RESUMO
BACKGROUND: The gut-brain axis has been discussed, directly or indirectly, for centuries, with the ideas of the gut affecting anything from moods to overall physiology being discussed across the centuries. With a recent explosion in research that looks to the microbiota as a mechanistic link between the gut and the brain, one sees that the gut-brain axis has various means of communication, such as through the vagus nerve and the enteric nervous system and can use the metabolites in the gut to communicate to the brain. METHODS: The purpose of this review is to view the gut-brain axis through the lens of stress and how stress, from the prenatal period all the way through adulthood can impact the physiology of a human being. Studies have shown multiple mechanisms of measurable change with disruption in the microbiota that lead to behavioral changes. There are also effects of gut inflammation on the brain and the corresponding systemic response observed. CONCLUSION: The overall literature is encouraging that the more understanding of the gut-brain axis, the greater ability to wield that understanding for therapeutic benefits.
Assuntos
Encéfalo/fisiologia , Microbioma Gastrointestinal , Inflamação/metabolismo , Neoplasias/microbiologia , Estresse Psicológico/microbiologia , Sistema Nervoso Entérico/fisiologia , Feminino , Humanos , Gravidez , Sepse/microbiologia , Estresse Psicológico/imunologia , Nervo Vago/fisiologiaRESUMO
Necrotizing enterocolitis (NEC) is an intestinal inflammatory disease with high morbidity and mortality that affects almost exclusively premature infants. Breast milk feeding is known to substantially lower NEC incidence, and specific components of breast milk, such as immunoglobulin (Ig) A, have been identified as mediating this protective effect. On the other hand, accumulating evidence suggests dysbiosis of the neonatal intestinal microbiome contributes to NEC pathogenesis. In mice, neonates can inherit a dysbiotic microbiome from dams that experience stress during pregnancy. Here we show that while prenatal stress lowers fecal IgA levels in pregnant mice, it does not result in lower levels of IgA in the breast milk. Nevertheless, coating of female, but not male, offspring microbiota by IgA is increased by prenatal stress. Accordingly, prenatal stress was found to alter the bacterial community composition in female neonates but not male neonates. Furthermore, female, but not male, offspring of prenatally stressed mothers exhibited more severe colonic tissue damage in a NEC-like injury model compared to offspring with non-stressed mothers. Our results point to prenatal stress as a possible novel risk factor for NEC and potentially reveal new avenues in NEC prevention and therapy.
Assuntos
Enterocolite Necrosante , Animais , Disbiose , Feminino , Imunoglobulina A , Camundongos , MicrobiotaRESUMO
BACKGROUND: Immunoglobulin A (IgA) plays a key role in coating luminal antigens and preventing translocation of harmful bacteria. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor that when stimulated activates factors important for barrier function and intestinal homeostasis. We hypothesize that AhR signaling is critical for establishment of intestinal homeostasis in neonates. MATERIAL AND METHODS: Mice: C57BL/6 (B6) AhR+/+ wild type (WT), B6.AhR-/- Aryl-hydrocarbon receptor knockout (KO), and B6.AhR+/+ raised on an AhR ligand-free diet (AhR LF). Enzyme-linked immunosorbent assay was used to measure fecal and serum IgA levels. Bacterial translocation was measured by culturing the mesenteric lymph nodes. RESULTS: Two week old KO mice had significantly less fecal IgA compared with WT (and AhR LF, P value = 0.0393. The amount of IgA from the gastric contents of 2-wk-old mice was not significantly different. At age 8 wk, AhR LF mice had significantly less fecal IgA than WT and KO P value = 0.0077. At 2 wk, KO mice had significantly higher levels of bacterial translocation and at 8 wk AhR LF had significantly higher levels of bacterial translocation compared with WT. CONCLUSIONS: In neonatal mice, the lack of AhR signaling is associated with loss of intestinal homeostasis, evidenced by decreased levels of IgA and increased bacterial translocation. In adult mice, exogenous AhR ligand and not receptor signaling is necessary for maintenance of intestinal integrity.
Assuntos
Intestinos/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Animais Recém-Nascidos , Linfócitos B/fisiologia , Translocação Bacteriana , Homeostase , Imunoglobulina A/sangue , Linfócitos/fisiologia , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
In species other than mouse, little is known about the origin and development of marginal zone (MZ) B cells. Using cross-reactive antibodies, we identified and characterized splenic MZ B cells in rabbits as CD27(+) CD23(-). In rabbits in which organized gut-associated lymphoid tissue (GALT) was surgically removed at birth, we found only CD23(+) follicular (FO) B cells and almost no CD27(+) MZ B cells in the spleen, indicating that GALT is required for the development of splenic MZ B cells. These findings lead us to suggest that commensal microbiota contribute to the development of MZ B cells.
Assuntos
Linfócitos B/imunologia , Intestinos/imunologia , Baço/imunologia , Animais , Animais Recém-Nascidos , Diferenciação Celular , Tecido Linfoide/cirurgia , Metagenoma/imunologia , Camundongos , Coelhos , Receptores de IgE/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
The growth and function of the vertebrate brain are impacted by environmental stimuli and early life stress. Adults who experience chronic stress during early life are more likely to suffer various neurodevelopmental and health issues. However, our understanding of how these specific environmental signals at different developmental stages affect brain development is poorly understood. In this study, we investigated if stress in parents prior to conception modulates neurodevelopment in offspring. We used a chronic unpredictable stress model adapted to zebrafish, which is an increasingly popular vertebrate model in neuroscience research to investigate the effects of both maternal and paternal preconception stress on offspring behavior. We evaluated the responsiveness of three anxiety-related behavioral paradigms in zebrafish: the novel tank test, thigmotaxis, and shoaling behavior. We found larvae from stressed females exhibited anxiety-like behavior in a thigmotaxis assay. As these larvae matured into adults, they continued to exhibit anxiety-like behavior in a novel tank and shoaling behavioral assay. These studies indicate preconception stress exposure in parents can induce life-long alterations in offspring neurodevelopment. Further, these results expand the hypothesis that chronically elevated glucocorticoid signaling not only in stressed mothers, but also stressed dads can affect neurodevelopment in offspring. We propose that zebrafish may be a useful model to study the transgenerational effects of chronic stress mediated via the maternal and paternal line.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Peixe-Zebra , Animais , Humanos , Feminino , Comportamento Animal , Ansiedade/etiologia , Transtornos de Ansiedade , Estresse Psicológico/complicaçõesRESUMO
The peripheral B cell compartment in mice and humans is maintained by continuous production of transitional B cells in the bone marrow. In other species, however, including rabbits, B lymphopoiesis in the bone marrow abates early in life, and it is unclear how the peripheral B cell compartment is maintained. We identified transitional B cells in rabbits and classified them into T1 (CD24(high)CD21(low)) and T2 (CD24(high)CD21(+)) B cell subsets. By neutralizing B cell-activating factor in vivo, we found an arrest in peripheral B cell development at the T1 B cell stage. Surprisingly, T1 B cells were present in GALT, blood, and spleen of adult rabbits, long after B lymphopoiesis was arrested. T1 B cells were distinct from their counterparts in other species because they are proliferating and the Ig genes are somatically diversified. We designate these newly described cells as T1d B cells and propose a model in which they develop in GALT, self renew, continuously differentiate into mature B cells, and thereby maintain peripheral B cell homeostasis in adults in the absence of B lymphopoiesis.
Assuntos
Linfócitos B/imunologia , Proliferação de Células , Homeostase/imunologia , Células Precursoras de Linfócitos B/imunologia , Animais , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Sequência de Bases , Antígeno CD24/imunologia , Antígeno CD24/metabolismo , Diferenciação Celular/imunologia , Citometria de Fluxo , Trato Gastrointestinal/citologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Humanos , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos , Dados de Sequência Molecular , Células Precursoras de Linfócitos B/metabolismo , Coelhos , Receptores de Complemento 3d/imunologia , Receptores de Complemento 3d/metabolismo , Homologia de Sequência do Ácido Nucleico , Fatores de TempoRESUMO
The field of human microbiome and gut microbial diversity research has witnessed a profound transformation, driven by advances in omics technologies. These advancements have unveiled essential connections between microbiome alterations and severe conditions, prompting the development of new frameworks through epidemiological studies. Traditionally, it was believed that each individual harbored unique microbial communities acquired early in life, evolving over the course of their lifetime, with little acknowledgment of any prenatal microbial development, but recent research challenges this belief. The neonatal microbiome's onset, influenced by factors like delivery mode and maternal health, remains a subject of intense debate, hinting at potential intrauterine microbial processes. In-depth research reveals associations between microbiome profiles and specific health outcomes, ranging from obesity to neurodevelopmental disorders. Understanding these diverse microbiome profiles is essential for unraveling the intricate relationships between the microbiome and health outcomes.
RESUMO
Necrotizing enterocolitis (NEC) is the leading cause of intestinal morbidity and mortality in neonates. A large body of work exists; however, the pathogenesis of NEC remains poorly understood. Numerous predictors have been implicated in the development of NEC, with relatively less emphasis on maternal factors. Utilizing human tissue plays a crucial role in enhancing our comprehension of the underlying mechanisms accountable for this devastating disease. In this review, we will discuss how maternal stress affects the pathogenesis of NEC and how changes in the intestinal microbiome can influence the development of NEC. We will also discuss the results of transcriptomics-based studies and analyze the gene expression changes in NEC tissues and other molecular targets associated with the pathogenesis of NEC.
RESUMO
Necrotizing Enterocolitis (NEC) is a devastating intestinal inflammatory disease with significant morbidity and mortality. Numerous predictors have been implicated in the development of NEC, with a relatively less emphasis on maternal factors. Pregnancy drives women into a new stage of life that increases their susceptibility to biological and psychological stress. Additionally, maternal stress during pregnancy has been linked to various complications that can negatively impact both the mother and the developing fetus. These detrimental effects are facilitated by various systemic modifications. Similarly, there is evidence from animal studies that suggest a relationship between maternal stress and the occurrence of NEC due to the alterations observed in neonates. In this review, we will (1) discuss the physiological and psychological burden of maternal stress and how it can be linked to NEC, (2) summarize various predictors and risk factors of NEC, and (3) discuss the most widely utilized animal models for assessing the effects of prenatal stress on offspring.
Assuntos
Enterocolite Necrosante , Doenças Fetais , Doenças do Recém-Nascido , Animais , Gravidez , Recém-Nascido , Humanos , Feminino , Enterocolite Necrosante/etiologia , Fatores de Risco , Recém-Nascido PrematuroRESUMO
Maternal prenatal stress exposure affects the development of offspring. We searched for articles in the PubMed database and reviewed the evidence for how prenatal stress alters the composition of the microbiome, the production of microbial-derived metabolites, and regulates microbiome-induced behavioral changes in the offspring. The gut-brain signaling axis has gained considerable attention in recent years and provides insights into the microbial dysfunction in several metabolic disorders. Here, we reviewed evidence from human studies and animal models to discuss how maternal stress can modulate the offspring microbiome. We will discuss how probiotic supplementation has a profound effect on the stress response, the production of short chain fatty acids (SCFAs), and how psychobiotics are emerging as novel therapeutic targets. Finally, we highlight the potential molecular mechanisms by which the effects of stress are transmitted to the offspring and discuss how the mitigation of early-life stress as a risk factor can improve the birth outcomes.
RESUMO
The effects of B cell-activating factor belonging to the TNF family (BAFF) on B cell maturation and survival in the mouse are relatively well understood. In contrast, little is known about the role of BAFF in B cell development in other mammals, such as rabbits, that use GALT to develop and maintain the B cell compartment. We examined the expression and requirement of BAFF and a proliferation-inducing ligand (APRIL) during peripheral B cell development in young rabbits. By neutralizing BAFF and APRIL in neonates with a soluble decoy receptor, transmembrane activator calcium modulator and cyclophilin ligand interactor-Fc, we found a marked reduction in the number of peripheral B cells, but found no change in the bone marrow (BM) compartment. In the appendix, the size and number of proliferating B cell follicles were greatly reduced, demonstrating that although BAFF/APRIL is dispensable for B cell development in BM, it is required for B cell development in GALT. We found that all rabbit B cells expressed BAFF receptor 3, but did not bind rBAFF, suggesting that the BAFF-binding receptors (BBRs) are bound by endogenous soluble BAFF. Further, we found that B cells themselves express BAFF, suggesting that the soluble BAFF bound to BBRs may be endogenously produced and stimulate B cells in an autocrine fashion. Additionally, we propose that this chronic occupancy of BBRs on B cells may provide a tonic and/or survival signal for the maintenance of peripheral B cells in adults after B lymphopoiesis is arrested in BM.
Assuntos
Fator Ativador de Células B/fisiologia , Subpopulações de Linfócitos B/imunologia , Diferenciação Celular/imunologia , Trato Gastrointestinal/imunologia , Tecido Linfoide/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologia , Envelhecimento/imunologia , Animais , Animais Recém-Nascidos , Fator Ativador de Células B/biossíntese , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/biossíntese , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células CHO , Linhagem Celular , Proliferação de Células , Cricetinae , Cricetulus , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , Humanos , Ligantes , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Linfopoese/imunologia , Coelhos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
Dysregulated activation of inflammatory signaling by the immature neonatal immune system could lead to the development of many pediatric diseases including necrotizing enterocolitis (NEC). While the mechanism(s) of pathogenesis is unknown, NEC is believed to have multifactorial causes. Microbial dysbiosis and intestinal immaturity have been implicated as potential triggers for this disease. We hypothesized that psychological stress during pregnancy negatively impacts the development of intestinal tissues in offspring and contributes to development of NEC. Consistent with this hypothesis, we previously observed shorter villi and a decrease in total surface area in the small intestine of pups derived from mice that were chronically stressed during gestation. In this study, we performed RNASeq analysis to determine the gene expression changes in the offspring gut following prenatal stress in pregnant mice and identified several differentially expressed genes (DEGs) and biological pathways. Notably, C3 was upregulated in the small intestine and contributed to a higher tissue injury score in a mesenteric ischemia model compared to unstressed controls. We discuss the potential implications of these stress-induced genes expression changes and their contribution to development of intestinal inflammation.
Assuntos
Complemento C3/genética , Regulação da Expressão Gênica , Intestino Delgado/metabolismo , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Fisiológico , Animais , Complemento C3/imunologia , Modelos Animais de Doenças , Enterocolite Necrosante/etiologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Intestino Delgado/imunologia , Isquemia Mesentérica/etiologia , Camundongos , Gravidez , Análise de Sequência de RNARESUMO
The intestinal microbiota is critical for maintaining homeostasis. Dysbiosis, an imbalance in the microbial community, contributes to the susceptibility of several diseases. Many factors are known to influence gut microbial composition, including diet. We have previously shown that fecal immunoglobulin (Ig) A levels are decreased in mice fed a diet free of aryl hydrocarbon receptor (AhR) ligands. Here, we hypothesize this IgA decrease is secondary to diet-induced dysbiosis. We assigned mice to a conventional diet, an AhR ligand-free diet, or an AhR ligand-free diet supplemented with the dietary AhR ligand indole-3-carbinol (I3C). We observed a global alteration of fecal microbiota upon dietary AhR ligand deprivation. Compared to mice on the conventional diet, family Erysipelotrichaceae was enriched in the feces of mice on the AhR ligand-free diet but returned to normal levels upon dietary supplementation with I3C. Faecalibaculum rodentium, an Erysipelotrichaceae species, depleted its growth media of AhR ligands. Cultured fecal bacteria from mice on the AhR ligand-free diet, but not the other two diets, were able to alter IgA levels in vitro, as was F. rodentium alone. Our data point to the critical role of AhR dietary ligands in shaping the composition and proper functioning of gut microbiota.
Assuntos
Dieta/métodos , Suplementos Nutricionais , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Receptores de Hidrocarboneto Arílico , Animais , DNA Ribossômico/genética , Dieta/efeitos adversos , Disbiose/etiologia , Fezes/química , Fezes/microbiologia , Firmicutes/genética , Células HCT116 , Humanos , Imunoglobulina A/análise , Indóis , Ligantes , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection after disease resolution, effective immune protection has not yet been achieved by human vaccines. Although circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFN-γ and remain resident in the skin when transplanted by skin graft onto naive mice. They function to recruit circulating T cells to the skin in a CXCR3-dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells.