The Microbiota and Gut-Related Disorders: Insights from Animal Models

Over the past decade, the scientific committee has called for broadening our horizons in understanding host–microbe interactions and infectious disease progression. Owing to the fact that the human gut harbors trillions of microbes that exhibit various roles including the production of vitamins, absorption of nutrients, pathogen displacement, and development of the host immune system, particular attention has been given to the use of germ-free (GF) animal models in unraveling the effect of the gut microbiota on the physiology and pathophysiology of the host. In this review, we discuss common methods used to generate GF fruit fly, zebrafish, and mice model systems and highlight the use of these GF model organisms in addressing the role of gut-microbiota in gut-related disorders (metabolic diseases, inflammatory bowel disease, and cancer), and in activating host defense mechanisms and amending pathogenic virulence.

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Impact of Nutrition on Pulmonary Arterial Hypertension

Nutrients ◽

10.3390/nu12010169 ◽

2020 ◽

Vol 12 (1) ◽

pp. 169

Author(s):

María Callejo ◽

Joan Albert Barberá ◽

Juan Duarte ◽

Francisco Perez-Vizcaino

Keyword(s):

Pulmonary Arterial Hypertension ◽

Animal Models ◽

Gut Microbiota ◽

Arterial Hypertension ◽

Case Reports ◽

Host Immune System ◽

Dietary Polyphenols ◽

Pulmonary Arterial ◽

Near Future

Pulmonary arterial hypertension (PAH) is characterized by sustained vasoconstriction, vascular remodeling, inflammation, and in situ thrombosis. Although there have been important advances in the knowledge of the pathophysiology of PAH, it remains a debilitating, limiting, and rapidly progressive disease. Vitamin D and iron deficiency are worldwide health problems of pandemic proportions. Notably, these nutritional alterations are largely more prevalent in PAH patients than in the general population and there are several pieces of evidence suggesting that they may trigger or aggravate disease progression. There are also several case reports associating scurvy, due to severe vitamin C deficiency, with PAH. Flavonoids such as quercetin, isoflavonoids such as genistein, and other dietary polyphenols including resveratrol slow the progression of the disease in animal models of PAH. Finally, the role of the gut microbiota and its interplay with the diet, host immune system, and energy metabolism is emerging in multiple cardiovascular diseases. The alteration of the gut microbiota has also been reported in animal models of PAH. It is thus possible that in the near future interventions targeting the nutritional status and the gut dysbiosis will improve the outcome of these patients.

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Characteristics of in Vivo Model Systems for Ovarian Cancer Studies

Diagnostics ◽

10.3390/diagnostics9030120 ◽

2019 ◽

Vol 9 (3) ◽

pp. 120 ◽

Cited By ~ 6

Author(s):

Tudrej ◽

Kujawa ◽

Cortez ◽

Lisowska

Keyword(s):

Ovarian Cancer ◽

Animal Models ◽

Xenograft Model ◽

Cellular Migration ◽

Model Systems ◽

In Vivo Model ◽

Preclinical Studies ◽

Cell Of Origin ◽

Mice Model ◽

Mesenchymal Transition

An understanding of the molecular pathogenesis and heterogeneity of ovarian cancer holds promise for the development of early detection strategies and novel, efficient therapies. In this review, we discuss the advantages and limitations of animal models available for basic and preclinical studies. The fruit fly model is suitable mainly for basic research on cellular migration, invasiveness, adhesion, and the epithelial-to-mesenchymal transition. Higher-animal models allow to recapitulate the architecture and microenvironment of the tumor. We discuss a syngeneic mice model and the patient derived xenograft model (PDX), both useful for preclinical studies. Conditional knock-in and knock-out methodology allows to manipulate selected genes at a given time and in a certain tissue. Such models have built our knowledge about tumor-initiating genetic events and cell-of-origin of ovarian cancers; it has been shown that high-grade serous ovarian cancer may be initiated in both the ovarian surface and tubal epithelium. It is postulated that clawed frog models could be developed, enabling studies on tumor immunity and anticancer immune response. In laying hen, ovarian cancer develops spontaneously, which provides the opportunity to study the genetic, biochemical, and environmental risk factors, as well as tumor initiation, progression, and histological origin; this model can also be used for drug testing. The chick embryo chorioallantoic membrane is another attractive model and allows the study of drug response.

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Resistant potato starch fuels beneficial host-microbe interactions in the gut

10.1101/389007 ◽

2018 ◽

Cited By ~ 2

Author(s):

Julian Trachsel ◽

Cassidy Briggs ◽

Nicholas K. Gabler ◽

Heather K. Allen ◽

Crystal L. Loving

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Gut Microbiota ◽

Potato Starch ◽

Immunological Tolerance ◽

Bacterial Respiration ◽

Host Immune System ◽

Gut Health ◽

Disease States ◽

Host Microbe Interactions

AbstractInteractions between diet, the microbiota, and the host set the ecological conditions in the gut and have broad implications for health. Prebiotics are dietary compounds that may shift these conditions towards health by promoting the growth of beneficial microbes. Pigs fed a diet amended with 5% resistant potato starch (RPS) exhibited alterations associated with gut health relative to swine fed an unamended diet (CON). RPS intake increased abundances of anaerobicClostridiain feces and several tissues, as well as intestinal concentrations of butyrate. Functional gene amplicons suggested bacteria similar toAnaerostipes hadruswere stimulated by RPS intake. The CON treatment exhibited increased abundances of several genera ofProteobacteria(which utilize respiratory metabolisms) in several location. RPS intake increased the abundance of regulatory T cells in the cecum, but not periphery, and cecal immune status alterations were indicative of enhanced mucosal defenses. A network analysis of host and microbial changes in the cecum revealed that regulatory T cells positively correlated with butyrate concentration, luminal IgA concentration, expression of IL-6 and DEF1B, and several mucosa-associated bacterial taxa. Thus, the administration of RPS modulated the microbiota and host response, improved cecal barrier function, promoted immunological tolerance, and reduced the niche for bacterial respiration.ImportanceThe gut microbiota is central to host health. Many disease states and disorders appear to arise from interactions between the gut microbial community and host immune system. As a result, methods and interventions to support the growth and activity of beneficial gut microbes are being actively pursued. Feeding the gut microbiota with dietary compounds, known as prebiotics, is one of the most promising ways to support gut health. Here we describe a successful prebiotic intervention in weaning swine, a relevant translational model for human health. This work unites microbial and immunological data and demonstrates one way a prebiotic intervention can play out for the benefit of the host.

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The Queen Gut Refines with Age: Longevity Phenotypes in a Social Insect Model

10.1101/297507 ◽

2018 ◽

Author(s):

Kirk E. Anderson ◽

Vincent A. Ricigliano ◽

Brendon M. Mott ◽

Duan C. Copeland ◽

Amy S. Floyd ◽

...

Keyword(s):

Oxidative Stress ◽

Gut Microbiota ◽

Honey Bee ◽

Honey Bees ◽

Bacterial Species ◽

Microbial Interactions ◽

Model Systems ◽

Model Organisms ◽

Biological Aging ◽

Microbial Succession

AbstractBackgroundIn social insects, identical genotypes can show extreme lifespan variation providing a unique perspective on age-associated microbial succession. In honey bees, short and long-lived host phenotypes are polarized by a suite of age-associated factors including hormones, nutrition, immune senescence and oxidative stress. Similar to other model organisms, the aging gut microbiota of short-lived (worker) honey bees accrue Proteobacteria and are depleted of Lactobacillus and Bifidobacterium, consistent with a suite of host senescence markers. In contrast, long-lived (queen) honey bees maintain youthful cellular function without expressing oxidative stress genes, suggesting a very different host environment for age-associated microbial succession.ResultsWe sequenced the microbiota of 63 honey bee queens exploring two chronological ages and four alimentary tract niches. To control for individual variation we quantified carbonyl accumulation in queen fat body tissue as a proxy for biological aging. We compared our results to the age-specific microbial succession of worker guts. Accounting for queen source variation, two or more bacterial species per niche differed significantly by queen age. Biological aging in queens was correlated with microbiota composition highlighting the relationship of microbiota with oxidative stress. Queens and workers shared many major gut bacterial species, but differ markedly in community structure and age succession. In stark contrast to aging workers, carbonyl accumulation in queens was significantly associated with increased Lactobacillus and Bifidobacterium and depletion of various Proteobacteria.ConclusionsWe present a model system linking changes in gut microbiota to diet and longevity, two of the most confounding variables in human microbiota research. As described for other model systems, metabolic changes associated with diet and host longevity correspond to the changing microbiota. The pattern of age-associated succession in the queen microbiota is largely the reverse of that demonstrated for workers. The guts of short-lived worker phenotypes are progressively dominated by three major Proteobacteria, but these same species were sparse or significantly depleted in long-lived queen phenotypes. More broadly, our results suggest that lifespan evolution formed the context for host-microbial interactions and age-related succession of honey bee microbiota.

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Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.767457 ◽

2021 ◽

Vol 15 ◽

Author(s):

Erin Knock ◽

Lisa M. Julian

Keyword(s):

Stem Cells ◽

Animal Models ◽

Human Brain ◽

Pluripotent Stem Cells ◽

Human Pluripotent Stem Cells ◽

Model Systems ◽

Model Organisms ◽

Slice Culture ◽

Neural Cells ◽

Cell Culture Techniques

The brain is our most complex and least understood organ. Animal models have long been the most versatile tools available to dissect brain form and function; however, the human brain is highly distinct from that of standard model organisms. In addition to existing models, access to human brain cells and tissues is essential to reach new frontiers in our understanding of the human brain and how to intervene therapeutically in the face of disease or injury. In this review, we discuss current and developing culture models of human neural tissue, outlining advantages over animal models and key challenges that remain to be overcome. Our principal focus is on advances in engineering neural cells and tissue constructs from human pluripotent stem cells (PSCs), though primary human cell and slice culture are also discussed. By highlighting studies that combine animal models and human neural cell culture techniques, we endeavor to demonstrate that clever use of these orthogonal model systems produces more reproducible, physiological, and clinically relevant data than either approach alone. We provide examples across a range of topics in neuroscience research including brain development, injury, and cancer, neurodegenerative diseases, and psychiatric conditions. Finally, as testing of PSC-derived neurons for cell replacement therapy progresses, we touch on the advancements that are needed to make this a clinical mainstay.

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Thioester-Containing Proteins in the Drosophila melanogaster Immune Response against the Pathogen Photorhabdus

Insects ◽

10.3390/insects11020085 ◽

2020 ◽

Vol 11 (2) ◽

pp. 85

Author(s):

Ioannis Eleftherianos ◽

Upasana Sachar

Keyword(s):

Drosophila Melanogaster ◽

Immune Surveillance ◽

Fruit Fly ◽

Research Field ◽

Innate Immune ◽

Host Immune System ◽

Innate Immune Signaling ◽

Microbe Interactions ◽

Host Microbe Interactions

The fruit fly Drosophila melanogaster forms a magnificent model for interpreting conserved host innate immune signaling and functional processes in response to microbial assaults. In the broad research field of host-microbe interactions, model hosts are used in conjunction with a variety of pathogenic microorganisms to disentangle host immune system activities and microbial pathogenicity strategies. The pathogen Photorhabdus is considered an established model for analyzing bacterial virulence and symbiosis due to its unique life cycle that extends between two invertebrate hosts: an insect and a parasitic nematode. In recent years, particular focus has been given to the mechanistic participation of the D. melanogaster thioester-containing proteins (TEPs) in the overall immune capacity of the fly upon response against the pathogen Photorhabdus alone or in combination with its specific nematode vector Heterorhabditis bacteriophora. The original role of certain TEPs in the insect innate immune machinery was linked to the antibacterial and antiparasite reaction of the mosquito malaria vector Anopheles gambiae; however, revamped interest in the immune competence of these molecules has recently emerged from the D. melanogaster-Photorhabdus infection system. Here, we review the latest findings on this topic with the expectation that such information will refine our understanding of the evolutionary immune role of TEPs in host immune surveillance.

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Gut Microbiota Aberration in Patients of Systemic Sclerosis and Bleomycin-Induced Mice Model

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.647201 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jungen Tang ◽

Xin Zhou ◽

Xuefen Wu ◽

Shengyan Lin ◽

Bingxia Ming ◽

...

Keyword(s):

Systemic Sclerosis ◽

Animal Models ◽

Gut Microbiota ◽

Vascular Lesions ◽

Systemic Autoimmune Disease ◽

Unknown Etiology ◽

Rrna Gene ◽

High Morbidity ◽

Mice Model ◽

Gastrointestinal Lesions

Systemic sclerosis (SSc) is an immune-mediated systemic autoimmune disease with unknown etiology, which has high morbidity and mortality. Current treatments to dispose of this disorder are limited. And there are still no ideal animal models that can fully replicate the four basic pathophysiological features of SSc, including vascular lesions, fibrosis, inflammation, and autoimmunity, let alone animal models specifically designed to study gastrointestinal lesions. It’s essential to seek and establish appropriate animal models to explore the role of gut microbiota in the pathogenesis of SSc. In this study, we found similar gut microbiota aberration in patients of SSc and bleomycin (BLM)-induced mice model through 16S rRNA gene sequencing. In terms of phylum-level differences, the relative abundance of Bacteroidetes was significantly decreased and Firmicutes increased in the SSc patients and the mice. Notably, the genera of Lactobacillus, commonly used as a probiotic additive, was also elevated in SSc patients and BLM mice, which was consistent with a few of studies. Therefore, the model can likely mimic the pathological changes of gut microbiota in patients with SSc, which may offer an important potential platform for the in-depth understanding of gut microbiota aberration in patients with SSc and to devise potential disease-modifying treatments.

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Reductionist thinking and animal models in neuropsychiatric research

Behavioral and Brain Sciences ◽

10.1017/s0140525x18001231 ◽

2019 ◽

Vol 42 ◽

Cited By ~ 1

Author(s):

Nicole M. Baran

Keyword(s):

Animal Models ◽

Mental Disorders ◽

Environmental Factors ◽

Neuropsychiatric Disorders ◽

Model Organisms ◽

Developmental Genetic ◽

Term Study ◽

Genetic And Environmental Factors ◽

Mechanisms Of Plasticity

AbstractReductionist thinking in neuroscience is manifest in the widespread use of animal models of neuropsychiatric disorders. Broader investigations of diverse behaviors in non-model organisms and longer-term study of the mechanisms of plasticity will yield fundamental insights into the neurobiological, developmental, genetic, and environmental factors contributing to the “massively multifactorial system networks” which go awry in mental disorders.

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Folate and vitamin B-12 deficiencies additively impaired memory function and disturbed the gut microbiota in amyloid-β infused rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000624 ◽

2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Sunmin Park ◽

Sunna Kang ◽

Da Sol Kim

Keyword(s):

Insulin Resistance ◽

Gut Microbiota ◽

Insulin Signaling ◽

Gut Microbiome ◽

Metabolic Diseases ◽

Memory Function ◽

Amyloid Β ◽

Impaired Memory ◽

Ca1 Region ◽

Folate And Vitamin B12

Abstract. Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer’s disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-β infused rats, and its mechanism was explored. Rats that received an amyloid-β(25–35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 μg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 μg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 μg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 μg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P < 0.05). Only AD-FAB12 exacerbated memory impairment by 1.3 and 1.4 folds, respectively, as measured by passive avoidance and water maze tests, compared to AD-CON(P < 0.01). Hippocampal insulin signaling and neuroinflammation were attenuated in AD-CON compared to Non-AD-CON. AD-FAB12 impaired the signaling (pAkt→pGSK-3β) and serum TNF-α and IL-1β levels the most among all groups. AD-CON decreased glucose tolerance by increasing insulin resistance compared to Non-AD-CON. AD-VB12 and AD-FAB12 increased insulin resistance by 1.2 and 1.3 folds, respectively, compared to the AD-CON. AD-CON and Non-AD-CON had a separate communities of gut microbiota. The relative counts of Bacteroidia were lower and those of Clostridia were higher in AD-CON than Non-AD-CON. AD-FA, but not V-B12, separated the gut microbiome community compared to AD-CON and AD-VB12(P = 0.009). In conclusion, folate and B-12 deficiencies impaired memory function by impairing hippocampal insulin signaling and gut microbiota in AD rats.

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Microbiota-Immune System Interactions in Human Neurological Disorders

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200726222138 ◽

2020 ◽

Vol 19 (7) ◽

pp. 509-526

Author(s):

Qin Huang ◽

Fang Yu ◽

Di Liao ◽

Jian Xia

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Neurological Disorders ◽

Brain Function ◽

Neurological Diseases ◽

Host Immune System ◽

Gut Dysbiosis ◽

Characteristic Features ◽

Novel Therapeutic Strategies

: Recent studies implicate microbiota-brain communication as an essential factor for physiology and pathophysiology in brain function and neurodevelopment. One of the pivotal mechanisms about gut to brain communication is through the regulation and interaction of gut microbiota on the host immune system. In this review, we will discuss the role of microbiota-immune systeminteractions in human neurological disorders. The characteristic features in the development of neurological diseases include gut dysbiosis, the disturbed intestinal/Blood-Brain Barrier (BBB) permeability, the activated inflammatory response, and the changed microbial metabolites. Neurological disorders contribute to gut dysbiosis and some relevant metabolites in a top-down way. In turn, the activated immune system induced by the change of gut microbiota may deteriorate the development of neurological diseases through the disturbed gut/BBB barrier in a down-top way. Understanding the characterization and identification of microbiome-immune- brain signaling pathways will help us to yield novel therapeutic strategies by targeting the gut microbiome in neurological disease.

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