Chronic dietary protein-restriction can create essential amino acid deficiencies and induce metabolic adaptation through the hepatic FGF21 pathway which serves to maintain host fitness during ...prolonged states of nutritional imbalance. Similarly, the gut microbiome undergoes metabolic adaptations when dietary nutrients are added or withdrawn. Here we confirm previous reports that dietary protein-restriction triggers the hepatic FGF21 adaptive metabolic pathway and further demonstrate that this response is mediated by the gut microbiome and can be tuned through dietary supplementation of fibers that alter the gut microbiome. In the absence of a gut microbiome, we discover that FGF21 is de-sensitized to the effect of protein-restriction. These data suggest that host-intrinsic adaptive pathways to chronic dietary protein-restriction, such as the hepatic FGF21 pathway, may in-fact be responding first to adaptive metabolic changes in the gut microbiome.
PfEMP1 is a family of adhesive proteins expressed on the surface of Plasmodium falciparum-infected erythrocytes (IEs), where they mediate adhesion of IEs to a range of host receptors. Efficient ...PfEMP1-dependent IE sequestration often depends on soluble serum proteins, including IgM. Here, we report a comprehensive investigation of which of the about 60 var gene-encoded PfEMP1 variants per parasite genome can bind IgM via the Fc part of the antibody molecule, and which of the constituent domains of those PfEMP1 are involved. We erased the epigenetic memory of var gene expression in three distinct P. falciparum clones, 3D7, HB3, and IT4/FCR3 by promoter titration, and then isolated individual IEs binding IgM from malaria-unexposed individuals by fluorescence-activated single-cell sorting. The var gene transcription profiles of sub-clones measured by real-time qPCR were used to identify potential IgM-binding PfEMP1 variants. Recombinant DBL and CIDR domains corresponding to those variants were tested by ELISA and protein arrays to confirm their IgM-binding capacity. Selected DBL domains were used to raise specific rat anti-sera to select IEs with uniform expression of candidate PfEMP1 proteins. Our data document that IgM-binding PfEMP1 proteins are common in each of the three clones studied, and that the binding epitopes are mainly found in DBLε and DBLζ domains near the C-terminus.
The relationship between microbiota, short chain fatty acids (SCFAs), and obesity remains enigmatic. We employ amplicon sequencing and targeted metabolomics in a large (n = 1904) African origin ...cohort from Ghana, South Africa, Jamaica, Seychelles, and the US. Microbiota diversity and fecal SCFAs are greatest in Ghanaians, and lowest in Americans, representing each end of the urbanization spectrum. Obesity is significantly associated with a reduction in SCFA concentration, microbial diversity, and SCFA synthesizing bacteria, with country of origin being the strongest explanatory factor. Diabetes, glucose state, hypertension, obesity, and sex can be accurately predicted from the global microbiota, but when analyzed at the level of country, predictive accuracy is only universally maintained for sex. Diabetes, glucose, and hypertension are only predictive in certain low-income countries. Our findings suggest that adiposity-related microbiota differences differ between low-to-middle-income compared to high-income countries. Further investigation is needed to determine the factors driving this association.
Asthma is the most common chronic disease within the paediatric population. Although it is multifactorial, its onset may be linked to early-life exposures with subsequent impact on immune system ...development. Microbial and dietary metabolic products have been implicated in the development and exacerbation of paediatric asthma. Linoleic acid is the most common omega-6 polyunsaturated fatty acid in the Western diet. In this review, we summarise the literature regarding the involvement of linoleic acid in the development of and its impact on existing paediatric asthma. First, we summarise the existing knowledge surrounding the relationship between human microbial metabolism and allergic diseases in children. Next, we examine cellular or animal model-based mechanistic studies that investigated the impact of dietary- and microbial-derived linoleic acid metabolites on asthma. Finally, we review the literature investigating the impact of linoleic acid metabolites on the development and exacerbation of childhood asthma. While there is conflicting evidence, there is growing support for a role of linoleic acid in the onset and pathophysiology of asthma. We recommend that additional cellular, animal, and longitudinal studies are performed that target linoleic acid and its metabolites.
Disparities for women and minorities in science, technology, engineering, and math (STEM) careers have continued even amidst mounting evidence for the superior performance of diverse workforces. In ...response, we launched the Diversity and Science Lecture series, a cross-institutional platform where junior life scientists present their research and comment on diversity, equity, and inclusion in STEM. We characterize speaker representation from 79 profiles and investigate topic noteworthiness via quantitative content analysis of talk transcripts. Nearly every speaker discussed interpersonal support, and three-fifths of speakers commented on race or ethnicity. Other topics, such as sexual and gender minority identity, were less frequently addressed but highly salient to the speakers who mentioned them. We found that significantly co-occurring topics reflected not only conceptual similarity, such as terms for racial identities, but also intersectional significance, such as identifying as a Latina/Hispanic woman or Asian immigrant, and interactions between concerns and identities, including the heightened value of friendship to the LGBTQ community, which we reproduce using transcripts from an independent seminar series. Our approach to scholar profiles and talk transcripts serves as an example for transmuting hundreds of hours of scholarly discourse into rich datasets that can power computational audits of speaker diversity and illuminate speakers' personal and professional priorities.
The human gut microbiota harbors a heterogeneous and dynamic community of microorganisms that coexist with the host to exert a marked influence on human physiology and health. Throughout the ...lifespan, diet can shape the composition and diversity of the members of the gut microbiota by determining the microorganisms that will colonize, persist, or become extinct. This is no more pronounced than during early-life succession of the gut microbiome when food type and source changes relatively often and food preferences are established, which is largely determined by geographic location and the customs and cultural practices of that environment. These dietary selection pressures continue throughout life, as society has become increasingly mobile and as we consume new foods to which we have had no previous exposure. Dietary selection pressures also come in the form of overall reduction or excess such as with the growing problems of food insecurity (lack of food) as well as of dietary obesity (overconsumption). These are well-documented forms of dietary selection pressures that have profound impact on the gut microbiota that ultimately may contribute to or worsen disease. However, diets and dietary components can also be used to promote healthy microbial functions in the gut, which will require tailored approaches taking into account an individual’s personal history and doing away with one-size-fits-all nutrition. Herein, we summarize current knowledge on major dietary selection pressures that influence gut microbiota structure and function across and within populations, and discuss both the potential of personalized dietary solutions to health and disease and the challenges of implementation.
The lack of suitable animal models for the study of cytoadhesion of P. falciparum-infected erythrocytes (IEs) has necessitated in vitro studies employing a range of cell lines of either human tumour ...origin (e.g., BeWo and C32 cells) or non-human origin (e.g., CHO cells). Of the human cells available, many were isolated from adults, or derived from a pool of donors (e.g., HBEC-5i). Here we demonstrate, for the first time, the successful isolation of blood outgrowth endothelial cells (BOECs) from frozen stabilates of peripheral blood mononuclear cells obtained from small-volume peripheral blood samples from paediatric malaria patients. BOECs are a sub-population of human endothelial cells, found within the peripheral blood. We demonstrate that these cells express receptors such as Intercellular Adhesion Molecule 1 (ICAM-1/CD54), Endothelial Protein C Receptor (EPCR/CD201), platelet/endothelial cell adhesion molecule 1 (PECAM-1/CD31), Thrombomodulin (CD141), and support adhesion of P. falciparum IEs.
Background: Resting metabolic rate (RMR) has significantly declined over the last 100 years. Several factors, including a lowered body temperature and decreased immune activity, have, in part, ...explained this decline. However, recently it was shown that replacing refined grains with whole grains is associated with a normalization of RMR. As consuming more whole grain fiber can promote increased obligate anaerobic bacterial fermentation activity in the gut microbiome, resulting in increased short chain fatty acid (SCFA) production, it is possible that the microbiome may mediate the association between whole grain consumption and RMR normalization. Currently, many countries are experiencing an epidemiological transition by adopting diets high in ultra-processed foods and low in fiber. Indeed 10 Year NHANES trend for fiber and whole grain intake show that less than half of the US meet the current fiber recommendations. Methods: We explored the associations between measured RMR, dietary fiber intake, gut microbiota (ASVs) and fecal SCFAs in 104 METSMicrobiome adults from Ghana (N=33), South Africa (SA, N=42) and US (N=29). Results: Ghanaians had the lowest average BMIs and obesity prevalence, followed by SA and then US participants, and both Ghanaians and SAs had higher measured RMR compared to the US. Ghanaians consumed almost twice as much fiber (25.1 vs. 16.9 g/d) compared to US, which associated with greater fecal SCFA concentrations. Across all sites, meeting dietary fiber recommendations (14g/1000kcal) resulted in a greater microbial alpha diversity and the enrichment of 18 ASVs mostly associated with the SCFA-producing class Clostridia. Similarly, participants who's measured RMR met their predicted RMRs using the Cunningham equation, had significantly different microbial beta diversity and were enriched for 43 ASVs mostly from the class Clostridia when compared to those who did not. Conclusions: In an international cohort of African-origin adults, country of origin is significantly associated with both fiber intake, fecal SCFAs and measured RMR, which is reflected by differential abundance and diversity in the gut microbiota. As countries experience the epidemiologic transition, the importance of a dietary fiber should be emphasized as a low-cost method to maintain metabolic health.
Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the ...PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.
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•Structural basis for P. falciparum PfEMP1 binding to endothelial receptor ICAM-1defined•A sequence motif derived from structure predicts group A PfEMP1 binding to ICAM-1•These ICAM-1-binding PfEMP1s also all bind to endothelial protein C receptor (EPCR)•Expression of dual ICAM-1- and EPCR-binding PfEMP1 is associated with cerebral malaria
Plasmodium falciparum-infected erythrocytes display PfEMP1 proteins that bind various endothelial receptors, including ICAM-1. Lennartz et al. structurally characterize PfEMP1 binding to ICAM-1, allowing them to identify a PfEMP1 family that simultaneously binds to both ICAM-1 and EPCR. Dual-binding PfEMP1s display stronger endothelial adhesion and are associated with cerebral malaria.
•Current literature suggests immune-microbiome signaling could be relevant to OCD.•We discuss mechanisms by which gut-brain-immune axis dysfunction could underlie OCD.•OCD is heterogeneous, and ...future microbiome investigations should take this into account.•This offers to be a novel area of inquiry to further our understanding and treatment of OCD.
Obsessive-compulsive disorder (OCD) is disabling and often treatment-refractory. Host immunity and gut microbiota have bidirectional communication with each other and with the brain. Perturbations to this axis have been implicated in neuropsychiatric disorders, but immune-microbiome signaling in OCD is relatively underexplored. We review support for further pursuing such investigations in OCD, including: 1) gut microbiota has been associated with OCD, but causal pathogenic mechanisms remain unclear; 2) early environmental risk factors for OCD overlap with critical periods of immune-microbiome development; 3) OCD is associated with increased risk of immune-mediated disorders and changes in immune parameters, which are separately associated with the microbiome; and 4) gut microbiome manipulations in animal models are associated with changes in immunity and some obsessive-compulsive symptoms. Theoretical pathogenic mechanisms could include microbiota programming of cytokine production, promotion of expansion and trafficking of peripheral immune cells to the CNS, and regulation of microglial function. Immune-microbiome signaling in OCD requires further exploration, and may offer novel insights into pathogenic mechanisms and potential treatment targets for this disabling disorder.
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