Role Of Commensal Enteric Bacteria In The Pathogenesis Of Immune-Mediated Intestinal Inflammation: Lessons From Animal Models And Implications For Translational Research

Abstract Placental microRNAs (miRNAs) regulate the placental transcriptome and play a pathological role in preeclampsia (PE), a hypertensive disorder of pregnancy. Three PE rodent model studies explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their inducers, and potential gene targets. This review evaluates the role of miR-210, miR-126, and miR-148/152 in PE by comparing findings from the three rodent model studies with in vitro studies, other animal models, and preeclamptic patients to provide comprehensive insight into genetic components and pathological processes in the placenta contributing to PE. The majority of studies demonstrate miR-210 is upregulated in PE in part driven by HIF-1α and NF-κBp50, stimulated by hypoxia and/or immune-mediated processes. Elevated miR-210 may contribute to PE via inhibiting anti-inflammatory Th2-cytokines. Studies report an up- and downregulation of miR-126, arguably reflecting differences in expression between cell types and its multifunctional capacity. MiR-126 may play a pro-angiogenic role by mediating the PI3K-Akt pathway. Most studies report miR-148/152 family members are upregulated in PE. Evidence suggests they may inhibit DNA methylation of genes involved in metabolic and inflammatory pathways. Given the genetic heterogeneity of PE, it is unlikely that a single placental miRNA is a suitable therapeutic target for all patients. Investigating miRNAs in PE subtypes in patients and animal models may represent a more appropriate approach going forward. Developing methods for targeting placental miRNAs and specific placental cell types remains crucial for research seeking to target placental miRNAs as a novel treatment for PE.

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Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90685.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. G685-G695 ◽

Cited By ~ 104

Author(s):

Stephan C. Bischoff ◽

Reiner Mailer ◽

Oliver Pabst ◽

Gisela Weier ◽

Wanda Sedlik ◽

...

Keyword(s):

Serotonin Reuptake ◽

Sulfonic Acid ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Colonic Motility ◽

Trinitrobenzene Sulfonic Acid ◽

Targeted Deletion ◽

Immune Mediated ◽

Serotonin Reuptake Transporter

Serotonin (5-HT) regulates peristaltic and secretory reflexes in the gut. The serotonin reuptake transporter (SERT; SLC6A4), which inactivates 5-HT, is expressed in the intestinal mucosa and the enteric nervous system. Stool water content is increased and colonic motility is irregular in mice with a targeted deletion of SERT. We tested the hypotheses that 5-HT plays a role in regulating intestinal inflammation and that the potentiation of serotonergic signaling that results from SERT deletion is proinflammatory. Rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce an immune-mediated colitis, which was compared in SERT knockout mice and littermate controls. Intestinal myeloperoxidase and histamine levels were significantly increased, whereas the survival rate and state of health were significantly decreased in TNBS-treated mice that lacked SERT. Deletion of SERT thus increases the severity of TNBS colitis. These data suggest that 5-HT and its SERT-mediated termination play roles in intestinal immune/inflammatory responses in mice.

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Modeling the Encephalopathy of Prematurity in Animals: The Important Role of Translational Research

Neurology Research International ◽

10.1155/2012/295389 ◽

2012 ◽

Vol 2012 ◽

pp. 1-17 ◽

Cited By ~ 32

Author(s):

Hannah C. Kinney ◽

Joseph J. Volpe

Keyword(s):

Brain Injury ◽

White Matter ◽

Animal Models ◽

Translational Research ◽

Developmental Trajectories ◽

Axonal Injury ◽

White Matter Lesions ◽

Human Condition ◽

Cerebral White Matter

Translational research in preterm brain injury depends upon the delineation of the human neuropathology in order that animal models faithfully reiterate it, thereby ensuring direct relevance to the human condition. The major substrate of human preterm brain injury is the encephalopathy of prematurity that is characterized by gray and white matter lesions reflecting combined acquired insults, altered developmental trajectories, and reparative phenomena. Here we highlight the key features of human preterm brain development and the encephalopathy of prematurity that are critical for modeling in animals. The complete mimicry of the complex human neuropathology is difficult in animal models. Many models focus upon mechanisms related to a specific feature, for example, loss of premyelinating oligodendrocytes in the cerebral white matter. Nevertheless, animal models that simultaneously address oligodendrocyte, neuronal, and axonal injury carry the potential to decipher shared mechanisms and synergistic treatments to ameliorate the global consequences of the encephalopathy of prematurity.

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Central Role of the Gut Epithelial Barrier in the Pathogenesis of Chronic Intestinal Inflammation: Lessons Learned from Animal Models and Human Genetics

Frontiers in Immunology ◽

10.3389/fimmu.2013.00280 ◽

2013 ◽

Vol 4 ◽

Cited By ~ 224

Author(s):

Luca Pastorelli ◽

Carlo De Salvo ◽

Joseph R. Mercado ◽

Maurizio Vecchi ◽

Theresa T. Pizarro

Keyword(s):

Animal Models ◽

Human Genetics ◽

Intestinal Inflammation ◽

Lessons Learned ◽

Epithelial Barrier ◽

Chronic Intestinal Inflammation

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The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2017432118 ◽

2021 ◽

Vol 118 (4) ◽

pp. e2017432118

Author(s):

Yalong Wang ◽

Kaixin He ◽

Baifa Sheng ◽

Xuqiu Lei ◽

Wanyin Tao ◽

...

Keyword(s):

Rna Splicing ◽

Intestinal Inflammation ◽

Paneth Cell ◽

Enteric Bacteria ◽

Paneth Cells ◽

Antimicrobial Protein ◽

Rna Helicases

RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases. Here, we investigated the in vivo role of Dhx15 in intestinal antibacterial responses by generating mice that were intestinal epithelial cell (IEC)-specific deficient for Dhx15 (Dhx15 f/f Villin1-cre, Dhx15ΔIEC). These mice are susceptible to infection with enteric bacteria Citrobacter rodentium (C. rod), owing to impaired α-defensin production by Paneth cells. Moreover, mice with Paneth cell-specific depletion of Dhx15 (Dhx15 f/f Defensinα6-cre, Dhx15ΔPaneth) are more susceptible to DSS (dextran sodium sulfate)-induced colitis, which phenocopy Dhx15ΔIEC mice, due to the dysbiosis of the intestinal microbiota. In humans, reduced protein levels of Dhx15 are found in ulcerative colitis (UC) patients. Taken together, our findings identify a key regulator of Wnt-induced α-defensins in Paneth cells and offer insights into its role in the antimicrobial response as well as intestinal inflammation.

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Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research

Frontiers in Physiology ◽

10.3389/fphys.2020.614591 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xinmin Yang ◽

Linbo Yao ◽

Xianghui Fu ◽

Rajarshi Mukherjee ◽

Qing Xia ◽

...

Keyword(s):

Acute Pancreatitis ◽

Animal Models ◽

Translational Research ◽

Specific Treatment ◽

Current Status ◽

Anatomical Site ◽

Human Pancreas ◽

The Past ◽

Substantial Morbidity

Acute pancreatitis is a potentially severe inflammatory disease that may be associated with a substantial morbidity and mortality. Currently there is no specific treatment for the disease, which indicates an ongoing demand for research into its pathogenesis and development of new therapeutic strategies. Due to the unpredictable course of acute pancreatitis and relatively concealed anatomical site in the retro-peritoneum, research on the human pancreas remains challenging. As a result, for over the last 100 years studies on the pathogenesis of this disease have heavily relied on animal models. This review aims to summarize different animal models of acute pancreatitis from the past to present and discuss their main characteristics and applications. It identifies key studies that have enhanced our current understanding of the pathogenesis of acute pancreatitis and highlights the instrumental role of animal models in translational research for developing novel therapies.

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Children Developing Celiac Disease Have a Distinct and Proinflammatory Gut Microbiota in the First 5 Years of Life

10.1101/2020.02.29.971242 ◽

2020 ◽

Cited By ~ 1

Author(s):

Qian Huang ◽

Yi Yang ◽

Vladimir Tolstikov ◽

Michael A. Kiebish ◽

Jonas F Ludvigsson ◽

...

Keyword(s):

Celiac Disease ◽

Gut Microbiota ◽

Intestinal Inflammation ◽

Plasma Metabolites ◽

List Type ◽

Healthy Controls ◽

Microbiota Composition ◽

Immune Mediated ◽

Gut Microbiota Composition

ABSTRACTObjectiveCeliac disease (CD) is an immune-mediated disease characterized by small intestinal inflammation. CD is associated with HLA-DQ2 and HLA-DQ8 haplotypes, however, genetics alone cannot explain the increasing incidence rates. The main goal of this study was to determine the role of the gut microbiota in CD pathogenesis in the first five years of life.DesignWe conducted a longitudinal study focusing on three developmental phases of the gut microbiota (ages 1, 2.5 and 5 years). The fecal samples were obtained from 16 children who developed CD and 16 matched controls. We used 16S sequencing combined with functional analysis, flow cytometry, immunoglobulin A (IgA) sequencing (IgA-seq), and plasma metabolomics to determine a microbial link to CD pathogenesis.ResultsWe identified a distinct gut microbiota composition in CD progressors (CDP, children who developed CD during or after their gut microbiota were sampled) in each developmental phase. Pathogenesis and inflammation-related microbial pathways were enriched in CDP. Moreover, they had significantly more IgA coated bacteria and the IgA targets were significantly different compared to controls. Proinflammatory and pathogenesis-related metabolic pathways were enriched in CDP. Further, we identified inflammatory metabolites, particularly microbiota-derived taurodeoxycholic acid (TDCA) as increased in CDP.ConclusionOur study defines an inflammatory gut microbiota for the CDP including its composition, function, IgA response and related plasma metabolites. The inflammatory nature of CD gut microbiota during development is potentially related to the onset of the disease. Targeting inflammatory bacteria in this critical window could affect the pathogenesis and prognosis of CD.Significance of this studyWhat is already known on this subject?Celiac Disease (CD) is a gluten induced immune-mediated disease in genetically predisposed individuals.CD incidence is increasing worldwide which genetics alone cannot explain. Previous studies have shown that the gut microbiota of CD patients differ from that of healthy populations. However, the role of the microbiome in CD pathogenesis and its role in chronic inflammation is yet be established.What are the new findings?In a prospective longitudinal study in children using samples representing all three phases of gut microbiota development (ages 1, 2.5 and 5), we identified significant differences in the composition and function of gut microbiota at each phase. Pathogenesis and inflammation-related functions are enriched in the gut microbiome of CD progressors.We applied IgA-sequencing to identify inflammatory bacteria in both healthy subjects and CD progressors. Flow Cytometry analysis identified more IgA coated bacteria at ages 1 and 5 in CD progressors, indicating an early inflammatory response. CD bacterial IgA targets also differed significantly from healthy controls.We analyzed plasma metabolites obtained at age 5. The CD plasma metabolome was significantly different from healthy controls. Particularly, proinflammatory plasma metabolites, including microbiota-derived taurodeoxycholic acid (TDCA) and isobutyryl-L-carnitine, were increased two-fold in CD progressors.How might it impact clinical practice in the foreseeable future?Our results establish a link between gut microbiota composition and chronic inflammation in CD during child development. The highly IgA-coated bacteria identified in IgA sequencing and inflammatory bacteria potentially contribute to CD pathogenesis. Targeting these bacteria in the early stages of CD development could be a preventative tool.TDCA is a microbiota-derived proinflammatory metabolite increased two-fold in CD progressors. Increased TDCA levels may be used as a predictive/diagnostic tool in genetically predisposed subjects. Moreover, targeting TDCA-producing bacteria (e.g., Clostridium XIVa species) could potentially help to control the intestinal inflammation in CD.Developing anti-inflammatory probiotics/prebiotics might be viable therapeutics for altering microbiota composition in children genetically predisposed for CD. These microbes/compounds may also complement a gluten-free diet in patients that continue to experience persistent CD symptoms.

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Animal models of narcolepsy and the hypocretin/orexin system: Past, present, and future

SLEEP ◽

10.1093/sleep/zsaa278 ◽

2020 ◽

Author(s):

Ryan K Tisdale ◽

Akihiro Yamanaka ◽

Thomas S Kilduff

Keyword(s):

Animal Models ◽

Sleep Disorder ◽

Critical Role ◽

Rapid Eye Movement Sleep ◽

Neuron Degeneration ◽

Immune Mediated ◽

Hypocretin Neuron ◽

Initial Description ◽

The Relationship

Abstract Animal models have advanced not only our understanding of the etiology and phenotype of the sleep disorder narcolepsy but have also informed sleep/wake regulation more generally. The identification of an inheritable narcolepsy phenotype in dogs in the 1970s allowed the establishment of a breeding colony at Stanford University, resulting in studies that provided the first insights into the genetics and neurotransmitter systems that underlie cataplexy and rapid-eye movement sleep atonia. Although the discovery of the hypocretin/orexin neuropeptides in 1998 initially seemed unrelated to sleep/wake control, the description of the phenotype of the prepro-orexin knockout (KO) mouse as strongly resembling cataplexy, the pathognomonic symptom of narcolepsy, along with identification of a mutation in hypocretin receptor-2 gene as the source of canine narcolepsy, unequivocally established the relationship between this system and narcolepsy. The subsequent discovery of hypocretin neuron degeneration in human narcolepsy demystified a disorder whose etiology had been unknown since its initial description 120 years earlier. These breakthroughs prompted the development of numerous other animal models that have allowed manipulation of the hypocretin/orexin system, thereby advancing our understanding of sleep/wake circuitry. While animal models have greatly informed understanding of this fascinating disorder and the role of the hypocretin/orexin system in sleep/wake control, the question of why these neurons degenerate in human narcolepsy is only beginning to be understood. The development of new immune-mediated narcolepsy models are likely to further inform the etiology of this sleep disorder and animal models will undoubtedly play a critical role in the development of novel narcolepsy therapeutics.

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