RESUMO
Irritable bowel syndrome and related disorders of gut-brain interaction (DGBI) are common and exhibit a complex, poorly understood etiology that manifests as abnormal gut motility and pain. Risk factors such as biological sex, stressors during critical periods, and inflammation are thought to influence DGBI vulnerability by reprogramming gut-brain circuits, but the specific cells affected are unclear. Here, we used a model of early life stress to understand cellular mechanisms in the gut that produce DGBIs. Our findings identify enteric glia as a key cellular substrate in which stress and biological sex converge to dictate DGBI susceptibility. Enteric glia exhibit sexual dimorphism in genes and functions related to cellular communication, inflammation, and disease susceptibility. Experiencing early life stress has sex-specific effects on enteric glia that cause a phenotypic switch in male glia toward a phenotype normally observed in females. This phenotypic transformation is followed by physiological changes in the gut, mirroring those observed in DGBI in humans. These effects are mediated, in part, by alterations to glial prostaglandin and endocannabinoid signaling. Together, these data identify enteric glia as a cellular integration site through which DGBI risk factors produce changes in gut physiology and suggest that manipulating glial signaling may represent an attractive target for sex-specific therapeutic strategies in DGBIs.
RESUMO
Mast cells are innate immune cells that play a crucial role in numerous physiological processes across tissues by releasing pre-stored and newly synthesized mediators in response to stimuli, an activity largely driven by changes in gene expression. Given their widespread influence, dysfunction in mast cells can contribute to a variety of pathologies including allergies, long COVID, and autoimmune and neuroinflammatory disorders. Despite this, the specific transcriptional mechanisms that control mast cell mediator release remain poorly understood, significantly hindering the development of effective therapeutic strategies. We found that the two proteins encoded by the transcription factor FosB, FOSB and the highly stable variant ΔFOSB, are robustly expressed upon stimulation in both murine and human mast cell progenitors. Motivated by these findings, we generated a novel mouse model with targeted ablation of FosB gene expression specifically in mast cells (MC FosB- ) by crossing a mast cell-specific Cre reporter line (Mcpt5-Cre) with a Cre-dependent floxed FosB mouse lines. We found that mast cell progenitors derived from MC FosB- mice, compared to wild types (WT), exhibit baseline increased histamine content and vesicle numbers. Additionally, they show enhanced calcium mobilization, degranulation, and histamine release following allergy-related IgE-mediated stimulation, along with heightened IL-6 release in response to infection-like LPS stimulation. In vivo experiments with IgE- mediated and LPS challenges revealed that MC FosB- mice experience greater drops in body temperature, heightened activation of tissue-resident mast cells, and increased release of pro-inflammatory mediators compared to their WT counterparts. These findings suggest that FosB products play a crucial regulatory role in moderating stimulus-induced mast cell activation in response to both IgE and LPS stimuli. Lastly, by integrating CUT&RUN and RNAseq data, we identified several genes targeted by ΔFOSB that could mediate these observed effects, including Mir155hg, CLCF1, DUSP4, and Trib1. Together, this study provides the first evidence that FOSB/ΔFOSB modulate mast cell functions and provides a new possible target for therapeutic interventions aimed at ameliorating mast cell-related diseases.
RESUMO
Objectives were to examine the temporal pattern of intestinal mast cell dynamics and the effects of a mast cell stabilizer (ketotifen [Ket]) during acute heat stress (HS) in growing pigs. Crossbred barrows (nâ =â 42; 32.3â ±â 1.9 kg body weight [BW]) were randomly assigned to 1 of 7 environmental-therapeutic treatments: (1) thermoneutral (TN) control (TNCon; nâ =â 6), (2) 2 h HS control (2 h HSCon; nâ =â 6), (3) 2 h HSâ +â Ket (2 h HSKet; nâ =â 6); (4) 6 h HSCon (nâ =â 6), (5) 6 h HSKet (nâ =â 6), (6) 12 h HSCon (nâ =â 6), or (7) 12 h HSKet (nâ =â 6). Following 5 d of acclimation to individual pens, pigs were enrolled in two experimental periods (P). During P1 (3 d), pigs were housed in TN conditions (21.5â ±â 0.8 °C) for the collection of baseline measurements. During P2, TNCon pigs remained in TN conditions for 12 h, while HS pigs were exposed to constant HS (38.1â ±â 0.2 °C) for either 2, 6, or 12 h. Pigs were euthanized at the end of P2, and blood and tissue samples were collected. Regardless of time or therapeutic treatment, pigs exposed to HS had increased rectal temperature, skin temperature, and respiration rate compared to their TNCon counterparts (1.9 °C, 6.9° C, and 119 breaths/min; Pâ <â 0.01). As expected, feed intake and BW gain markedly decreased in HS pigs relative to their TNCon counterparts (Pâ <â 0.01). Irrespective of therapeutic treatment, circulating corticotropin-releasing factor decreased from 2 to 12 h of HS relative to TNCon pigs (Pâ <â 0.01). Blood cortisol increased at 2 h of HS (2-fold; Pâ =â 0.04) and returned to baseline by 6 h. Plasma histamine (a proxy of mast cell activation) remained similar across thermal treatments and was not affected by Ket administration (Pâ >â 0.54). Independent of Ket or time, HS increased mast cell numbers in the jejunum (94%; Pâ <â 0.01); however, no effects of HS on mast cell numbers were detected in the ileum or colon. Jejunum and ileum myeloperoxidase area remained similar among treatments (Pâ >â 0.58) but it tended to increase (12%; Pâ =â 0.08) in the colon in HSCon relative to TNCon pigs. Circulating lymphocytes and basophils decreased in HSKet relative to TN and HSCon pigs (Pâ ≤â 0.06). Blood monocytes and eosinophils were reduced in HS pigs relative to their TNCon counterparts (Pâ <â 0.01). In summary, HS increased jejunum mast cell numbers and altered leukocyte dynamics and proinflammatory biomarkers. However, Ket administration had no effects on mast cell dynamics measured herein.
Heat stress (HS) affects various physiological, metabolic, and endocrine parameters, ostensibly due to reduced intestinal barrier integrity and the ensuing immune response. Evidence indicates that generalized "stress" may be a critical component of HS-induced leaky gut, a mechanism likely mediated by mast cells. Mast cell activation has been extensively associated with various stress-related intestinal inflammatory conditions; however, its contribution to intestinal barrier dysfunction during HS remains unclear. Thus, this study was designed to evaluate mast cell dynamics during an acute HS challenge and to assess the effects a mast cell stabilizer on biomarkers of intestinal inflammation. Herein, HS induced a rapid increase in circulating cortisol, increased jejunum mast cell numbers, and altered metabolism, leukocyte dynamics, and proinflammatory biomarkers. Contrary to our hypothesis, HS did not alter circulating histamine (a biomarker of mast cell activation), and mast cell stabilization did not affect mast cell numbers nor altered histamine concentrations. Altogether, our observations support a connection between HS and intestinal mast cell infiltration that may contribute to the pathophysiology of intestinal dysfunction during a heat load.
Assuntos
Transtornos de Estresse por Calor , Doenças dos Suínos , Suínos , Animais , Dieta , Mastócitos , Resposta ao Choque Térmico , Temperatura Cutânea , Reto , Temperatura Alta , Transtornos de Estresse por Calor/veterináriaRESUMO
During the early pre and postnatal life, host and environmental factors can impart a major influence on immune development, thus shaping lifelong disease resistance. Two major factors known to influence immune function and mortality in animals and people are early life stress and biological sex. How these two factors interact to shape long-term immune development and later life disease risk is poorly understood. Here we investigated how early weaning, a common early life stressor in pigs, and biological sex impacts long-term systemic inflammatory responses and hypothalamic-pituitary-adrenal axis (HPA axis) activation later in life. Ten-week-old female (F), intact-male (IM) and castrated-male (CM) pigs that were randomly assigned to early weaning (EW) and later weaning (LW) (at 15 or 28 days of age, respectively) were intramuscularly injected with either saline vehicle or lipopolysaccharide (LPS) to induce a systemic inflammatory response. Complete blood counts (CBC), proinflammatory cytokines, cortisol, testosterone, estradiol, and rectal temp were measured at 0 h, 2 h, and 4 h post-LPS challenge. At 4 h post-LPS, peritoneal fluid (PF) and white blood cells (WBC) were collected for differential analysis. LPS challenge significantly increased rectal temp and plasma cortisol level in all treatment groups. Together, the CBC results and immune cell counts in peritoneal cavity indicated that EW-F exhibited greater systemic immune response characterized by increased neutrophils to lymphocytes ratio (NLR) and enhanced neutrophil trafficking to the peritoneal cavity. Early weaning had an opposite effect on IM and CM pigs, which exhibited a suppressed LPS-induced neutrophil migration. Early weaning induced significantly greater cortisol responses only in IM pigs indicating a heightened HPA axis responses in EW-IM. how early weaning and biological sex affect immune and stress responses in pigs. Together, these results demonstrate that early weaning and biological sex and castration shape later life immune responses in pigs and provides insight into potential mechanisms driving sex differences in later life inflammatory disease risk and mortality.
Assuntos
Hidrocortisona , Sistema Hipotálamo-Hipofisário , Animais , Feminino , Masculino , Lipopolissacarídeos/farmacologia , Sistema Hipófise-Suprarrenal , Suínos , DesmameRESUMO
A 7 yr old female spayed mixed-breed dog was presented for a 1 wk history of neck pain and pelvic limb weakness. Examination revealed nonambulatory paraparesis and thoracolumbar hyperesthesia. MRI revealed extensive intramedullary T2-weighted/short tau inversion recovery hyperintensity and diffuse severe T1-post contrast meningeal enhancement of the thoracolumbar spinal cord. An L5-L6 cerebrospinal fluid sample revealed a suppurative pleocytosis (81% neutrophils, total protein 4362.5 mg/dL and nucleated cell count 352,000/µL). While awaiting the results of infectious disease testing, the dog was treated for suspected meningoencephalitis of unknown etiology with corticosteroids, cyclosporine, and a cytarabine arabinoside infusion. The dog neurologically declined and was started on broad-spectrum antibiotics. The dog continued to decline despite antibiotics, and infectious disease titers subsequently revealed serum antibody positivity for blastomycosis. The dog was then referred to a multispecialty referral hospital and was treated with amphotericin B followed by fluconazole. Prednisone was continued at anti-inflammatory doses. Urine blastomycosis antigen testing was submitted for subsequent disease monitoring but was negative. Five months after presentation the dog was clinically doing well with no identifiable neurologic deficits. This case demonstrates that neurologic blastomycosis may have negative urine antigen concentrations in some dogs and that other diagnostic modalities should be pursued when central nervous system fungal disease is suspected.
Assuntos
Blastomicose , Doenças do Cão , Cães , Feminino , Animais , Blastomicose/diagnóstico , Blastomicose/tratamento farmacológico , Blastomicose/veterinária , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Doenças do Cão/cirurgia , Prednisona/uso terapêutico , Sistema Nervoso Central , Antibacterianos/uso terapêuticoRESUMO
Invasive bacterial infections remain a major cause of human morbidity. Group B streptococcus (GBS) are Gram-positive bacteria that cause invasive infections in humans. Here, we show that factor XIIIA-deficient (FXIIIA-deficient) female mice exhibited significantly increased susceptibility to GBS infections. Additionally, female WT mice had increased levels of FXIIIA and were more resistant to GBS infection compared with isogenic male mice. We observed that administration of exogenous FXIIIA to male mice increased host resistance to GBS infection. Conversely, administration of a FXIIIA transglutaminase inhibitor to female mice decreased host resistance to GBS infection. Interestingly, male gonadectomized mice exhibited decreased sensitivity to GBS infection, suggesting a role for gonadal androgens in host susceptibility. FXIIIA promoted GBS entrapment within fibrin clots by crosslinking fibronectin with ScpB, a fibronectin-binding GBS surface protein. Thus, ScpB-deficient GBS exhibited decreased entrapment within fibrin clots in vitro and increased dissemination during systemic infections. Finally, using mice in which FXIIIA expression was depleted in mast cells, we observed that mast cell-derived FXIIIA contributes to host defense against GBS infection. Our studies provide insights into the effects of sexual dimorphism and mast cells on FXIIIA expression and its interactions with GBS adhesins that mediate bacterial dissemination and pathogenesis.
Assuntos
Fator XIIIa , Infecções Estreptocócicas , Androgênios/metabolismo , Animais , Fator XIIIa/metabolismo , Feminino , Fibrina/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Masculino , Mastócitos/metabolismo , Camundongos , Infecções Estreptocócicas/genética , Streptococcus agalactiae/metabolismo , Transglutaminases/metabolismoRESUMO
The objective of this experiment was to evaluate the effects of a multi-strain Bacillus subtilis-based direct-fed microbial (DFM) on nursery pig health as indicated by intestinal mucosal and blood plasma immunological markers and intestinal morphology. Eighty pigs, of equal number of barrows and gilts (initial BW: 7.0â ±â 0.60 kg), weaned at 21â ±â 1 d of age were randomly allotted to sixteen pens, with five pigs per pen. Two dietary treatments were implemented, a basal control (CON) and a basal control plus DFM (CDFM). Both diets were corn, soybean meal, and distillers dried grains based and were formulated to meet or exceed all nutritional requirements (NRC, 2012) and manufactured on site. Diets were fed for 42 d. On d 21 and 42 of the experiment, one pig per pen was randomly selected and euthanized, with equal number of males and females represented. Blood samples were collected prior to euthanasia for assessment of plasma concentrations of immunoglobulin A (IgA) and intestinal fatty acid binding protein. Segments of the gastrointestinal tract including duodenum, jejunum, ileum, ascending and distal colon were removed for analysis of intestinal morphology, and levels of interleukin 6, interleukin 10 (IL-10), and tumor necrosis factor alpha. Jejunal villus height was greater in the CDFM pigs as compared with CON pigs (Pâ =â 0.02) and ascending colon crypt depth tended to be greater on d 21 (Pâ =â 0.10). Compared to CON, CDFM significantly increased overall plasma IgA (Pâ =â 0.03) (0.58 vs. 0.73 0.05 mg/mL, respectively), while it tended to increase plasma IgA (Pâ =â 0.06) on d 21 (0.34 vs. 0.54â ±â 0.07 mg/mL, respectively) and tended to increase overall IL-10 (Pâ =â 0.10) in the jejunum (113 vs. 195â ±â 35 pg/mL, respectively). Addition of a multi-strain Bacillus subtilis-based DFM may have an early benefit to nursery pig health status, observed through specific changes in morphology and both systemic and localized immunological markers.
RESUMO
Mast cells are critical innate immune effectors located throughout the body that are crucial for host defense mechanisms via orchestrating immune responses to a variety of host and environmental stimuli necessary for survival. The role of mast cells in brain development and behavior, meningeal function, and stress-related disorders has also been increasingly recognized. While critical for survival and development, excessive mast cell activation has been linked with an increasing number of inflammatory, stress-associated, and neuroimmune disorders including allergy/anaphylaxis, autoimmune diseases, migraine headache, and chronic pain disorders. Further, a strong sex bias exists for mast cell-associated diseases with females often at increased risk. Here we review sex differences in human mast cell-associated diseases and animal models, and the underlying biological mechanisms driving these sex differences, which include adult gonadal sex hormones as well the emerging organizational role of perinatal gonadal hormones on mast cell activity and development.
Assuntos
Mastócitos , Caracteres Sexuais , Animais , Feminino , Humanos , Longevidade , MasculinoRESUMO
Biological sex is a major host factor influencing risk for infectious disease-associated mortality, and chronic inflammatory and metabolic diseases. Research in human and rodent models -has revealed sex differences that exist across organ systems during health and disease that may contribute to sex biases in disease risk. Despite the robust and growing literature on the role of sex as a risk factor in human disease, comparatively little attention has been focused on investigating the role of biological sex in disease susceptibility in agriculturally important animal populations such as the pig. To date, comparisons between sexes have focused on carcass composition, growth rate, and feed efficiency in pigs. However, there is a large gap in the literature regarding the effects of biological sex on other integral aspects of health and disease. The objective of this review is to highlight the available literature reporting sex differences in pig health and biology with an emphasis on sex differences in mortality, immunity, and gastrointestinal (GI) physiology and to address biological sex as a significant biological variable in disease risk and research study design. A basic overview of the biology of sex differences including the major hormonal and genetic/chromosomal mechanisms of sexual differentiation and the developmental periods in which sex differences emerge will be covered. This review will also discuss how production-relevant management and environmental factors (e.g., wean age, castration, stress, and nutrition) interact with biological sex to shape host immune and GI development and function. Perceived gaps in knowledge and areas of future research will also be discussed.
It has become increasingly evident that females and males differ in their susceptibility to disease and mortality. Females typically have higher survivability rates during pandemics and environmental challenges compared with males. In many cases, females mount a greater immune response compared with males which may have survival benefits, but at the same time may predispose them to chronic inflammatory disorders. Despite this accumulated knowledge on the key role that sex plays on immunity and disease outcomes in humans, little attention has been placed on sex differences in agriculturally important species such as the pig. The objective of this review is to highlight the literature on sex differences in swine with a focus on mortality, immunity, and GI health.
Assuntos
Caracteres Sexuais , Doenças dos Suínos , Animais , Suscetibilidade a Doenças/veterinária , Feminino , Masculino , Orquiectomia/veterinária , Projetos de Pesquisa , Fatores de Risco , Fatores Sexuais , SuínosRESUMO
Exposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- dura mater, arachnoid, and piamater - possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on sucrose preference behavior, dura mater expression of inflammatory markers and mast cell histology in adult male and female C57Bl/6 mice. We found that NMSEW alone does not affect sucrose preference behavior in males or females, but it increases the dura mater expression of the genes coding for mast cell protease CMA1 (cma1) and the inflammatory cytokine TNF alpha (tnf alpha) in females. When NMSEW is combined with an adult mild stress (that does not affect behavior or gene expression in NH animals) females show reduced sucrose preference and even greater increases in meningeal cma1 levels. Interestingly, systemic administration of the mast cell stabilizer Ketotifen before exposure to adult stress prevents both, reduction in sucrose preference an increases in cma1 expression in NMSEW females, but facilitates stress-induced sucrose anhedonia in NMSEW males and NH females. Finally, histological analyses showed that, compared to males, females have increased baseline activation levels of mast cells located in the transverse sinus of the dura mater, where the meningeal lymphatics run along, and that, in males and females exposed to adult stress, NMSEW increases the number of mast cells in the interparietal region of the dura mater and the levels of mast cell activation in the sagittal sinus regions of the dura mater. Together, our results indicate that ELA induces long-term meningeal immune gene changes and heightened sensitivity to adult stress-induced behavioral and meningeal immune responses and that these effects could mediated via mast cells.
Assuntos
Anedonia , Mastócitos , Fatores Sexuais , Estresse Psicológico , Animais , Feminino , Masculino , Apresentação de Antígeno , Expressão Gênica , Privação Materna , Meninges , Sacarose , Fator de Necrose Tumoral alfa , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Recent clinical studies report that chromosomal 12q24.31 microdeletions are associated with autism spectrum disorder (ASD) and intellectual disability (ID). However, the causality and underlying mechanisms linking 12q24.31 microdeletions to ASD/ID remain undetermined. Here we show Kdm2b, one gene located in chromosomal 12q24.31, plays a critical role in maintaining neural stem cells (NSCs) in the mouse brain. Loss of the CxxC-ZF domain of KDM2B impairs its function in recruiting Polycomb repressive complex 1 (PRC1) to chromatin, resulting in de-repression of genes involved in cell apoptosis, cell-cycle arrest, NSC senescence, and loss of NSC populations in the brain. Of importance, the Kdm2b mutation is sufficient to induce ASD/ID-like behavioral and memory deficits. Thus, our study reveals a critical role of KDM2B in normal brain development, a causality between the Kdm2b mutation and ASD/ID-like phenotypes in mice, and potential molecular mechanisms linking the function of KDM2B-PRC1 in transcriptional regulation to the 12q24.31 microdeletion-associated ASD/ID.
RESUMO
Early-life adversity (ELA) is linked with the increased risk for inflammatory and metabolic diseases in later life, but the mechanisms remain poorly understood. Intestinal epithelial glucose transporters sodium-glucose-linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are the major route for intestinal glucose uptake but have also received increased attention as modulators of inflammatory and metabolic diseases. Here, we tested the hypothesis that early weaning (EW) in pigs, an established model of ELA, alters the development of epithelial glucose transporters and coincides with elevated markers of metabolic inflammation. The jejunum and ileum of 90-day-old pigs previously exposed to EW (16 days wean age), exhibited reduced SGLT1 activity (by â¼ 30%, P < 0.05) than late weaned (LW, 28 days wean age) controls. In contrast, GLUT2-mediated glucose transport was increased (P = 0.003) in EW pigs than in LW pigs. Reciprocal changes in SGLT1- and GLUT2-mediated transport coincided with transporter protein expression in the intestinal brush-border membranes (BBMs) that were observed at 90 days and 150 days of age. Ileal SGLT1-mediated glucose transport and BBM expression were inhibited by the ß-adrenergic receptor (ßAR) blocker propranolol in EW and LW pigs. In contrast, propranolol enhanced ileal GLUT2-mediated glucose transport (P = 0.015) and brush-border membrane vesicle (BBMV) abundance (P = 0.035) in LW pigs, but not in EW pigs. Early-weaned pigs exhibited chronically elevated blood glucose and C-reactive protein (CRP) levels, and adipocyte hypertrophy and upregulated adipogenesis-related gene expression in visceral adipose tissue. Altered development of intestinal glucose transporters by EW could underlie the increased risk for later life inflammatory and metabolic diseases.NEW & NOTEWORTHY These studies reveal that early-life adversity in the form of early weaning in pigs causes a developmental shift in intestinal glucose transport from SGLT1 toward GLUT2-mediated transport. Early weaning also induced markers of metabolic inflammation including persistent elevations in blood glucose and the inflammatory marker CRP, along with increased visceral adiposity. Altered intestinal glucose transport might contribute to increased risk for inflammatory and metabolic diseases associated with early-life adversity.
Assuntos
Glicemia , Propranolol , Animais , Glicemia/metabolismo , Feminino , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Transportador 1 de Glucose-Sódio/genética , Suínos , DesmameRESUMO
Increased knowledge of reproduction and health of domesticated animals is integral to sustain and improve global competitiveness of U.S. animal agriculture, understand and resolve complex animal and human diseases, and advance fundamental research in sciences that are critical to understanding mechanisms of action and identifying future targets for interventions. Historically, federal and state budgets have dwindled and funding for the United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) competitive grants programs remained relatively stagnant from 1985 through 2010. This shortage in critical financial support for basic and applied research, coupled with the underappreciated knowledge of the utility of non-rodent species for biomedical research, hindered funding opportunities for research involving livestock and limited improvements in both animal agriculture and animal and human health. In 2010, the National Institutes of Health and USDA NIFA established an interagency partnership to promote the use of agriculturally important animal species in basic and translational research relevant to both biomedicine and agriculture. This interagency program supported 61 grants totaling over $107 million with 23 awards to new or early-stage investigators. This article will review the success of the 9-year Dual Purpose effort and highlight opportunities for utilizing domesticated agricultural animals in research.
Assuntos
Agricultura , Animais Domésticos , Animais , Gado , National Institutes of Health (U.S.) , Estados Unidos , United States Department of AgricultureRESUMO
A study was conducted to evaluate the effects of a multi-strain Bacillus subtilis-based direct-fed microbial (DFM) on growth performance and apparent nutrient digestibility of nursery pigs. Eighty pigs, of equal number of barrows and gilts (initial body weight: 7.0 ± 0.60 kg), were weaned at 21 ± 1 d and randomly allotted to 1 of the 16 pens, with 5 pigs per pen. Two dietary treatments were implemented, a basal control (CON) and a control plus DFM (CDFM). Both diets were corn, soybean meal, and distillers dried grains based. Diets were fed for 42 d and growth performance measures were recorded weekly. On days 21 and 42 of the experiment, one pig per pen, with equal number of males and females, was randomly selected and euthanized. Digestibility of nitrogen (N), amino acids (AA), and energy were evaluated within the duodenum, jejunum, ileum, and ascending and distal colon. Relative to CON, CDFM tended to increase ADG during week 2 (P = 0.08) and significantly increased ADFI during week 2 (P = 0.04) and week 3 (P = 0.02). In addition, CDFM decreased the gain to feed ratio (G:F) during week 6 relative to CON (P = 0.04). Within the jejunum, pigs fed the DFM had greater digestibility of tryptophan (P = 0.04) and cysteine (P = 0.04) and tended to have greater digestibility of lysine (P = 0.07), methionine (P = 0.06), and threonine (P = 0.08), relative to CON. The content pH in the ascending colon did not differ between CDFM and CON. Compared with CON, apparent total tract digestibility (ATTD) of energy did not differ from CDFM, whereas ATTD of nitrogen of CDFM was lower (P = 0.05). The addition of a multi-strain B. subtilis-based DFM appears to impact growth performance, AA, and N digestibility depending upon the location in the gastrointestinal tract, with primary AA differences occurring within the mid-jejunum.
RESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.
Assuntos
Transtorno do Espectro Autista/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Animais , Transtorno do Espectro Autista/metabolismo , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Depression is one of the leading causes of disability worldwide and a major contributor to the global burden of disease, yet the cellular and molecular etiology of depression remain largely unknown. Major Depressive Disorder (MDD) is associated with a variety of chronic physical inflammatory and autoimmune disorders, and mood disorders may act synergistically with other medical disorders to worsen patient outcomes. Here, we outline the neuroimmune complement, explore the evidence for altered immune system function in MDD, and present some of the potential mechanisms by which immune cells and molecules may drive the onset and course of MDD. These include pro-inflammatory signaling, alterations in the hypothalamic-pituitary-adrenal axis, dysregulation of the serotonergic and noradrenergic neurotransmitter systems, neuroinflammation, and meningeal immune dysfunction. Finally, we discuss the interactions between current antidepressants and the immune system and propose the possibility of immunomodulatory drugs as potential novel antidepressant treatments.
Assuntos
Transtorno Depressivo Maior , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-SuprarrenalRESUMO
Sleep is a fundamental process in mammals, including domestic dogs. Disturbances in sleep affect physiological functions like cognitive and physical performance, immune response, pain sensation and increase the risk of diseases. In dogs, sleep can be affected by several conditions, with narcolepsy, REM sleep behavior disorder and sleep breathing disorders being the most frequent causes. Furthermore, sleep disturbances can be a symptom of other primary diseases where they can contribute to the worsening of clinical signs. This review describes reciprocally interacting sleep and wakefulness promoting systems and how their dysfunction can explain the pathophysiological mechanisms of sleep disorders. Additionally, this work discusses the clinical characteristics, diagnostic tools and available treatments for these disorders while highlighting areas in where further studies are needed so as to improve their treatment and prevention.
Assuntos
Doenças do Cão , Narcolepsia , Transtorno do Comportamento do Sono REM , Transtornos do Sono-Vigília , Animais , Cães , Narcolepsia/veterinária , Transtorno do Comportamento do Sono REM/veterinária , Sono , Transtornos do Sono-Vigília/veterinária , VigíliaRESUMO
Epidemiological studies suggest that men exhibit a higher mortality rate to COVID-19 than women, yet the underlying biology is largely unknown. Here, we seek to delineate sex differences in the gene expression of viral entry proteins ACE2 and TMPRSS2, and host transcriptional responses to SARS-CoV-2 through large-scale analysis of genomic and clinical data. We first compiled 220,000 human gene expression profiles from three databases and completed the meta-information through machine learning and manual annotation. Large scale analysis of these profiles indicated that male samples show higher expression levels of ACE2 and TMPRSS2 than female samples, especially in the older group (>60 years) and in the kidney. Subsequent analysis of 6,031 COVID-19 patients at Mount Sinai Health System revealed that men have significantly higher creatinine levels, an indicator of impaired kidney function. Further analysis of 782 COVID-19 patient gene expression profiles taken from upper airway and blood suggested men and women present distinct expression changes. Computational deconvolution analysis of these profiles revealed male COVID-19 patients have enriched kidney-specific mesangial cells in blood compared to healthy patients. Together, this study suggests biological differences in the kidney between sexes may contribute to sex disparity in COVID-19.
RESUMO
Early-life adversity contributes to the development of functional bowel disorders later in life through unresolved mechanisms. Here, we tested the hypothesis that early-life adversity alters anatomical and functional interactions between mast cells and enteric glia. The effects of early-life stress were studied using the neonatal maternal separation (NMS) stress mouse model. Anatomical relationships between mast cells and enteric glia were assessed using immunohistochemistry and mast cell reporter mice (Mcpt5Cre;GCaMP5g-tdT). Immunohistochemistry was used to assess the expression of histamine, histamine 1 (H1) receptors, and glial fibrillary acidic protein. Functional responses of glia to mast cell mediators were assessed in calcium imaging experiments using Sox10CreERT2;GCaMP5g-tdT mice and cultured human enteric glial cells. NMS increases mast cell numbers at the level of the myenteric plexus and their proximity to myenteric ganglia. Myenteric glia respond to mediators released by activated mast cells that are blocked by H1 receptor antagonists in mice and humans and by blocking neuronal activity with tetrodotoxin in mouse tissue. Histamine replicates the effects of mast cell supernatants on enteric glia, and NMS increases histamine production by mast cells. NMS reduces glial responses to mast cell mediators in mouse tissue, while potentiating responses in cultured human enteric glia. NMS increases myenteric glial fibrillary acidic protein expression and reduces glial process length but does not cause neurodegeneration. Histamine receptor expression is not altered by NMS and is localized to neurons in mice, but glia in humans. Early-life stress increases the potential for interactions between enteric glia and mast cells, and histamine is a potential mediator of mast cell-glial interactions through H1 receptors. We propose that glial-mast cell signaling is a mechanism that contributes to enteric neuroplasticity driven by early-life adversity.NEW & NOTEWORTHY Early-life adversity places an individual at risk for developing functional gastrointestinal disorders later in life through unknown mechanisms. Here, we show that interactions between mast cells and glia are disrupted by early-life stress in mice and that histamine is a potential mediator of mast cell-glial interactions.
Assuntos
Histamina/fisiologia , Acontecimentos que Mudam a Vida , Mastócitos/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Animais , Animais Recém-Nascidos , Contagem de Células , Células Cultivadas , Quimases/genética , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Privação Materna , Camundongos , Camundongos Endogâmicos C57BL , Plexo Mientérico/citologia , Plexo Mientérico/metabolismo , Gravidez , Receptores Histamínicos H1/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
Mast cell (MC)-associated diseases, including allergy/anaphylaxis and neuroinflammatory pain disorders, exhibit a sex bias, with females at increase risk. While much attention has been directed toward adult sex hormones as drivers of sex differences, that female sex bias in MC-associated diseases is evident in prepubertal children, suggesting early-life origins of sex differences which have yet to be explored. Utilizing rodent models of MC-mediated anaphylaxis, our data here reveal that, 1) compared with females, males exhibit significantly reduced severity of MC-mediated anaphylactic responses that emerge prior to puberty and persist into adulthood, 2) reduced severity of MC-mediated anaphylaxis in males is linked with the naturally high level of perinatal androgens and can be recapitulated in females by perinatal exposure to testosterone proprionate, 3) perinatal androgen exposure guides bone marrow MC progenitors toward a masculinized tissue MC phenotype characterized by decreased concentration of prestored MC granule mediators (e.g., histamine, serotonin, and proteases) and reduced mediator release upon degranulation, and 4) engraftment of MC-deficient Kit W-sh/W-sh mice with adult male, female, or perinatally androgenized female MCs results in MC-mediated anaphylaxis response that reflects the MC sex and not host sex. Together, these data present evidence that sex differences in MC phenotype and resulting disease severity are established in early life by perinatal androgens. Thus, factors affecting levels of perinatal androgens could have a significant impact on MC development and MC-associated disease risk across the life span.