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Analysis of immune, microbiota and metabolome maturation in infants in a clinical trial of Lactobacillus paracasei CBA L74-fermented formula.
Roggero, P, Liotto, N, Pozzi, C, Braga, D, Troisi, J, Menis, C, Giannì, ML, Berni Canani, R, Paparo, L, Nocerino, R, et al
Nature communications. 2020;(1):2703
Abstract
Mother's milk is the best choice for infants nutrition, however when it is not available or insufficient to satisfy the needs of the infant, formula is proposed as an effective substitute. Here, we report the results of a randomized controlled clinical trial (NCT03637894) designed to evaluate the effects of two different dietary regimens (standard formula and Lactobacillus paracasei CBA L74-fermented formula) versus breastfeeding (reference group) on immune defense mechanisms (primary endpoint: secretory IgA, antimicrobial peptides), the microbiota and its metabolome (secondary outcomes), in healthy full term infants according to the type of delivery (n = 13/group). We show that the fermented formula, safe and well tolerated, induces an increase in secretory IgA (but not in antimicrobial peptides) and reduces the diversity of the microbiota, similarly, but not as much as, breastmilk. Metabolome analysis allowed us to distinguish subjects based on their dietary regimen and mode of delivery. Together, these results suggest that a fermented formula favors the maturation of the immune system, microbiota and metabolome.
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Metabolomic effects of androgen deprivation therapy treatment for prostate cancer.
Chi, JT, Lin, PH, Tolstikov, V, Oyekunle, T, Chen, EY, Bussberg, V, Greenwood, B, Sarangarajan, R, Narain, NR, Kiebish, MA, et al
Cancer medicine. 2020;(11):3691-3702
Abstract
Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT-associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3-hydroxybutyric acid and ketogenesis. Third, many acyl-carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3-formyl indole (a.k.a. indole-3-carboxaldehyde), a microbiota-derived metabolite from the dietary tryptophan. Indole-3-carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT-associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT-linked comorbidities and diabetes risk.
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The Food-gut Human Axis: The Effects of Diet on Gut Microbiota and Metabolome.
De Angelis, M, Garruti, G, Minervini, F, Bonfrate, L, Portincasa, P, Gobbetti, M
Current medicinal chemistry. 2019;(19):3567-3583
Abstract
Gut microbiota, the largest symbiont community hosted in human organism, is emerging as a pivotal player in the relationship between dietary habits and health. Oral and, especially, intestinal microbes metabolize dietary components, affecting human health by producing harmful or beneficial metabolites, which are involved in the incidence and progression of several intestinal related and non-related diseases. Habitual diet (Western, Agrarian and Mediterranean omnivore diets, vegetarian, vegan and gluten-free diets) drives the composition of the gut microbiota and metabolome. Within the dietary components, polymers (mainly fibers, proteins, fat and polyphenols) that are not hydrolyzed by human enzymes seem to be the main leads of the metabolic pathways of gut microbiota, which in turn directly influence the human metabolome. Specific relationships between diet and microbes, microbes and metabolites, microbes and immune functions and microbes and/or their metabolites and some human diseases are being established. Dietary treatments with fibers are the most effective to benefit the metabolome profile, by improving the synthesis of short chain fatty acids and decreasing the level of molecules, such as p-cresyl sulfate, indoxyl sulfate and trimethylamine N-oxide, involved in disease state. Based on the axis diet-microbiota-health, this review aims at describing the most recent knowledge oriented towards a profitable use of diet to provide benefits to human health, both directly and indirectly, through the activity of gut microbiota.
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Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children.
Patel, K, Lindsey, J, Angelidou, K, Aldrovandi, G, Palumbo, P, ,
AIDS (London, England). 2018;(16):2327-2336
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Abstract
OBJECTIVE The aim of this study was to estimate the long-term metabolic effects of initiating a lopinavir/ritonavir (LPV/r)-based regimen as a first-line therapy for HIV-infected children less than 3 years of age in resource-limited settings. DESIGN A prospective cohort study after conclusion of the P1060 randomized clinical trials (ClinicalTrials.gov Identifier: NCT00307151), with an overall follow-up of 7 years. METHODS Longitudinal total cholesterol and triglyceride measures were compared between 222 and 227 children randomized to initiate LPV/r and nevirapine (NVP)-based regimens, respectively. Adipokines (adiponectin and leptin) and biomarkers of inflammation [C-reactive protein and interleukin (IL)-6], microbial translocation (lipopolysaccharide) and immune activation (sCD14), measured in 117 participants at a median of 45 weeks of follow-up, were also compared by a randomized arm. RESULTS Mean total cholesterol and the percentage of participants with borderline or high total cholesterol was higher in the LPV/r arm from years 3 to 7 of follow-up than in the NVP arm (adjusted relative differences ranging from 10.9 to 23.4 mg/dl and adjusted relative risks ranging from a 60% increased risk to a more than four-fold increased risk for cholesterol ≥170 mg/dl at 7 years of follow-up). Initiation of a LPV/r-based regimen was not associated with high triglycerides over follow-up or large differences in markers of metabolic syndrome, inflammation, microbial translocation or immune activation. CONCLUSION Given the virologic superiority of LPV/r-based regimens in young children and open questions regarding the roll-out of dolutegravir in resource-limited settings, children are currently being maintained on LPV/r-based regimens. Our results suggest continual assessment of total cholesterol among young children initiating a LPV/r-based regimen to monitor cardiometabolic health.
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Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis.
Falconer, J, Murphy, AN, Young, SP, Clark, AR, Tiziani, S, Guma, M, Buckley, CD
Arthritis & rheumatology (Hoboken, N.J.). 2018;(7):984-999
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Abstract
Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast-like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset-specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early-stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.