scholarly journals Biomimetic Gut Model Systems for Development of Targeted Microbial Solutions for Enhancing Warfighter Health and Performance

mSystems ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Lauren M. Brinkac ◽  
Nandita Rahman ◽  
Loun-Loun Chua ◽  
Sterling Thomas
Keyword(s):  
Human Health ◽  
Gut Microbiome ◽  
Human Microbiome ◽  
Research Priorities ◽  
Performance Outcomes ◽  
Vital Role ◽  
Model Systems ◽  
Experimental Model Systems ◽  
And Performance

ABSTRACT The human gut microbiome plays a vital role in both health and disease states and as a mediator of cognitive and physical performance. Despite major advances in our understanding of the role of gut microbes in host physiology, mechanisms underlying human-microbiome dynamics have yet to be fully elucidated. This knowledge gap represents a major hurdle to the development of targeted gut microbiome solutions influencing human health and performance outcomes. The microbiome as it relates to warfighter health and performance is of interest to the Department of Defense (DoD) with the development of interventions impacting gut microbiome resiliency among its top research priorities. While technological advancements are enabling the development of experimental model systems that facilitate mechanistic insights underpinning human health, disease, and performance, translatability to human outcomes is still questionable. This review discusses some of the drivers influencing the DoD’s interest in the warfighter gut microbiome and describes current in vitro gut model systems supporting direct microbial-host interactions.

scholarly journals Controversies on Endocrine and Reproductive Effects of Glyphosate and Glyphosate-Based Herbicides: A Mini-Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Anderson Tadeu de Araújo-Ramos ◽  
Marcella Tapias Passoni ◽  
Marco Aurélio Romano ◽  
Renata Marino Romano ◽  
Anderson Joel Martino-Andrade
Keyword(s):  
Human Health ◽  
Active Ingredient ◽  
Model Systems ◽  
Regulatory Agencies ◽  
Technical Grade ◽  
Organ Systems ◽  
Endocrine Disrupting ◽  
Experimental Model Systems

Glyphosate-based herbicides (GBHs) are among the most used pesticides worldwide, presenting high potential for human exposure. Recently, a debate was raised on glyphosate risks to human health due to conflicting views over its potential carcinogenic and endocrine disruptive properties. Results from regulatory guideline studies, reports from Regulatory Agencies, and some literature studies point to a lack of endocrine disrupting properties of the active ingredient glyphosate. On the other hand, many in vivo and in vitro studies, using different experimental model systems, have demonstrated that GBHs can disrupt certain hormonal signaling pathways with impacts on the hypothalamic-pituitary-gonadal axis and other organ systems. Importantly, several studies showed that technical-grade glyphosate is less toxic than formulated GBHs, indicating that the mixture of the active ingredient and formulants can have cumulative effects on endocrine and reproductive endpoints, which requires special attention from Regulatory Agencies. In this mini-review, we discuss the controversies related to endocrine-disrupting properties of technical-grade glyphosate and GBHs emphasizing the reproductive system and its implications for human health.

scholarly journals Controlled Complexity: Optimized Systems to Study the Role of the Gut Microbiome in Host Physiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Robert W. P. Glowacki ◽  
Morgan J. Engelhart ◽  
Philip P. Ahern
Keyword(s):  
Gut Microbiome ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Human Microbiome ◽  
Model Systems ◽  
Wild Mice ◽  
Host Health ◽  
Host Physiology ◽  
The Impact

The profound impact of the gut microbiome on host health has led to a revolution in biomedical research, motivating researchers from disparate fields to define the specific molecular mechanisms that mediate host-beneficial effects. The advent of genomic technologies allied to the use of model microbiomes in gnotobiotic mouse models has transformed our understanding of intestinal microbial ecology and the impact of the microbiome on the host. However, despite incredible advances, our understanding of the host-microbiome dialogue that shapes host physiology is still in its infancy. Progress has been limited by challenges associated with developing model systems that are both tractable enough to provide key mechanistic insights while also reflecting the enormous complexity of the gut ecosystem. Simplified model microbiomes have facilitated detailed interrogation of transcriptional and metabolic functions of the microbiome but do not recapitulate the interactions seen in complex communities. Conversely, intact complex communities from mice or humans provide a more physiologically relevant community type, but can limit our ability to uncover high-resolution insights into microbiome function. Moreover, complex microbiomes from lab-derived mice or humans often do not readily imprint human-like phenotypes. Therefore, improved model microbiomes that are highly defined and tractable, but that more accurately recapitulate human microbiome-induced phenotypic variation are required to improve understanding of fundamental processes governing host-microbiome mutualism. This improved understanding will enhance the translational relevance of studies that address how the microbiome promotes host health and influences disease states. Microbial exposures in wild mice, both symbiotic and infectious in nature, have recently been established to more readily recapitulate human-like phenotypes. The development of synthetic model communities from such “wild mice” therefore represents an attractive strategy to overcome the limitations of current approaches. Advances in microbial culturing approaches that allow for the generation of large and diverse libraries of isolates, coupled to ever more affordable large-scale genomic sequencing, mean that we are now ideally positioned to develop such systems. Furthermore, the development of sophisticated in vitro systems is allowing for detailed insights into host-microbiome interactions to be obtained. Here we discuss the need to leverage such approaches and highlight key challenges that remain to be addressed.

scholarly journals The Gut Microbiome as a Component of the Gut–Brain Axis in Cognitive Health

2020 ◽  
Vol 22 (4) ◽  
pp. 485-494
Author(s):  
Wen Gao ◽  
Kelley L. Baumgartel ◽  
Sheila A. Alexander
Keyword(s):  
Cognitive Development ◽  
Gut Microbiome ◽  
Human Microbiome ◽  
Vital Role ◽  
The Body ◽  
Nursing Research ◽  
Brain Physiology ◽  
Cognitive States ◽  
And Function ◽  
Development Stability

Introduction: The human microbiome, the microorganisms living in and on the body, plays a vital role in brain physiology and pathophysiology. The gut microbiome (GMB) has been identified as a link in the gut–brain axis moderating cognitive development and health. Objectives: The objectives of this scoping review are to discuss mechanisms of the microbiome–gut–brain axis in cognition, review the existing literature on the GMB and cognition, and discuss implications for nursing research. Methods: We searched Pubmed using the terms “gut microbiome,” “brain,” and “cognition” and the terms “gut brain axis,” “microbiome,” and “cognition”; removed duplicates, studies not published in English, and unrelated publications; and added additional articles identified through references. We retained the 85 most relevant publications for this review. Results: Common themes in the current literature include GMB components; interactions on cognitive development; effects of GMB–gut–brain interactions on cognition, mild cognitive impairment and Alzheimer’s disease; effects of GMB interactions with physiologic stress on cognition in critical care; and GMB modification for improved cognition. Review of the literature on each of these topics reveals multiple theoretical mechanisms of action for GMB–gut–brain interaction that modify cognitive development and function across the lifespan. Discussion: GMB components and dysbiosis have been implicated in many cognitive states, and specific microbiota constituents contribute to cognitive development, stability, and impairment. The study of these interactions is relevant to nursing research as it addresses the holistic human experience and microbiome constituents are modifiable, facilitating translation into the clinical setting.

scholarly journals The Gut Microbiome and Xenobiotics: Identifying Knowledge Gaps

2020 ◽  
Vol 176 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Vicki L Sutherland ◽  
Charlene A McQueen ◽  
Donna Mendrick ◽  
Donna Gulezian ◽  
Carl Cerniglia ◽  
...  
Keyword(s):  
Human Health ◽  
Gut Microbiome ◽  
Critical Role ◽  
Drug Efficacy ◽  
Model Systems ◽  
Microbial Composition ◽  
Breakout Group ◽  
Data Gaps ◽  
Critical Issues ◽  
And Function

Abstract There is an increasing awareness that the gut microbiome plays a critical role in human health and disease, but mechanistic insights are often lacking. In June 2018, the Health and Environmental Sciences Institute (HESI) held a workshop, “The Gut Microbiome: Markers of Human Health, Drug Efficacy and Xenobiotic Toxicity” (https://hesiglobal.org/event/the-gut-microbiome-workshop) to identify data gaps in determining how gut microbiome alterations may affect human health. Speakers and stakeholders from academia, government, and industry addressed multiple topics including the current science on the gut microbiome, endogenous and exogenous metabolites, biomarkers, and model systems. The workshop presentations and breakout group discussions formed the basis for identifying data gaps and research needs. Two critical issues that emerged were defining the microbial composition and function related to health and developing standards for models, methods and analysis in order to increase the ability to compare and replicate studies. A series of key recommendations were formulated to focus efforts to further understand host-microbiome interactions and the consequences of exposure to xenobiotics as well as identifying biomarkers of microbiome-associated disease and toxicity.

Cooperativity and regulation through conformational changes as features of phage assembly

1976 ◽  
Vol 276 (943) ◽  
pp. 3-13 ◽  
Keyword(s):  
Experimental Model ◽  
Conformational Changes ◽  
Model Systems ◽  
Conformational States ◽  
Phage Assembly ◽  
Specific Stage ◽  
T4 Phage ◽  
Experimental Model Systems ◽  
Complete Dissociation

The assembly of bacteriophages provides experimental model systems for the study of regulation at the level of gene products. We discuss the hypothesis of regulation through sequentially induced conformational changes by which precursor-assemblies become ready at a specific stage of maturation to interact with an additional gene product or nucleic acids. Phage mutants provide excellent experimental model systems for studying, for example, the role and fate of the core in the prehead assembly. The conservative maturation of the prehead to the final, stable head consists of several steps whose complexity reflect that of the virus. It includes packaging of DNA. The surface lattice of maturing preheads apparently undergoes several steps characterized by different conformational states as suggested by in vitro studies on a morphological variant of the prehead, the polyhead of phage T4 (Steven, Couture, Aebi & Showe 1976; Laemmli, Amos & Klug 1976). Addition of a partly purified, enriched proteolytic fraction - which is gene 21-dependent - to empty purified polyheads leads to different conformational states. These seem to go in a direction approaching the structure of the surface of finished capsids as studied by Aebi et al . on gene 24 related (Bijlenga, Aebi & Kellenberger 1976) and other genetically defined giant-variants of T4 phage (Doermann, Eiserling & Boehner 1973). We show some experiments which suggest that high cooperativity is responsible for the stabilization of capsids. The activation energy necessary for dissociation of capsids is very high, 247 kJ for T4 capsids, and 10% smaller for T2. Once the energy barrier has been overcome, the capsids are first structurally modified before they undergo partial and finally complete dissociation.

scholarly journals Tuberculostearic acid (TSA)-containing phosphatidylinositols as reliable marker to determine Mycobacterium tuberculosis bacterial burden

2021 ◽  
Author(s):  
Julius Brandenburg ◽  
Jan Heyckendorf ◽  
Franziska Waldow ◽  
Nicole Zehethofer ◽  
Lara Linnemann ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mononuclear Cells ◽  
Model Systems ◽  
Human Neutrophils ◽  
Bacterial Burden ◽  
Peripheral Blood Mononuclear ◽  
Causative Agents ◽  
Tuberculostearic Acid ◽  
Experimental Model Systems

AbstractIt is estimated that approximately one-fourth of the world's population is infected with strains of the Mycobacterium tuberculosis complex (MTBC), the causative agents of tuberculosis (TB). In this study, we present rationally developed molecular markers for bacterial burden, which are derived from mycobacterial phospholipids. Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PI) are present in all clinically relevant MTBC lineages investigated. For the major abundant lipid PI 16:0_19:0 (TSA), a detection limit equivalent to 102 colony forming units (CFU) was determined for bacterial cultures and approximately 103 for cell culture systems. We further developed a mass spectrometry based targeted lipid assay, which – in contrast to bacterial quantification on solid medium – can be performed within several hours including sample preparation. Translation of this indirect and culture-free detection approach allowed the determination of pathogen loads in infected murine macrophages, human neutrophils and murine lung tissue. We show that marker lipids inferred from the mycobacterial PIs are increased in peripheral blood mononuclear cells (PBMCs) of TB patients beyond the lipid metabolic background in comparison to healthy controls. In a small cohort of drug-susceptible TB patients elevated levels of these marker molecules were detected at therapy start and declined following successful anti-tuberculosis treatment. The concentration of TSA-containing PIs can be used as correlate for reliable and rapid quantification of Mycobacterium tuberculosis (Mtb) burden in experimental in vitro model systems and may also provide a clinically relevant tool for monitoring TB therapy.One Sentence SummaryTuberculostearic acid containing phosphatidylinositols represent a novel, fast to measure, reliable correlate of Mycobacterium tuberculosis bacterial burden in experimental model systems, which makes a future clinical application conceivable.

scholarly journals Gut Microbiome Functional and Taxonomic Diversity within an Amazonian semi-nomadic hunter-gatherer group

2019 ◽  
Author(s):  
LC Conteville ◽  
J Oliveira-Ferreira ◽  
AC Vicente
Keyword(s):  
Human Health ◽  
Gut Microbiome ◽  
Human Microbiome ◽  
Gene Families ◽  
Taxonomic Diversity ◽  
South American ◽  
Traditional Group ◽  
Hunter Gatherers ◽  
Functional Features ◽  
Number Of Individuals

AbstractBackgroundHuman gut microbiome profiles have been associated with human health and disease. These profiles have been defined based on microbes’ taxonomy and more recently, on their functionality. Human groups that still maintain traditional modes of subsistence (hunter-gatherers and rural agriculturalists) represent the groups non-impacted by urban-industrialized lifestyles, and therefore study them provide the basis for understanding the human microbiome evolution. The Yanomami is the largest semi-nomadic hunter-gatherer group of the Americas, exploring different niches of the Amazon rainforest in Brazil and Venezuela. In order to extend the analysis of this unique and diverse group, we focused on the gut microbiome of the Yanomami from Brazil and compared with those from Venezuela, and also with other traditional groups from the Amazon, considering taxonomic and functional profiles.ResultsA diversity of taxonomic biomarkers were identified to each South American traditional group studied, including the two Yanomami groups, despite their overall similarity in the taxonomic gut microbiome profiles. Broader levels of functional categories poorly discriminated traditional and urban-industrialized groups. Interestingly, a diversity was observed with the stratification of these categories, clearly segregating those groups. The Yanomami/Brazil gut microbiome presented unique functional features, such as a higher abundance of gene families involved in regulation/cell signaling, motility/chemotaxis, and virulence, contrasting with the microbiomes from the Yanomami/Venezuela and other groups.ConclusionsOur study revealed biomarkers, taxonomic and functional differences between the gut microbiome of Yanomami/Brazil and Yanomami/Venezuela individuals. This intra-Yanomami group diversity was accessed due to the increase number of individuals and group studied. These differences may reflect their semi-nomadic behavior, as well as, the local and seasonal diversity of the vast rainforest niche they explore, despite their shared cultural and genetic background. Overall, their microbiome profiles are shared with South American and African traditional groups, probably due to their lifestyle. The unique features identified within the Yanomami highlight the bias imposed by underrepresented sampling, and factors such as variations over space and time (seasonality) that impact, mainly, the hunter-gatherers. Therefore, to reach knowledge about human microbiome variations and their implications in human health, it is essential to enlarge data concerning the number of individuals, as well as the groups representing different lifestyles.

scholarly journals Optical interrogation of sympathetic neuronal effects on macroscopic cardiac monolayer dynamics

2019 ◽  
Author(s):  
R.A.B. Burton ◽  
J. Tomek ◽  
C.M. Ambrosi ◽  
H.E. Larsen ◽  
A.R. Sharkey ◽  
...  
Keyword(s):  
Experimental Model ◽  
Autonomic Function ◽  
Sympathetic Neurons ◽  
Cellular Level ◽  
Neural Stimulation ◽  
Model Systems ◽  
Adrenergic Stimulation ◽  
Cardiac Stimulation ◽  
Experimental Model Systems

ABSTRACTAlterations in autonomic function are known to occur in cardiac conditions including sudden cardiac death. Cardiac stimulation via sympathetic neurons can potentially trigger arrhythmias. Dissecting direct neural-cardiac interactions at the cellular level is technically challenging and understudied due to the lack of experimental model systems and methodologies. Here we demonstrate the utility of optical interrogation of sympathetic neurons and their effects on macroscopic cardiac monolayer dynamics to address research targets such as the effects of adrenergic stimulation via the release of neurotransmitters, the effect of neuronal numbers on cardiac wave behaviour and the applicability of optogenetics in mechanistic in vitro studies. We combine photo-uncaging or optogenetic neural stimulation with imaging of cardiac monolayers to measure electrical activity in an automated fashion, illustrating the power and high throughput capability of such interrogations. The methods described highlight the challenges and benefits of co-cultures as experimental model systems.

scholarly journals Harnessing Colon Chip Technology to Identify Commensal Bacteria That Promote Host Tolerance to Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Francesca S. Gazzaniga ◽  
Diogo M. Camacho ◽  
Meng Wu ◽  
Matheus F. Silva Palazzo ◽  
Alexandre L. M. Dinis ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Human Microbiome ◽  
Commensal Bacteria ◽  
Bacterial Strains ◽  
Mucus Production ◽  
16S Sequencing ◽  
Chip Technology ◽  
Host Microbe Interactions ◽  
Host Tolerance

Commensal bacteria within the gut microbiome contribute to development of host tolerance to infection, however, identifying specific microbes responsible for this response is difficult. Here we describe methods for developing microfluidic organ-on-a-chip models of small and large intestine lined with epithelial cells isolated from duodenal, jejunal, ileal, or colon organoids derived from wild type or transgenic mice. To focus on host-microbiome interactions, we carried out studies with the mouse Colon Chip and demonstrated that it can support co-culture with living gut microbiome and enable assessment of effects on epithelial adhesion, tight junctions, barrier function, mucus production, and cytokine release. Moreover, infection of the Colon Chips with the pathogenic bacterium, Salmonella typhimurium, resulted in epithelial detachment, decreased tight junction staining, and increased release of chemokines (CXCL1, CXCL2, and CCL20) that closely mimicked changes previously seen in mice. Symbiosis between microbiome bacteria and the intestinal epithelium was also recapitulated by populating Colon Chips with complex living mouse or human microbiome. By taking advantage of differences in the composition between complex microbiome samples cultured on each chip using 16s sequencing, we were able to identify Enterococcus faecium as a positive contributor to host tolerance, confirming past findings obtained in mouse experiments. Thus, mouse Intestine Chips may represent new experimental in vitro platforms for identifying particular bacterial strains that modulate host response to pathogens, as well as for investigating the cellular and molecular basis of host-microbe interactions.

scholarly journals New Insights into Long Non-Coding RNA MALAT1 in Cancer and Metastasis

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 216 ◽  
Author(s):  
Yutong Sun ◽  
Li Ma
Keyword(s):  
Cancer Metastasis ◽  
Mammalian Species ◽  
Model Systems ◽  
Normal Tissues ◽  
Lung Cancer Metastasis ◽  
Non Coding Rna ◽  
Cancer Types ◽  
Experimental Model Systems ◽  
Long Non Coding Rna

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the most abundant, long non-coding RNAs (lncRNAs) in normal tissues. This lncRNA is highly conserved among mammalian species, and based on in vitro results, has been reported to regulate alternative pre-mRNA splicing and gene expression. However, Malat1 knockout mice develop and grow normally, and do not show alterations in alternative splicing. While MALAT1 was originally described as a prognostic marker of lung cancer metastasis, emerging evidence has linked this lncRNA to other cancers, such as breast cancer, prostate cancer, pancreatic cancer, glioma, and leukemia. The role described for MALAT1 is dependent on the cancer types and the experimental model systems. Notably, different or opposite phenotypes resulting from different strategies for inactivating MALAT1 have been observed, which led to distinct models for MALAT1′s functions and mechanisms of action in cancer and metastasis. In this review, we reflect on different experimental strategies used to study MALAT1′s functions, and discuss the current mechanistic models of this highly abundant and conserved lncRNA.

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