNA methylation. We reported that vitamin B12 and low methionine synthase activity were the two determinants of DNA hypomethylation. Choline- or choline/methionine-deficient diets have been shown to cause hepatocellular carcinoma in 20-50% of animals after 12-24 months. In contrast, the effect of vitamin B12 withdrawal, in addition to choline, methionine and folate, induced hepatocellular carcinoma in less than 5% of rats.

Membrane topology of the Streptococcus pneumoniae FtsW division protein.

The topology of FtsW from Streptococcus pneumoniae, an essential membrane protein involved in bacterial cell division, was predicted by computational methods and probed by the alkaline phosphatase fusion and cysteine accessibility techniques. Consistent results were obtained for the seven N-terminal membrane-spanning segments. However, the results from alkaline phosphatase fusions did not confirm the hydropathy analysis of the C-terminal part of FtsW, whereas the accessibility of introduced cysteine residues was in agreement with the theoretical prediction. Based on the combined results, we propose the first topological model of FtsW, featuring 10 membrane-spanning segments, a large extracytoplasmic loop, and both N and C termini located in the cytoplasm.