Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle.

The body-wide human microbiome plays a role in health, but its full diversity remains uncharacterized, particularly outside of the gut and in international populations. We leveraged 9,428 metagenomes to reconstruct 154,723 microbial genomes (45% of high quality) spanning body sites, ages, countries, and lifestyles. We recapitulated 4,930 species-level genome bins (SGBs), 77% without genomes in public repositories (unknown SGBs [uSGBs]). uSGBs are prevalent (in 93% of well-assembled samples), expand underrepresented phyla, and are enriched in non-Westernized populations (40% of the total SGBs). We annotated 2.85 M genes in SGBs, many associated with conditions including infant development (94,000) or Westernization (106,000). SGBs and uSGBs permit deeper microbiome analyses and increase the average mappability of metagenomic reads from 67.76% to 87.51% in the gut (median 94.26%) and 65.14% to 82.34% in the mouth. We thus identify thousands of microbial genomes from yet-to-be-named species, expand the pangenomes of human-associated microbes, and allow better exploitation of metagenomic technologies.

The person-to-person transmission landscape of the gut and oral microbiomes.

The human microbiome is an integral component of the human body and a co-determinant of several health conditions1,2. However, the extent to which interpersonal relations shape the individual genetic makeup of the microbiome and its transmission within and across populations remains largely unknown3,4. Here, capitalizing on more than 9,700 human metagenomes and computational strain-level profiling, we detected extensive bacterial strain sharing across individuals (more than 10 million instances) with distinct mother-to-infant, intra-household and intra-population transmission patterns. Mother-to-infant gut microbiome transmission was considerable and stable during infancy (around 50% of the same strains among shared species (strain-sharing rate)) and remained detectable at older ages. By contrast, the transmission of the oral microbiome occurred largely horizontally and was enhanced by the duration of cohabitation. There was substantial strain sharing among cohabiting individuals, with 12% and 32% median strain-sharing rates for the gut and oral microbiomes, and time since cohabitation affected strain sharing more than age or genetics did. Bacterial strain sharing additionally recapitulated host population structures better than species-level profiles did. Finally, distinct taxa appeared as efficient spreaders across transmission modes and were associated with different predicted bacterial phenotypes linked with out-of-host survival capabilities. The extent of microorganism transmission that we describe underscores its relevance in human microbiome studies5, especially those on non-infectious, microbiome-associated diseases.

The influence of pre- and postnatal exposure to air pollution and green spaces on infant's gut microbiota: Results from the MAMI birth cohort study.

BACKGROUND: Animal and human studies indicate that exposure to air pollution and natural environments might modulate the gut microbiota, but epidemiological evidence is very scarce. OBJECTIVES: To assess the potential impact of pre- and postnatal exposure to air pollution and green spaces on infant gut microbiota assembly and trajectories during the first year of life. METHODS: MAMI ("MAternal MIcrobes") birth cohort (Valencia, Spain, N = 162) was used to study the impact of environmental exposure (acute and chronic) on infant gut microbiota during the first year of life (amplicon-based 16S rRNA sequencing). At 7 days and at 1, 6 and 12 months, residential pre- and postnatal exposure to air pollutants (NO2, black carbon -BC-, PM2.5 and O3) and green spaces indicators (NDVI and area of green spaces at 300, 500 and 1000 m buffers) were obtained. For the association between exposures and alpha diversity indicators linear regression models (cross-sectional analyses) and mixed models, including individual as a random effect (longitudinal analyses), were applied. For the differential taxon analysis, the ANCOM-BC package with a log count transformation and multiple-testing corrections were used. RESULTS: Acute exposure in the first week of life and chronic postnatal exposure to NO2 were associated with a reduction in microbial alpha diversity, while the effects of green space exposure were not evident. Acute and chronic (prenatal or postnatal) exposure to NO2 resulted in increased abundance of Haemophilus, Akkermansia, Alistipes, Eggerthella, and Tyzerella populations, while increasing green space exposure associated with increased Negativicoccus, Senegalimassilia and Anaerococcus and decreased Tyzzerella and Lachnoclostridium populations. DISCUSSION: We observed a decrease in the diversity of the gut microbiota and signs of alteration in its composition among infants exposed to higher levels of NO2. Increasing green space exposure was also associated with changes in gut microbial composition. Further research is needed to confirm these findings.

Omics insights into the responses to dietary selenium.

Selenium is a well-known health-relevant element related with cancer chemoprevention, neuroprotective roles, beneficial in diabetes, and in several infectious diseases, among others. It is naturally present in some foods, but deficiency in people led to the production of nutraceuticals, supplements, and functional food enriched in this element. There is a U-shaped link between selenium levels and health and a narrow range between toxic and essential levels, and thus, supplementation should be performed carefully. Omics methodologies have become valuable approaches to delve into the responses of dietary selenium in mammals that allowed a deeper knowledge about the metabolism of this element as well as its biological role. In this review, we discuss omics approaches from the workflows to their applications that has been previously used to deep insight into the metabolism of dietary selenium. There is a special focus on selenoproteins, metabolomics responses in blood and tissues (e.g., brain, reproductive organs, etc.) as well as the impact on gut microbiota and its metabolites profile. Thus, we mainly reviewed heteroatom-tagged proteomics, metallomics, metabolomics, and metataxonomics, usually combined with transcriptomics, genomics, and other molecular methods.

Metabolic effects of early life stress and pre-pregnancy obesity are long lasting and sex specific in mice.

Early life stress (ELS) is associated with metabolic, cognitive, and psychiatric diseases and has a very high prevalence, highlighting the urgent need for a better understanding of the versatile physiological changes and identification of predictive biomarkers. In addition to programming the hypothalamic-pituitary-adrenal (HPA) axis, ELS may also affect the gut microbiota and metabolome, opening up a promising research direction for identifying early biomarkers of ELS-induced (mal)adaptation. Other factors affecting these parameters include maternal metabolic status and diet, with maternal obesity shown to predispose offspring to later metabolic disease. The aim of the present study was to investigate the long-term effects of ELS and maternal obesity on the metabolic and stress phenotype of rodent offspring. To this end, offspring of both sexes were subjected to an adverse early-life experience, and their metabolic and stress phenotypes were examined. In addition, we assessed whether a prenatal maternal and an adult high-fat diet (HFD) stressor further shape observed ELS-induced phenotypes. We show that ELS has long-term effects on male body weight (BW) across the lifespan, whereas females more successfully counteract ELS-induced weight loss, possibly by adapting their microbiota, thereby stabilizing a balanced metabolome. Furthermore, the metabolic effects of a maternal HFD on BW are exclusively triggered by a dietary challenge in adult offspring and are more pronounced in males than in females. Overall, our study suggests that the female microbiota protects against an ELS challenge, rendering them more resilient to additional maternal- and adult nutritional stressors than males.

Protein tyrosine phosphatase 1B targets focal adhesion kinase and paxillin in cell-matrix adhesions.

Protein tyrosine phosphatase 1B (PTP1B, also known as PTPN1) is an established regulator of cell-matrix adhesion and motility. However, the nature of substrate targets at adhesion sites remains to be validated. Here, we used bimolecular fluorescence complementation assays, in combination with a substrate trapping mutant of PTP1B, to directly examine whether relevant phosphotyrosines on paxillin and focal adhesion kinase (FAK, also known as PTK2) are substrates of the phosphatase in the context of cell-matrix adhesion sites. We found that the formation of catalytic complexes at cell-matrix adhesions requires intact tyrosine residues Y31 and Y118 on paxillin, and the localization of FAK at adhesion sites. Additionally, we found that PTP1B specifically targets Y925 on the focal adhesion targeting (FAT) domain of FAK at adhesion sites. Electrostatic analysis indicated that dephosphorylation of this residue promotes the closed conformation of the FAT 4-helix bundle and its interaction with paxillin at adhesion sites.

Anatomy of the complete mouse eye vasculature explored by light-sheet fluorescence microscopy exposes subvascular-specific remodeling in development and pathology.

Eye development and function rely on precise establishment, regression and maintenance of its many sub-vasculatures. These crucial vascular properties have been extensively investigated in eye development and disease utilizing genetic and experimental mouse models. However, due to technical limitations, individual studies have often restricted their focus to one specific sub-vasculature. Here, we apply a workflow that allows for visualization of complete vasculatures of mouse eyes of various developmental stages. Through tissue depigmentation, immunostaining, clearing and light-sheet fluorescence microscopy (LSFM) entire vasculatures of the retina, vitreous (hyaloids) and uvea were simultaneously imaged at high resolution. In silico dissection provided detailed information on their 3D architecture and interconnections. By this method we describe successive remodeling of the postnatal iris vasculature, involving sprouting and pruning, following its disconnection from the embryonic feeding hyaloid vasculature. In addition, we demonstrate examples of conventional and LSFM-mediated analysis of choroidal neovascularization after laser-induced wounding, showing added value of the presented workflow in analysis of modelled eye disease. These advancements in visualization and analysis of the respective eye vasculatures in development and complex eye disease open for novel observations of their functional interplay at a whole-organ level.

Effect of beta-glucan supplementation on cystic fibrosis colonic microbiota: an in vitro study.

BACKGROUND: Children with cystic fibrosis (CF) present with gut dysbiosis, and current evidence impedes robust recommendations on the use of prebiotics. This study aimed at establishing the prebiotic potential of a commercial beta-glucan on the in vitro colonic microbiota of a child with CF compared to a healthy counterpart (H). METHODS: A dynamic simulator of colonic fermentation (twin-SHIME® model) was set up including the simulation of the proximal (PC) and distal colon (DC) of the CF and the H subjects by colonizing the bioreactors with faecal microbiota. During two weeks the system was supplied with the beta-glucan. At baseline, during treatment and post-treatment, microbiota composition was profiled by 16 S rRNA and short-chain fatty acids (SCFA) production was determined by GS-MS. RESULTS: At baseline, Faecalibacterium, was higher in CF' DC than in the H, along higher Acidaminococcus and less Megasphaera and Sutterella. Beta-glucan supplementation induced increased microbiota richness and diversity in both subjects during the treatment. At genus level, Pseudomonas and Veillonella decreased, while Akkermansia and Faecalibacterium increased significantly in CF. CONCLUSION: The supplementation with beta-glucan suggests positive results on CF colonic microbiota in the in vitro context, encouraging further research in the in vivo setting. IMPACT: Current evidence supports assessing the effect of prebiotics on modifying cystic fibrosis microbiota. The effect of beta-glucan supplementation was evaluated in a controlled dynamic in vitro colonic ecosystem. Beta-glucan supplement improved diversity in cystic fibrosis colonic microbiota. The treatment showed increased abundance of Faecalibacterium and Akkermansia in cystic fibrosis. New evidence supports the use of prebiotics in future clinical studies.

Human milk: From complex tailored nutrition to bioactive impact on child cognition and behavior.

Human milk is a highly complex liquid food tailor-made to match an infant's needs. Beyond documented positive effects of breastfeeding on infant and maternal health, there is increasing evidence that milk constituents also impact child neurodevelopment. Non-nutrient milk bioactives would contribute to the (long-term) development of child cognition and behavior, a process termed 'Lactocrine Programming'. In this review we discuss the current state of the field on human milk composition and its links with child cognitive and behavioral development. To promote state-of-the-art methodologies and designs that facilitate data pooling and meta-analytic endeavors, we present detailed recommendations and best practices for future studies. Finally, we determine important scientific gaps that need to be filled to advance the field, and discuss innovative directions for future research. Unveiling the mechanisms underlying the links between human milk and child cognition and behavior will deepen our understanding of the broad functions of this complex liquid food, as well as provide necessary information for designing future interventions.

Gut Microbiota and Derived Short-Chain Fatty Acids Are Linked to Evolution of Heart Failure Patients.

There is a lack of direct evidence regarding gut microbiota dysbiosis and changes in short-chain fatty acids (SCFAs) in heart failure (HF) patients. We sought to assess any association between gut microbiota composition, SCFA production, clinical parameters, and the inflammatory profile in a cohort of newly diagnosed HF patients. In this longitudinal prospective study, we enrolled eighteen newly diagnosed HF patients. At admission and after 12 months, blood samples were collected for the assessment of proinflammatory cytokines, monocyte populations, and endothelial dysfunction, and stool samples were collected for analysis of gut microbiota composition and quantification of SCFAs. Twelve months after the initial HF episode, patients demonstrated improved clinical parameters and reduced inflammatory state and endothelial dysfunction. This favorable evolution was associated with a reversal of microbiota dysbiosis, consisting of the increment of health-related bacteria, such as genus Bifidobacterium, and levels of SCFAs, mainly butyrate. Furthermore, there was a decrease in the abundance of pathogenic bacteria. In vitro, fecal samples collected after 12 months of follow-up exhibited lower inflammation than samples collected at admission. In conclusion, the favorable progression of HF patients after the initial episode was linked to the reversal of gut microbiota dysbiosis and increased SCFA production, particularly butyrate. Whether restoring butyrate levels or promoting the growth of butyrate-producing bacteria could serve as a complementary treatment for these patients deserves further studies.

In Vitro Bioactivities of Food Grade Extracts from Yarrow (Achillea millefolium L.) and Stinging Nettle (Urtica dioica L.) Leaves.

Yarrow (Achillea millefolium L., AM) and nettle (Urtica dioica L., UD) are bioactive plants used commercially in functional food and supplement applications and traditionally to alleviate gastric disorders. In this work, the effects of food-grade optimized extracts of Finnish early-season AM and UD were tested on bacterial growth including potential beneficial and foodborne pathogens, as well as murine norovirus (MNV). The anti-inflammatory properties of the extracts were also tested in vitro by NF-κB reporter cells. The food-grade extraction was optimized with the response surface modelling in terms of total carotenoid, chlorophyll, and phenolic compounds contents and antioxidant capacities. The optimal food-grade extraction parameters were a 1-h extraction in 70% ethanol at 45 °C for AM, and at 49 °C for UD. There were no significant effects on the beneficial bacteria (Lacticaseibacillus and Bifidobacterium strains), and the extracts were more effective against gram-positive than gram-negative foodborne bacteria and potential pathogens. Listeria innocua was the most susceptible strain in the optimized extracts with a growth rate of 0.059 ± 0.004 for AM and 0.067 ± 0.006 for UD, p < 0.05 compared to control. The optimized extracts showed a logarithmic growth reduction of 0.67 compared to MNV. The hydroethanolic extracts were cytotoxic to both cell lines, whereas aqueous AM and UD extracts induced and reduced TLR4 signalling in a reporter cell line, respectively. The results provide novel food-grade extraction parameters and support the bioactive effects of AM and UD in functional food applications, but more research is needed to elucidate the precise biological activity in vivo for gastric health.

Untargeted Gut Metabolomics to Delve the Interplay between Selenium Supplementation and Gut Microbiota.

Selenium (Se) is an essential trace element with important health roles due to the antioxidant properties of selenoproteins. To analyze the interplay between Se and gut microbiota, gut metabolomic profiles were determined in conventional (C) and microbiota depleted mice (Abx) after Se-supplementation (Abx-Se) by untargeted metabolomics, using an analytical multiplatform based on GC-MS and UHPLC-QTOF-MS (MassIVE ID MSV000087829). Gut microbiota profiling was performed by 16S rRNA gene amplicon sequencing. Significant differences in the levels of about 70% of the gut metabolites determined, including fatty acyls, glycerolipids, glycerophospholipids, and steroids, were found in Abx-Se compared to Abx, and only 30% were different between Abx-Se and C, suggesting an important effect of Se-supplementation on Abx mice metabolism. At genus level, the correlation analysis showed strong associations between metabolites and gut bacterial profiles. Likewise, higher abundance of Lactobacillus spp., a potentially beneficial genus enriched after Se-supplementation, was associated with higher levels of prenol lipids, phosphatidylglycerols (C-Se), steroids and diterpenoids (Abx-Se), and also with lower levels of fatty acids (Abx-Se). Thus, we observed a crucial interaction between Se intake-microbiota-metabolites, although further studies to clarify the specific mechanisms are needed. This is the first study about untargeted gut metabolomics after microbiota depletion and Se-supplementation.

Timing of chocolate intake affects hunger, substrate oxidation, and microbiota: A randomized controlled trial.

Eating chocolate in the morning or in the evening/at night, may differentially affect energy balance and impact body weight due to changes in energy intake, substrate oxidation, microbiota (composition/function), and circadian-related variables. In a randomized controlled trial, postmenopausal females (n = 19) had 100 g of chocolate in the morning (MC), in the evening/at night (EC), or no chocolate (N) for 2 weeks and ate any other food ad libitum. Our results show that 14 days of chocolate intake did not increase body weight. Chocolate consumption decreased hunger and desire for sweets (P < .005), and reduced ad libitum energy intake by ~300 kcal/day during MC and ~150 kcal/day during EC (P = .01), but did not fully compensate for the extra energy contribution of chocolate (542 kcal/day). EC increased physical activity by +6.9%, heat dissipation after meals +1.3%, and carbohydrate oxidation by +35.3% (P < .05). MC reduced fasting glucose (4.4%) and waist circumference (-1.7%) and increased lipid oxidation (+25.6%). Principal component analyses showed that both timings of chocolate intake resulted in differential microbiota profiles and function (P < .05). Heat map of wrist temperature and sleep records showed that EC induced more regular timing of sleep episodes with lower variability of sleep onset among days than MC (60 min vs 78 min; P = .028). In conclusion, having chocolate in the morning or in the evening/night results in differential effects on hunger and appetite, substrate oxidation, fasting glucose, microbiota (composition and function), and sleep and temperature rhythms. Results highlight that the "when" we eat is a relevant factor to consider in energy balance and metabolism.

Maternal pre-pregnancy overweight and neonatal gut bacterial colonization are associated with cognitive development and gut microbiota composition in pre-school-age offspring.

Maternal gestational obesity is a risk factor for offspring's neurodevelopment and later neuro-cognitive disorders. Altered gut microbiota composition has been found in patients with neurocognitive disorders, and in relation to maternal metabolic health. We explored the associations between gut microbiota and cognitive development during infancy, and their link with maternal obesity. In groups of children from the Pisa birth Cohort (PISAC), we analysed faecal microbiota composition by 16S rRNA marker gene sequencing of first-pass meconium samples and of faecal samples collected at age 3, 6, 12, 24, 36 months, and its relationship with maternal gestational obesity or diabetes, and with cognitive development, as measured from 6 to 60 months of age by the Griffith's Mental Development Scales. Gut microbiota composition in the first phases of life is dominated by Bifidobacteria (Actinobacteria phylum), with contribution of Escherichia/Shigella and Klebsiella genera (Proteobacteria phylum), whereas Firmicutes become more dominant at 36 months of age. Maternal overweight leads to lower abundance of Bifidobacterium, Blautia and Ruminococcus, and lower practical reasoning scores in the offspring at the age of 36 months. In the whole population, microbiota in the first-pass meconium samples shows much higher alpha diversity compared to later samples, and its composition, particularly Bifidobacterium and Veillonella abundances, correlates with practical reasoning scores at 60 months of age. Maternal overweight correlates with bacterial colonization and with the development of reasoning skills at pre-school age. Associations between neonatal gut colonization and later cognitive function provide new perspectives of primary (antenatal) prevention of neurodevelopmental disorders.

Spontaneous preterm delivery is reflected in both early neonatal and maternal gut microbiota.

BACKGROUND: Aberrant gut microbiota composition in preterm neonates is linked to adverse health consequences. Little is known about the impact of perinatal factors or maternal gut microbiota on initial preterm gut colonization. METHODS: Fecal samples were collected from 55 preterm neonates (<35 gestational weeks), 51 mothers, and 25 full-term neonates during the first 3-4 postpartum days. Gut microbiota composition was assessed using 16S ribosomal RNA gene sequencing. RESULTS: Preterm neonates exhibited significantly lower gut microbiota alpha diversity and distinct beta diversity clustering compared to term neonates. Spontaneous preterm birth was associated with distinct initial gut microbiota beta diversity as compared to iatrogenic delivery. Gestational age or delivery mode had no impact on the preterm gut microbiota composition. The cause of preterm delivery was also reflected in the maternal gut microbiota composition. The contribution of maternal gut microbiota to initial preterm gut colonization was more pronounced after spontaneous delivery than iatrogenic delivery and not dependent on delivery mode. CONCLUSIONS: The initial preterm gut microbiota is distinct from term microbiota. Spontaneous preterm birth is reflected in the early neonatal and maternal gut microbiota. Transmission of gut microbes from mother to neonate is determined by spontaneous preterm delivery, but not by mode of birth. IMPACT: The initial gut microbiota in preterm neonates is distinct from those born full term. Spontaneous preterm birth is associated with changes in the gut microbiota composition of both preterm neonates and their mothers. The contribution of the maternal gut microbiota to initial neonatal gut colonization was more pronounced after spontaneous preterm delivery as compared to iatrogenic preterm delivery and not dependent on delivery mode. Our study provides new evidence regarding the early gut colonization patterns in preterm infants. Altered preterm gut microbiota has been linked to adverse health consequences and may provide a target for early intervention.

Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling.

RATIONALE: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. OBJECTIVE: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. METHODS AND RESULTS: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. CONCLUSIONS: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.

The role of novel instruments of brand communication and brand image in building consumers' brand preference and intention to visit wineries.

This research aims to analyze brand communication and brand image as specific drivers of wine brand preference and their influence on wine consumers' intention to visit associated wineries. Specifically, this paper enhances the understanding of the roles of advertising-promotion, sponsorship-public relations, corporate social responsibility, and social media in brand communication, as well as functional, emotional and reputation components in brand image development in the context of wine tourism industry. Data was collected through a structured and self-administered questionnaire from 486 visitors to wineries in Spain. Partial least squares regression was used to evaluate the measurement model and the hypotheses. The empirical analysis shows that brand communication and brand image have similar positive effects on brand preference, and that brand image mediates the relationship between brand communication and brand preference. This research suggests implications for theory and practice relative to brand management in terms of communication and image; and it proposes insights into novel communication tools and marketing activities for the winery tourism industry. Firms should employ a holistic evaluation of brand communication to involve the whole organization, which would enhance the strategic role that brand communication plays. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12144-021-02656-w.

A novel small molecule approach for the treatment of propionic and methylmalonic acidemias.

Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) are inborn errors of metabolism affecting the catabolism of valine, isoleucine, methionine, threonine and odd-chain fatty acids. These are multi-organ disorders caused by the enzymatic deficiency of propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT), resulting in the accumulation of propionyl-coenzyme A (P-CoA) and methylmalonyl-CoA (M-CoA in MMA only). Primary metabolites of these CoA esters include 2-methylcitric acid (MCA), propionyl-carnitine (C3), and 3-hydroxypropionic acid, which are detectable in both PA and MMA, and methylmalonic acid, which is detectable in MMA patients only (Chapman et al., 2012). We deployed liver cell-based models that utilized PA and MMA patient-derived primary hepatocytes to validate a small molecule therapy for PA and MMA patients. The small molecule, HST5040, resulted in a dose-dependent reduction in the levels of P-CoA, M-CoA (in MMA) and the disease-relevant biomarkers C3, MCA, and methylmalonic acid (in MMA). A putative working model of how HST5040 reduces the P-CoA and its derived metabolites involves the conversion of HST5040 to HST5040-CoA driving the redistribution of free and conjugated CoA pools, resulting in the differential reduction of the aberrantly high P-CoA and M-CoA. The reduction of P-CoA and M-CoA, either by slowing production (due to increased demands on the free CoA (CoASH) pool) or enhancing clearance (to replenish the CoASH pool), results in a net decrease in the CoA-derived metabolites (C3, MCA and MMA (MMA only)). A Phase 2 study in PA and MMA patients will be initiated in the United States.

Maternal Diet Shapes the Breast Milk Microbiota Composition and Diversity: Impact of Mode of Delivery and Antibiotic Exposure.

BACKGROUND: Breast milk is a complex biofluid that provides nutrients and bioactive agents, including bacteria, for the development of the infant gut microbiota. However, the impact of maternal diet and other factors, such as mode of delivery and antibiotic exposure, on the breast milk microbiota has yet to be understood. OBJECTIVES: This study aimed to examine the association between maternal diet and breast milk microbiota and to ascertain the potential role of mode of delivery and antibiotic exposure. METHODS: In a cross-sectional study of the MAMI cohort, breast milk microbiota profiling was assessed in 120 samples from healthy mothers by 16S rRNA gene sequencing. Maternal dietary information was recorded through an FFQ, and clinical characteristics, including mode of delivery, antibiotic exposure, and exclusive breastfeeding, were collected. RESULTS: Maternal diet was grouped into 2 clusters: Cluster I (high intake of plant protein, fiber, and carbohydrates), and Cluster II (high intake of animal protein and lipids). Breast milk microbiota was shaped by maternal dietary clusters. Staphylococcus and Bifidobacterium were associated with carbohydrate intake whereas the Streptococcus genus was associated with intakes of the n-3 PUFAs [EPA and docosapentaenoic acid (22:5ω-3)]. Mode of delivery and antibiotic exposure influenced breast milk microbiota in a diet cluster-dependent manner. Differences between/among the maternal dietary clusters were found in the milk microbiota of the cesarean-section (C-section)/antibiotic group, whereas no differences were observed in vaginal births. Lower abundances of Lactobacillus, Bacteroides, and Sediminibacterium genera were observed in Cluster II/C-section/antibiotic exposure compared with the other groups. CONCLUSIONS: Maternal diet shapes the composition and diversity of breast milk microbiota, with the most important contributions coming from dietary fiber and both plant and animal protein intakes. The relation between the maternal diet and the milk microbiota needs further research because it has a key impact on infant microbiota development and contributes to infant health outcomes in the short and long term.This trial was registered at clinicaltrials.gov as NCT03552939.

Validation and adaptation of the Spanish version of the systemic lupus activity questionnaire (S-SLAQ) in an Argentinean population.

OBJECTIVES: To validate the systemic lupus activity questionnaire (SLAQ) in Spanish language. METHODS: The SLAQ questionnaire was translated and adapted in Spanish. Consecutive SLE patients from 8 centers in Argentina were included. A rheumatologist completed a Systemic Lupus Activity Measure (SLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K, and a physician's assessment. Reliability was assessed by internal consistency (Cronbach's alpha), stability by test-retest reliability (intraclass correlation coefficient), and construct validity by evaluating the correlation with clinically relevant scores. Sensitivity and specificity for clinically significant disease activity (SLEDAI ≥6) of different S-SLAQ cut-off points were evaluated. RESULTS: We included 97 patients ((93% female, mean age: 40 years (SD14.7)). Internal consistency was excellent (Cronbach's alpha = 0.84, p < 0.001), and the intraclass correlation coefficient was 0.95 (p < 0.001). Mean score of S-SLAQ was 8.2 (SD 7.31). Correlation of S-SLAQ was moderate with Patient NRS (r= 0.63 p< 0.001), weak with SLAM-no lab (r = 0.42, p <0.001) and SLAM (r = 0.38, p < 0.0001), and very weak with SLEDAI-2K (r = 0.15, p =0.1394). Using the S-SLAQ cutoff of five points, the sensitivity was 72.2% and specificity was 37.9%, for clinically significant disease activity. CONCLUSIONS: The S-SLAQ showed good validity and reliability. A good correlation, similar to the original instrument, was observed with patient´s global disease activity. No correlation was found between S-SLAQ and gold standard disease activity measures like SLEDAI-2K and SLAM. The S-SLAQ cutoff point of 5 showed a good sensitivity to identify the active SLE population and therefore could be an appropriate screening instrument for disease activity in clinical and epidemiological studies.