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Background The obesogenic potential of high-fat diets (HFD) in rodents is attenuated when the protein:carbohydrate ratio is increased. However, it is not known if intake of an HFD irrespective of the protein:carbohydrate ratio and in the absence of weight gain, affects glucose homeostasis and the gut microbiota. Methods We fed C57BL6/J mice 3 different HFDs with decreasing protein:carbohydrate ratios for 8 weeks and compared the results to a LFD reference group. We analyzed the gut microbiota composition by 16S rDNA amplicon sequencing and the intestinal gene expression by real-time PCR. Whole body glucose homeostasis was evaluated by insulin and glucose tolerance tests as well as by a hyperinsulinemic euglycemic clamp experiment. Results Compared with LFD-fed reference mice, HFD-fed mice, irrespective of protein:carbohydrate ratio, exhibited impaired glucose tolerance, whereas no differences were observed during insulin tolerance tests. The hyperinsulinemic euglycemic clamp revealed tissue-specific effects on glucose homeostasis in all HFD-fed groups. HFD-fed mice exhibited decreased insulin-stimulated glucose uptake in white but not in brown adipose tissue, and sustained endogenous glucose production under insulin-stimulated conditions. We observed no impairment of insulin-stimulated glucose uptake in skeletal muscles of different fiber type composition. HFD-feeding altered the gut microbiota composition paralleled by increased expression of pro-inflammatory cytokines and genes involved in gluconeogenesis in intestinal epithelial cells of the jejunum. Conclusions Intake of a HFD profoundly affected glucose homeostasis, gut inflammatory responses, and gut microbiota composition in the absence of fat mass accretion. [ABSTRACT FROM AUTHOR]

The quantitative methodology derived from replicator dynamics for empirical studies of economic evolution is becoming increasingly well developed in theory but is rarely applied in practice. One reason is the relatively naïve nature of current methods, which focus on the evolution of a single characteristic in a single environment. This assumption constrains the analysis of real selection processes in which firms operate in several markets and their products have several characteristics that interact to determine fitness. This entails that measurement of economic selection becomes confounded: characteristics that are associated with firm growth are not becoming more frequent in the population. The reason for confounded selection is that characteristics interact to augment or constrain the rate and direction of evolution and one-dimensional, single trait replicator dynamics cannot cope with confounded selection. The contribution of this paper is to develop an approach that serves to explicitly analyse confounded selection. The primary elements of the method are the selection gradients of the characteristics and the covariance matrix of the characteristics. Based on these, the method motivates a taxonomy of selection based on the interaction of characteristics. Applying the method to a population of firms will shed light on potentially confounded selection. It will reveal the indirect effects of characteristics on selection and the augmentation and constraints created thereby. [ABSTRACT FROM AUTHOR]

Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life. [ABSTRACT FROM AUTHOR]

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The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson's disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of Ruminococcaceae. Additionally, the abundance of Clostridiaceae was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients. [ABSTRACT FROM AUTHOR]

Enteroendocrine L-cell derived peptide hormones, notably glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2), have become important targets in the treatment of type 2 diabetes, obesity and intestinal diseases. As gut microbial imbalances and maladaptive host responses have been implicated in the pathology of obesity and diabetes, this study aimed to determine the effects of pharmacologically stimulated GLP-1 and GLP-2 receptor function on the gut microbiome composition in diet-induced obese (DIO) mice. DIO mice received treatment with a selective GLP-1 receptor agonist (liraglutide, 0.2 mg/kg, BID) or dual GLP-1/GLP-2 receptor agonist (GUB09–145, 0.04 mg/kg, BID) for 4 weeks. Both compounds suppressed caloric intake, promoted a marked weight loss, improved glucose tolerance and reduced plasma cholesterol levels. 16S rDNA sequencing and deep-sequencing shotgun metagenomics was applied for comprehensive within-subject profiling of changes in gut microbiome signatures. Compared to baseline, DIO mice assumed phylogenetically similar gut bacterial compositional changes following liraglutide and GUB09-145 treatment, characterized by discrete shifts in low-abundant species and related bacterial metabolic pathways. The microbiome alterations may potentially associate to the converging biological actions of GLP-1 and GLP-2 receptor signaling on caloric intake, glucose metabolism and lipid handling. [ABSTRACT FROM AUTHOR]

A graph U is an induced universal graph for a family F of graphs if every graph in F is a vertex-induced subgraph of U. Recently, for the family of all undirected graphs on n vertices, Alon [Geom. Funct. Anal. 2017] [3] proved the existence of an induced universal graph with (1 + o (1)) ⋅ 2 (n − 1) ∕ 2 vertices improving the previous best bound of 16 ⋅ 2 n ∕ 2 by Alstrup et al. (2015) and matching the lower bound of 2 (n − 1) ∕ 2 by Moon (1965) up to lower order additive terms. We continue this line of research of finding the size of the smallest induced universal graph up to lower order additive terms for some basic graph families. For the family of graphs with n vertices and bounded degree D = O (1) , Alon and Nenadov [Math. Proc. Camb. Philos. Soc. 2017] [4] showed that the smallest induced universal graph has size Θ n D ∕ 2 , but it remains to find the constant hidden in the O -notation. For even D the bound O n D ∕ 2 was already shown by Butler (2009). In order to find the correct constants for general D > 0 , it is natural first to consider the case D = 2. For D = 2 , Butler gave an induced universal graph of size 6. 5 n and subsequently, Esperet et al. (2008) found an induced universal graph for D = 2 of size 2. 5 n. We construct for D = 2 an even smaller induced universal graph with 2 n − 1 vertices. This proves a conjecture by Esperet et al. stating the existence of such a graph with 2 n + o (n) vertices. For the family of acyclic graphs on n vertices with maximum degree 2 we show that the smallest induced universal graph has size 3 n 2 . We also introduce the notion of size oblivious and size aware decoding, and relate this to families of induced universal graphs. For the family of graphs consisting of a single cycle we prove new upper and lower bounds on the complexity of size aware and size oblivious decoders. These new bounds separate the two notions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid ß-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis. [ABSTRACT FROM AUTHOR]

OSA is a common sleep-breathing disorder linked to increased risk of cardiovascular disease. Intermittent upper airway obstruction and hypoxia, hallmarks of OSA, have been shown in animal models to induce substantial changes to the gut microbiota composition, and subsequent transplantation of fecal matter to other animals induced changes in BP and glucose metabolism. Does OSA in adults associate with the composition and functional potential of the human gut microbiota? We used respiratory polygraphy data from up to 3,570 individuals 50 to 64 years of age from the population-based Swedish Cardiopulmonary bioimage Study combined with deep shotgun metagenomics of fecal samples to identify cross-sectional associations between three OSA parameters covering apneas and hypopneas, cumulative sleep time in hypoxia, and number of oxygen desaturation events with gut microbiota composition. Data collection about potential confounders was based on questionnaires, onsite anthropometric measurements, plasma metabolomics, and linkage with the Swedish Prescribed Drug Register. We found that all three OSA parameters were associated with lower diversity of species in the gut. Furthermore, in multivariable-adjusted analysis, the OSA-related hypoxia parameters were associated with the relative abundance of 128 gut bacterial species, including higher abundance of Blautia obeum and Collinsella aerofaciens. The latter species was also independently associated with increased systolic BP. Furthermore, the cumulative time in hypoxia during sleep was associated with the abundance of genes involved in nine gut microbiota metabolic pathways, including propionate production from lactate. Finally, we observed two heterogeneous sets of plasma metabolites with opposite association with species positively and negatively associated with hypoxia parameters, respectively. OSA-related hypoxia, but not the number of apneas/hypopneas, is associated with specific gut microbiota species and functions. Our findings lay the foundation for future research on the gut microbiota-mediated health effects of OSA. [ABSTRACT FROM AUTHOR]

Summary The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ + and CD4 + CD8αα + T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent CD103 + CD11b - DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis. [ABSTRACT FROM AUTHOR]

Background: Scavenging indigenous village chickens play a vital role in sub-Saharan Africa, sustaining the livelihood of millions of farmers. These chickens are exposed to vastly different environments and feeds compared to commercial chickens. In this study, we analysed the caecal microbiota of 243 Ethiopian village chickens living in different altitude-dependent agro-ecologies., Results: Differences in bacterial diversity were significantly correlated with differences in specific climate factors, topsoil characteristics, and supplemental diets provided by farmers. Microbiota clustered into three enterotypes, with one particularly enriched at high altitudes. We assembled 9977 taxonomically and functionally diverse metagenome-assembled genomes. The vast majority of these were not found in a dataset of previously published chicken microbes or in the Genome Taxonomy Database., Conclusions: The wide functional and taxonomic diversity of these microbes highlights their importance in the local adaptation of indigenous poultry, and the significant impacts of environmental factors on the microbiota argue for further discoveries in other agro-ecologies. Video Abstract., (© 2024. The Author(s).)

Here, we present a longitudinal shotgun sequencing metagenomics study of 16 healthy, Danish women in the reproductive age. The aim of the study was to investigate whether lactobacilli, orally consumed, had any impact on the vaginal microbiome and its functional potential. The 16 women aged 19-45 years were recruited from Copenhagen, Denmark. One baseline vaginal sample (Day 0) and two study samples (Days 25-30 and Days 55-60, respectively), were sampled. The vaginal samples were analyzed by shotgun metagenomics. We detected 26 species in the vaginal microbiota of the 16 women, of which six belonged to the Lactobacillus genus. We observed three vaginal microbiome clusters mainly dominated by Gardnerella vaginalis, Lactobacillus iners, or Lactobacillus crispatus. The oral probiotic had no detectable effect on either the composition or the functional potential of the vaginal microbiota. Most of the study subjects (11 out of 16 women) exhibited only minor changes in the vaginal microbiome during the treatment with probiotics. Any compositional changes could not be associated to the probiotic treatment. Future studies may benefit from an increased number of participants, and administration of the probiotics during conditions with bacterial imbalance (e.g., during/after antibiotic treatment) or the use of different Lactobacillus spp. known to colonize the vagina., (© 2022 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Medical Microbiology and Pathology.)

Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 58% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas ( https://gutsyatlas.serve.scilifelab.se/ ). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition., (© 2022. The Author(s).)

Background: Microbial dysbiosis with increased Staphylococcus aureus (S. aureus) colonization on the skin is a hallmark of atopic dermatitis (AD), however most microbiome studies focus on bacteria in the flexures and the microbial composition at other body sites have not been studied systematically., Objectives: The aim of the study is to characterize the skin microbiome, including bacteria, fungi and virus, at different body sites in relation to AD, lesional state, and S. aureus colonization, and to test whether the nares could be a reservoir for S. aureus strain colonization., Methods: Using shotgun metagenomics we characterized microbial compositions from 14 well defined skin sites from 10 patients with AD and 5 healthy controls., Results: We found clear differences in microbial composition between AD and controls at multiple skin sites, most pronounced on the flexures and neck. The flexures exhibited lower alpha-diversity and were colonized by S. aureus, accompanied by S. epidermidis in lesions. Malassezia species were absent on the neck in AD. Virus mostly constituted Propionibacterium and Staphylococcus phages, with increased abundance of Propionibacterium phages PHL041 and PHL092 and Staphylococcus epidermidis phages CNPH82 and PH15 in AD. In lesional samples, both the genus Staphylococcus and Staphylococcus phages were more abundant. S. aureus abundance was higher across all skin sites except from the feet. In samples where S. aureus was highly abundant, lower abundances of S. hominis and Cutibacterium acnes were observed. M. osloensis and M. luteus were more abundant in AD. By single nucleotide variant analysis of S. aureus we found strains to be subject specific. On skin sites some S. aureus strains were similar and some dissimilar to the ones in the nares., Conclusions: Our data indicate a global and site-specific dysbiosis in AD, involving both bacteria, fungus and virus. When defining targeted treatment clinicians should both consider the individual and skin site and future research into potential crosstalk between microbiota in AD yields high potential., (© 2021. The Author(s).)

Interactions between host and gut microbial communities are modulated by diets and play pivotal roles in immunological homeostasis and health. We show that exchanging the protein source in a high fat, high sugar, westernized diet from casein to whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath is sufficient to reverse western diet-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22 °C) and at thermoneutrality (T30 °C). Concomitant with microbiota changes, mice fed the Methylococcus-based western diet exhibit improved glucose regulation, reduced body and liver fat, and diminished hepatic immune infiltration. Intake of the Methylococcu-based diet markedly boosts Parabacteroides abundances in a manner depending on adaptive immunity, and upregulates triple positive (Foxp3 + RORγt + IL-17 + ) regulatory T cells in the small and large intestine. Collectively, these data point to the potential for leveraging the use of McB lysates to improve immunometabolic homeostasis.

Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs., Competing Interests: Declaration of Interests R.G. and A.H. have filed a patent on the supportive immunomodulatory effect of C3-C8 aliphatic fatty acids., (Copyright © 2020 Elsevier Inc. All rights reserved.)