Bloodless Gynecological Surgery in Blood Products Refusing Patients: Experience of a Single Institution.

Propose: This pilot study aimed to apply the central tenets of bloodless surgery and to analyze the effectiveness of specific preoperative, intraoperative, and postoperative strategies to minimize the risk for blood transfusion after gynecological surgery in a specific group of patients who refused blood products. Methods: A total of 83 patients undergoing gynecological surgery were included in the study. Forty-two patients received preoperatively oral iron, acid folic, and vitamin B12 supplementation in the 30 days before surgery, and 41 patients did not receive therapy. Results: No significant differences were found when comparing the two study groups. The implementation of all procedures to maintain a bloodless surgery has been helpful, in association with the other available procedures, in achieving optimal management and maintenance of hemoglobin levels, even in the most critical situations. Conclusion: In conclusion, implementing the bloodless approach as much as possible could guarantee the patient better and safer clinical and care management. Furthermore, well-designed research is required to clarify further the effects of bloodless surgery in gynecological patients.

Recommendations to Improve Quality of Probiotic Systematic Reviews With Meta-Analyses.

Importance: Systematic reviews and meta-analyses often report conflicting results when assessing evidence for probiotic efficacy, partially because of the lack of understanding of the unique features of probiotic trials. As a consequence, clinical decisions on the use of probiotics have been confusing. Objective: To provide recommendations to improve the quality and consistency of systematic reviews with meta-analyses on probiotics, so evidence-based clinical decisions can be made with more clarity. Evidence Review: For this consensus statement, an updated literature review was conducted (January 1, 2020, to June 30, 2022) to supplement a previously published 2018 literature search to identify areas where probiotic systematic reviews with meta-analyses might be improved. An expert panel of 21 scientists and physicians with experience on writing and reviewing probiotic reviews and meta-analyses was convened and used a modified Delphi method to develop recommendations for future probiotic reviews. Findings: A total of 206 systematic reviews with meta-analysis components on probiotics were screened and representative examples discussed to determine areas for improvement. The expert panel initially identified 36 items that were inconsistently reported or were considered important to consider in probiotic meta-analyses. Of these, a consensus was reached for 9 recommendations to improve the quality of future probiotic meta-analyses. Conclusions and Relevance: In this study, the expert panel reached a consensus on 9 recommendations that should promote improved reporting of probiotic systematic reviews with meta-analyses and, thereby, assist in clinical decisions regarding the use of probiotics.

Type 2-resistant starch and Lactiplantibacillus plantarum NCIMB 8826 result in additive and interactive effects in diet-induced obese mice.

Little is known about how combining a probiotic with prebiotic dietary fiber affects the ability of either biotic to improve health. We hypothesized that prebiotic, high-amylose maize type 2-resistant starch (RS) together with probiotic Lactiplantibacillus plantarum NCIMB8826 (LP) as a complementary synbiotic results in additive effects on the gut microbiota in diet-induced obese mice and other body sites. Diet-induced obese C57BL/6J male mice were fed a high-fat diet adjusted to contain RS (20% by weight), LP (109 cells every 48 hours), or both (RS+LP) for 6 weeks. As found for mice fed RS, cecal bacterial alpha diversity was significantly reduced in mice given RS+LP compared with those fed LP and high-fat controls. Similarly, both RS+LP and RS also conferred lower quantities of cecal butyrate and serum histidine and higher ileal TLR2 transcript levels and adipose tissue interleukin-6 protein. As found for mice fed LP, RS+LP-fed mice had higher colonic tissue TH17 cytokines, reduced epididymal fat immune and oxidative stress responses, reduced serum carnitine levels, and increased transcript quantities of hepatic carnitine palmitoyl transferase 1α. Notably, compared with RS and LP consumed separately, there were also synergistic increases in colonic glucose and hepatic amino acids as well antagonistic effects of LP on RS-mediated increases in serum adiponectin and urinary toxin levels. Our findings show that it is not possible to fully predict outcomes of synbiotic applications based on findings of the probiotic or the prebiotic tested separately; therefore, studies should be conducted to test new synbiotic formulations.

Calcium Determines Lactiplantibacillus plantarum Intraspecies Competitive Fitness.

The importance of individual nutrients for microbial strain robustness and coexistence in habitats containing different members of the same species is not well understood. To address this for Lactiplantibacillus plantarum in food fermentations, we performed comparative genomics and examined the nutritive requirements and competitive fitness for L. plantarum strains B1.1 and B1.3 isolated from a single sample of teff injera fermentation batter. Compared to B1.1 and other L. plantarum strains, B1.3 has a smaller genome, limited biosynthetic capacities, and large mobilome. Despite these differences, B1.3 was equally competitive with B1.1 in a suspension of teff flour. In commercially sourced, nutrient-replete MRS (cMRS) medium, strain B1.3 reached 3-fold-higher numbers than B1.1 within 2 days of passage. Because B1.3 growth and competitive fitness were poor in mMRS medium (here called mMRS), a modified MRS medium lacking beef extract, we used mMRS to identify nutrients needed for robust B1.3 growth. No improvement was observed when mMRS was supplemented with nucleotides, amino acids, vitamins, or monovalent metals. Remarkably, the addition of divalent metal salts increased the growth rate and cell yields of B1.3 in mMRS. Metal requirements were confirmed by inductively coupled plasma mass spectrometry, showing that total B1.3 intracellular metal concentrations were significantly (up to 2.7-fold) reduced compared to B1.1. Supplemental CaCl2 conferred the greatest effect, resulting in equal growth between B1.1 and B1.3 over five successive passages in mMRS. Moreover, calcium supplementation reversed a B1.3 strain-specific, stationary-phase, flocculation phenotype. These findings show how L. plantarum calcium requirements affect competitive fitness at the strain level. IMPORTANCE Ecological theory states that the struggle for existence is stronger between closely related species. Contrary to this assertion, fermented foods frequently sustain conspecific individuals, in spite of their high levels of phylogenetic relatedness. Therefore, we investigated two isolates of Lactiplantibacillus plantarum, B1.1 and B1.3, randomly selected from a single batch of teff injera batter. These strains spanned the known genomic and phenotypic range of the L. plantarum species, and in laboratory culture medium used for strain screening, B1.3 exhibited poor growth and was outcompeted by the more robust strain B1.1. Nonetheless, B1.1 and B1.3 were equally competitive in teff flour. This result shows how L. plantarum has adapted for coexistence in that environment. The capacity for the single macronutrient calcium to restore B1.3 competitive fitness in laboratory culture medium suggests that L. plantarum intraspecies diversity found in food systems is fine-tuned to nutrient requirements at the strain level.

A Classification System for Defining and Estimating Dietary Intake of Live Microbes in US Adults and Children.

BACKGROUND: Consuming live microbes in foods may benefit human health. Live microbe estimates have not previously been associated with individual foods in dietary databases. OBJECTIVES: We aimed to estimate intake of live microbes in US children (aged 2-18 y) and adults (≥19 y) (n = 74,466; 51.2% female). METHODS: Using cross-sectional data from the NHANES (2001-2018), experts assigned foods an estimated level of live microbes per gram [low (Lo), <104 CFU/g; medium (Med), 104-107 CFU/g; or high (Hi), >107 CFU/g]. Probiotic dietary supplements were also assessed. The mean intake of each live microbe category and the percentages of subjects who ate from each live microbe category were determined. Nutrients from foods with live microbes were also determined using the population ratio method. Because the Hi category comprised primarily fermented dairy foods, we also looked at aggregated data for Med or Hi (MedHi), which included an expanded range of live microbe-containing foods, including fruits and vegetables. RESULTS: Our analysis showed that 52%, 20%, and 59% of children/adolescents, and 61%, 26%, and 67% of adults, consumed Med, Hi, or MedHi foods, respectively. Per capita intake of Med, Hi, and MedHi foods was 69, 16, and 85 g/d for children/adolescents, and 106, 21, and 127 g/d for adults, respectively. The proportion of subjects who consumed live microbes and overall per capita intake increased significantly over the 9 cycles/18-y study period (0.9-3.1 g/d per cycle in children across categories and 1.4 g/d per cycle in adults for the Med category). CONCLUSIONS: This study indicated that children, adolescents, and adults in the United States steadily increased their consumption of foods with live microbes between the earliest (2001-2002) and latest (2017-2018) survey cycles. Additional research is needed to determine the relations between exposure to live microbes in foods and specific health outcomes or biomarkers.

Impact of Glucosamine Supplementation on Gut Health.

Glucosamine (GLU) is a natural compound found in cartilage, and supplementation with glucosamine has been shown to improve joint heath and has been linked to reduced mortality rates. GLU is poorly absorbed and may exhibit functional properties in the gut. The purpose of this study was to examine the impact of glucosamine on gastrointestinal function as well as changes in fecal microbiota and metabolome. Healthy males (n = 6) and females (n = 5) (33.4 ± 7.7 years, 174.1 ± 12.0 cm, 76.5 ± 12.9 kg, 25.2 ± 3.1 kg/m2, n = 11) completed two supplementation protocols that each spanned three weeks separated by a washout period that lasted two weeks. In a randomized, double-blind, placebo-controlled, crossover fashion, participants ingested a daily dose of GLU hydrochloride (3000 mg GlucosaGreen®, TSI Group Ltd., Missoula, MT, USA) or maltodextrin placebo. Study participants completed bowel habit and gastrointestinal symptoms questionnaires in addition to providing a stool sample that was analyzed for fecal microbiota and metabolome at baseline and after the completion of each supplementation period. GLU significantly reduced stomach bloating and showed a trend towards reducing constipation and hard stools. Phylogenetic diversity (Faith's PD) and proportions of Pseudomonadaceae, Peptococcaceae, and Bacillaceae were significantly reduced following GLU consumption. GLU supplementation significantly reduced individual, total branched-chain, and total amino acid excretion, with no glucosamine being detected in any of the fecal samples. GLU had no effect on fecal short-chain fatty acids levels. GLU supplementation provided functional gut health benefits and induced fecal microbiota and metabolome changes.

Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis.

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.

Should There Be a Recommended Daily Intake of Microbes?

The collective findings from human microbiome research, randomized controlled trials on specific microbes (i.e., probiotics), and associative studies of fermented dairy consumption provide evidence for the beneficial effects of the regular consumption of safe live microbes. To test the hypothesis that the inclusion of safe, live microbes in the diet supports and improves health, we propose assessment of the types and evidentiary quality of the data available on microbe intake, including the assembly and evaluation of evidence available from dietary databases. Such an analysis would help to identify gaps in the evidence needed to test this hypothesis, which can then be used to formulate and direct initiatives focused on prospective and randomized controlled trials on live microbe consumption. Outcomes will establish whether or not the evidence exists, or can be generated, to support the establishment of dietary recommendations for live microbes.

Prognostic impact of immune-microenvironment in colorectal liver metastases resected after triplets plus a biologic agent: A pooled analysis of five prospective trials.

BACKGROUND: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. METHODS: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. RESULTS: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. CONCLUSIONS: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.

PPARα-targeted mitochondrial bioenergetics mediate repair of intestinal barriers at the host-microbe intersection during SIV infection.

Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4+ T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the "leaky gut," which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic Lactobacillus plantarum into Simian immunodeficiency virus (SIV)-inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of L. plantarum administration, independent of mucosal CD4+ T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by L. plantarum-induced PPARα activation and restoration of mitochondrial structure and fatty acid ß-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.

The Role of the Gut Microbiome in Predicting Response to Diet and the Development of Precision Nutrition Models. Part II: Results.

The gut microbiota is increasingly implicated in the health and metabolism of its human host. The host's diet is a major component influencing the composition and function of the gut microbiota, and mounting evidence suggests that the composition and function of the gut microbiota influence the host's metabolic response to diet. This effect of the gut microbiota on personalized dietary response is a growing focus of precision nutrition research and may inform the effort to tailor dietary advice to the individual. Because the gut microbiota has been shown to be malleable to some extent, it may also allow for therapeutic alterations of the gut microbiota in order to alter response to certain dietary components. This article is the second in a 2-part review of the current research in the field of precision nutrition incorporating the gut microbiota into studies investigating interindividual variability in response to diet. Part I reviews the methods used by researchers to design and carry out such studies as well as analyze the results subsequently obtained. Part II reviews the findings of these studies and discusses the gaps in our current knowledge and directions for future research. The studies reviewed provide the current understanding in this field of research and a foundation from which we may build, utilizing and expanding upon the methods and results they present to inform future studies.

High-Amylose Maize, Potato, and Butyrylated Starch Modulate Large Intestinal Fermentation, Microbial Composition, and Oncogenic miRNA Expression in Rats Fed A High-Protein Meat Diet.

High red meat intake is associated with the risk of colorectal cancer (CRC), whereas dietary fibers, such as resistant starch (RS) seemed to protect against CRC. The aim of this study was to determine whether high-amylose potato starch (HAPS), high-amylose maize starch (HAMS), and butyrylated high-amylose maize starch (HAMSB)-produced by an organocatalytic route-could oppose the negative effects of a high-protein meat diet (HPM), in terms of fermentation pattern, cecal microbial composition, and colonic biomarkers of CRC. Rats were fed a HPM diet or an HPM diet where 10% of the maize starch was substituted with either HAPS, HAMS, or HAMSB, for 4 weeks. Feces, cecum digesta, and colonic tissue were obtained for biochemical, microbial, gene expression (oncogenic microRNA), and immuno-histochemical (O6-methyl-2-deoxyguanosine (O6MeG) adduct) analysis. The HAMS and HAMSB diets shifted the fecal fermentation pattern from protein towards carbohydrate metabolism. The HAMSB diet also substantially increased fecal butyrate concentration and the pool, compared with the other diets. All three RS treatments altered the cecal microbial composition in a diet specific manner. HAPS and HAMSB showed CRC preventive effects, based on the reduced colonic oncogenic miR17-92 cluster miRNA expression, but there was no significant diet-induced differences in the colonic O6MeG adduct levels. Overall, HAMSB consumption showed the most potential for limiting the negative effects of a high-meat diet.

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

Identification of potent bovine viral diarrhea virus inhibitors by a structure-based virtual screening approach.

Bovine viral diarrhea virus (BVDV) is a pestivirus whose infection in cattle is globally distributed. The use of antivirals could complement vaccination as a tool of control and reduce economic losses. The RNA-dependent RNA polymerase (RdRp) of the virus is essential for its genome replication and constitutes an attractive target for the identification of antivirals. With the aim of obtaining selective BVDV inhibitors, the crystal structure of BVDV RdRp was used to perform a virtual screening. Approximately 15,000 small molecules from commercial and in-house databases were evaluated and several structurally different compounds were tested in vitro for antiviral activity. Interestingly, of twelve evaluated compounds, five were active and displayed EC50 values in the sub and low-micromolar range. Time of drug addition experiment and measured intracellular BVDV RNA showed that compound 7 act during RNA synthesis. Molecular Dynamics and MM/PBSA calculation were done to characterize the interaction of the most active compounds with RdRp, which will allow future ligand optimization. These studies highlight the use of in silico screening to identify a new class of BVDV inhibitors.

Restaging Patients With Hepatocellular Carcinoma Before Additional Treatment Decisions: A Multicenter Cohort Study.

Prognostic assessment of patients with hepatocellular carcinoma (HCC) at the time of diagnosis remains controversial and becomes even more complex at the time of restaging when new variables need to be considered. The aim of the current study was to evaluate the prognostic utility of restaging patients before proceeding with additional therapies for HCC. Two independent Italian prospective databases were used to identify 1,196 (training cohort) and 648 (validation cohort) consecutive patients with HCC treated over the same study period (2008-2015) who had complete restaging before decisions about additional therapies. The performance of the Italian Liver Cancer (ITA.LI.CA) prognostic score at restaging was compared with that of the Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer, and Cancer of the Liver Italian Program systems. A multivariable Cox survival analysis was performed to identify baseline, restaging, or dynamic variables that were able to improve the predictive performance of the prognostic systems. At restaging, 35.3% of patients maintained stable disease; most patients were either down-staged by treatment (27.2%) or had disease progression (37.5%). The ITA.LI.CA scoring system at restaging demonstrated the best prognostic performance in both the training and validation cohorts (c-index 0.707 and 0.722, respectively) among all systems examined. On multivariable analysis, several variables improved the prognostic ability of the ITA.LI.CA score at restaging, including progressive disease after the first treatment, Model for End-Stage Liver Disease at restaging, and choice of nonsurgical treatment as additional therapy. A new ITA.LI.CA restaging model was created that demonstrated high discriminative power in both the training and validation cohorts (c-index 0.753 and 0.745, respectively). CONCLUSION: Although the ITA.LI.CA score demonstrated the best prognostic performance at restaging, other variables should be considered to improve the prognostic assessment of patients at the time of deciding additional therapies for HCC.

Supplementation of Lactobacillus plantarum Improves Markers of Metabolic Dysfunction Induced by a High Fat Diet.

Obesity is a prevalent chronic condition in many developed and developing nations that raises the risk for developing heart disease, stroke, and diabetes. Previous studies have shown that consuming particular probiotic strains of Lactobacillus is associated with improvement in the obese and diabetic phenotype; however, the mechanisms of these beneficial effects are not well understood. In this study, C57BL/6J male mice were fed a lard-based high fat diet for 15 weeks with Lactobacillus plantarum supplementation NCIMB8826 (Lp) between weeks 10 and 15 ( n = 10 per group). Systemic metabolic effects of supplementation were analyzed by NMR metabolomics, protein expression assays, gene transcript quantification, and 16S rRNA marker gene sequencing. Body and organ weights were not significantly different with Lp supplementation, and no microbiota community structure changes were observed in the cecum; however, L. plantarum numbers were increased in the treatment group according to culture-based and 16S rRNA gene quantification. Significant differences in metabolite and protein concentrations (serum, liver, and colon), gene expression (ileum and adipose), and cytokines (colon) were observed between groups with increases in the gene expression of tight junction proteins in the ileum and cecum and improvement of some markers of glucose homeostasis in blood and tissue with Lp supplementation. These results indicate Lp supplementation impacts systemic metabolism and immune signaling before phenotypic changes and without large-scale changes to the microbiome. This study supports the notion that Lp is a beneficial probiotic, even in the context of a high fat diet.

The Lactococcus lactis KF147 nonribosomal peptide synthetase/polyketide synthase system confers resistance to oxidative stress during growth on plant leaf tissue lysate.

Strains of Lactococcus lactis isolated from plant tissues possess adaptations that support their survival and growth in plant-associated microbial habitats. We previously demonstrated that genes coding for a hybrid nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS) system involved in production of an uncharacterized secondary metabolite are specifically induced in L. lactis KF147 during growth on plant tissues. Notably, this NRPS/PKS has only been identified in plant-isolated strains of L. lactis. Here, we show that the L. lactis KF147 NRPS/PKS genes have homologs in certain Streptococcus mutans isolates and the genetic organization of the NRPS/PKS locus is conserved among L. lactis strains. Using an L. lactis KF147 mutant deficient in synthesis of NrpC, a 4'-phosphopantetheinyl transferase, we found that the NRPS/PKS system improves L. lactis during growth under oxidative conditions in Arapidopsis thaliana leaf lysate. The NRPS/PKS system also improves tolerance of L. lactis to reactive oxygen species and specifically H2 O2 and superoxide radicals in culture medium. These findings indicate that this secondary metabolite provides a novel mechanism for reactive oxygen species detoxification not previously known for this species.

Effect of Antibiotics and Diet on Enterolactone Concentration and Metabolome Studied by Targeted and Nontargeted LC-MS Metabolomics.

High plant lignan intake is associated with a number of health benefits, possibly induced by the lignan metabolite enterolactone (ENL). The gut microbiota plays a crucial role in converting dietary lignans into ENL, and epidemiological studies have shown that use of antibiotics is associated with lower levels of ENL. Here we investigate the link between antibiotic use and lignan metabolism in pigs using LC-MS/MS. The effect of lignan intake and antibiotic use on the gut microbial community and the pig metabolome is studied by 16S rRNA sequencing and nontargeted LC-MS. Treatment with antibiotics resulted in substantially lower concentrations of ENL compared with concentrations detected in untreated animals, whereas the plasma concentrations of plant lignans were unchanged. Both diet and antibiotic treatment affected the clustering of urinary metabolites and significantly altered the proportions of taxa in the gut microbiota. Diet, but not antibiotic treatment, affected the plasma lipid profile, and a lower concentration of LDL cholesterol was observed in the pigs fed a high lignan diet. This study provides solid support for the associations between ENL concentrations and use of antibiotics found in humans and indicates that the lower ENL concentration may be a consequence of the ecological changes in the microbiota.

Curative therapies are superior to standard of care (transarterial chemoembolization) for intermediate stage hepatocellular carcinoma.

BACKGROUND & AIMS: The Barcelona Clinic Liver Cancer intermediate stage (BCLC-B) of hepatocellular carcinoma (HCC) includes extremely heterogeneous patients in terms of tumour burden and liver function. Transarterial-chemoembolization (TACE) is the first-line treatment for these patients although it may be risky/useless for someone, while others could undergo curative treatments. This study assesses the treatment type performed in a large cohort of BCLC-B patients and its outcome. METHODS: Retrospective analysis of 485 consecutive BCLC-B patients from the ITA.LI.CA database diagnosed with naïve HCC after 1999. Patients were stratified by treatment. RESULTS: 29 patients (6%) were lost to follow-up before receiving treatment. Treatment distribution was: TACE (233, 51.1%), curative treatments (145 patients, 31.8%), sorafenib (18, 3.9%), other (39, 8.5%), best supportive care (BSC) (21, 4.6%). Median survival (95% CI) was 45 months (37.4-52.7) for curative treatments, 30 (24.7-35.3) for TACE, 14 (10.5-17.5) for sorafenib, 14 (5.2-22.7) for other treatments and 10 (6.0-14.2) for BSC (P<.0001). Independent prognosticators were gender and treatment. Curative treatments reduced mortality (HR 0.197, 95%CI: 0.098-0.395) more than TACE (HR 0.408, 95%CI: 0.211-0.789) (P<.0001) as compared with BSC. Propensity score matching confirmed the superiority of curative therapies over TACE. CONCLUSIONS: In everyday practice TACE represents the first-line therapy in an half of patients with naïve BCLC-B HCC since treatment choice is driven not only by liver function and nodule characteristics, but also by contraindications to procedures, comorbidities, age and patient opinion. The treatment type is an independent prognostic factor in BCLC-B patients and curative options offer the best outcome.

Obese Mice Fed a Diet Supplemented with Enzyme-Treated Wheat Bran Display Marked Shifts in the Liver Metabolome Concurrent with Altered Gut Bacteria.

BACKGROUND: Enzyme-treated wheat bran (ETWB) contains a fermentable dietary fiber previously shown to decrease liver triglycerides (TGs) and modify the gut microbiome in mice. It is not clear which mechanisms explain how ETWB feeding affects hepatic metabolism, but factors (i.e., xenometabolites) associated with specific microbes may be involved. OBJECTIVE: The objective of this study was to characterize ETWB-driven shifts in the cecal microbiome and to identify correlates between microbial changes and diet-related differences in liver metabolism in diet-induced obese mice that typically display steatosis. METHODS: Five-week-old male C57BL/6J mice fed a 45%-lard-based fat diet supplemented with ETWB (20% wt:wt) or rapidly digestible starch (control) (n = 15/group) for 10 wk were characterized by using a multi-omics approach. Multivariate statistical analysis was used to identify variables that were strong discriminators between the ETWB and control groups. RESULTS: Body weight and liver TGs were decreased by ETWB feeding (by 10% and 25%, respectively; P < 0.001), and an index of liver reactive oxygen species was increased (by 29%; P < 0.01). The cecal microbiome showed an increase in Bacteroidetes (by 42%; P < 0.05) and a decrease in Firmicutes (by 16%; P < 0.05). Metabolites that were strong discriminators between the ETWB and control groups included decreased liver antioxidants (glutathione and α-tocopherol); decreased liver carbohydrate metabolites, including glucose; lower hepatic arachidonic acid; and increased liver and plasma ß-hydroxybutyrate. Liver transcriptomics revealed key metabolic pathways affected by ETWB, especially those related to lipid metabolism and some fed- or fasting-regulated genes. CONCLUSIONS: Together, these changes indicate that dietary fibers such as ETWB regulate hepatic metabolism concurrently with specific gut bacteria community shifts in C57BL/6J mice. It is proposed that these changes may elicit gut-derived signals that reach the liver via enterohepatic circulation, ultimately affecting host liver metabolism in a manner that mimics, in part, the fasting state.