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The human gut microbiome is well-recognized as a key player in maintaining health. However, it is a dynamic entity that changes across the lifespan. How the microbial changes that occur in later decades of life shape host health or impact age-associated inflammatory neurological diseases such as multiple sclerosis (MS) is still unclear. Current understanding of the aging gut microbiome is largely limited to cross-sectional observational studies. Moreover, studies in humans are limited by confounding host-intrinsic and extrinsic factors that are not easily disentangled from aging. This review provides a comprehensive summary of existing literature on the aging gut microbiome and its known relationships with neurological diseases, with a specific focus on MS. We will also discuss preclinical animal models and human studies that shed light on the complex microbiota-host interactions that have the potential to influence disease pathology and progression in aging individuals. Lastly, we propose potential avenues of investigation to deconvolute features of an aging microbiota that contribute to disease, or alternatively promote health in advanced age.
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Bacteriophages (phages) are viruses that infect bacteria with species- and strain-level specificity and are the most abundant biological entities across all known ecosystems. Within bacterial communities, such as those found in the gut microbiota, phages are implicated in regulating microbiota population dynamics and driving bacterial evolution. There has been renewed interest in phage research in the last decade, in part due to the host-specific killing capabilities of lytic phages, which offer a promising tool to counter the increasing threat of antimicrobial resistant bacteria. Furthermore, recent studies demonstrating that phages adhere to intestinal mucus suggest they may have a protective role in preventing bacterial invasion into the underlying epithelium. Importantly, like bacterial microbiomes, disrupted phageomes have been associated with worsened outcomes in diseases such as inflammatory bowel disease. Previous studies have demonstrated that phages can modulate the microbiome of animals and humans through fecal filtrate transplants, benefiting the host's health. With this recent wave of research comes the necessity to establish and standardize protocols for studying phages in the context of the gut microbiome. This protocol provides a set of procedures to study isolated T4 phages and their bacterial host, Escherichia coli, in the context of the murine gastrointestinal tract. The methods described here outline how to start from a phage lysate, administer it to mice and assess effects on bacterial host and phage levels. This protocol can be modified and applied to other phage-bacterial pairs and provides a starting point for studying host-phage dynamics in vivo.
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Bacteriófagos , Microbiota , Humanos , Ratones , Animales , Bacteriófagos/fisiología , Bacteriófago T4 , Escherichia coli , Tracto Gastrointestinal/microbiología , Intestinos , BacteriasRESUMEN
Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.
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Diabetes Mellitus Tipo 1 , Infecciones por Enterovirus , Humanos , Animales , Ratones , Ratones Endogámicos NOD , Disbiosis/complicaciones , Intestinos/microbiología , Infecciones por Enterovirus/complicaciones , Predisposición Genética a la EnfermedadRESUMEN
While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Here, we directly compared CD11c+T-bet+ ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes. EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE. Here, we demonstrate that ABCs are required for γHV68-enhanced disease. We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS. In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.
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Dietary fibers are potent modulators of immune responses that can restrain inflammation in multiple disease contexts. However, dietary fibers encompass a biochemically diverse family of carbohydrates, and it remains unknown how individual fiber sources influence immunity. In a direct comparison of four different high-fiber diets, we demonstrate a potent ability of guar gum to delay disease and neuroinflammation in experimental autoimmune encephalomyelitis, a T cell-mediated mouse model of multiple sclerosis. Guar gum-specific alterations to the microbiota are limited, and disease protection appears to be independent of fiber-induced increases in short-chain fatty acid levels or regulatory CD4+ T cells. Instead, CD4+ T cells of guar gum-supplemented mice are less encephalitogenic due to reduced activation, proliferation, Th1 differentiation, and altered migratory potential. These findings reveal specificity in the host response to fiber sources and define a pathway of fiber-induced immunomodulation that protects against pathologic neuroinflammation.
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Cyamopsis , Encefalomielitis Autoinmune Experimental , Animales , Cyamopsis/metabolismo , Dieta , Fibras de la Dieta/farmacología , Fibras de la Dieta/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Galactanos , Mananos , Ratones , Gomas de PlantasRESUMEN
Intestinal epithelial cells (IECs) serve as both a physical and an antimicrobial barrier against the microbiota, as well as a conduit for signaling between the microbiota and systemic host immunity. As individuals age, the balance between these systems undergoes a myriad of changes due to age-associated changes to the microbiota, IECs themselves, immunosenescence, and inflammaging. In this review, we discuss emerging data related to age-associated loss of intestinal barrier integrity and posit that IEC dysfunction may play a central role in propagating age-associated alterations in microbiota composition and immune homeostasis.
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Inmunosenescencia , Microbiota , Envejecimiento , Células Epiteliales , Homeostasis , HumanosRESUMEN
A plethora of studies have established the importance of eosinophils in protective immunity against infections and in allergy. In this issue of Immunity, Ignacio et al. (2022) define a vital for eosinophils in coordinating a microbiota-epithelial-immune axis that maintains intestinal homeostasis.
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Intestinos , Microbiota , Eosinófilos , HomeostasisRESUMEN
People living with multiple sclerosis (MS) experience episodic CNS white matter lesions instigated by autoreactive T cells. With age, patients with MS show evidence of gray matter demyelination and experience devastating nonremitting symptomology. What drives progression is unclear and studying this has been hampered by the lack of suitable animal models. Here, we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induced a nonremitting clinical phenotype that was associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young, SJL/J mice. Although the quantity and quality of T cells did not differ in the brains of old versus young EAE mice, an increase in neutrophils and a decrease in B cells were observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and gray matter pathology are dictated by age and associated with other immune cells, such as neutrophils.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Sustancia Gris/patología , Humanos , Inflamación , Ratones , Neutrófilos/patologíaRESUMEN
Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. In this study, we used colonization with the model commensal murine norovirus (MNV; strain CR6) to interrogate host-directed mechanisms of viral regulation, and we show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In addition to restricting CR6 replication to the intestinal tract, we show that STAT1 regulates antiviral CD4+ and CD8+ T cell responses and prevents systemic viral-induced tissue damage and disease. Despite altered T cell responses that resemble those that mediate lethal immunopathology in systemic viral infections in STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound limited viral replication, preventing virus-induced tissue damage and death without impacting the generation of inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa and that uncontrolled viral replication mediates disease rather than the concomitant development of dysregulated antiviral T cell responses in STAT1-deficient mice. IMPORTANCE The intestinal microbiota is a collection of bacteria, archaea, fungi, and viruses that colonize the mammalian gut. Coevolution of the host and microbiota has required development of immunological tolerance to prevent ongoing inflammatory responses against intestinal microbes. Breakdown of tolerance to bacterial components of the microbiota can contribute to immune activation and inflammatory disease. However, the mechanisms that are necessary to maintain tolerance to viral components of the microbiome, and the consequences of loss of tolerance, are less well understood. Here, we show that STAT1 is integral for preventing escape of a commensal-like virus, murine norovirus CR6 (MNV CR6), from the gut and that in the absence of STAT1, mice succumb to infection-induced disease. In contrast to the case with other systemic viral infections, mortality of STAT1-deficient mice is not driven by immune-mediated pathology. Our data demonstrate the importance of host-mediated geographical restriction of commensal-like viruses.
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Infecciones por Caliciviridae , Norovirus , Factor de Transcripción STAT1 , Linfocitos T , Replicación Viral , Animales , Infecciones por Caliciviridae/mortalidad , Infecciones por Caliciviridae/fisiopatología , Mucosa Intestinal/virología , Ratones , Norovirus/fisiología , Factor de Transcripción STAT1/deficiencia , Factor de Transcripción STAT1/genética , Linfocitos T/inmunología , Linfocitos T/virologíaRESUMEN
Neurons of the enteric nervous system (ENS) have limited regenerative capacity, and damage to these cells can cause neuropathies. In a recent issue of Cell, Ahrends et al. (2021) demonstrate that muscularis macrophages integrate distinct signals from diverse intestinal infections to protect ENS neurons from subsequent pathogenic insult.
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Sistema Nervioso Entérico , Emociones , Macrófagos , NeuronasRESUMEN
Group 3 innate lymphoid cells (ILC3s) control the formation of intestinal lymphoid tissues and play key roles in intestinal defense. They express neuropeptide vasoactive intestinal peptide (VIP) receptor 2 (VPAC2), through which VIP modulates their function, but whether VIP exerts other effects on ILC3 remains unclear. We show that VIP promotes ILC3 recruitment to the intestine through VPAC1 independent of the microbiota or adaptive immunity. VIP is also required for postnatal formation of lymphoid tissues as well as the maintenance of local populations of retinoic acid (RA)-producing dendritic cells, with RA up-regulating gut-homing receptor CCR9 expression by ILC3s. Correspondingly, mice deficient in VIP or VPAC1 suffer a paucity of intestinal ILC3s along with impaired production of the cytokine IL-22, rendering them highly susceptible to the enteric pathogen Citrobacter rodentium This heightened susceptibility to C. rodentium infection was ameliorated by RA supplementation, adoptive transfer of ILC3s, or by recombinant IL-22. Thus, VIP regulates the recruitment of intestinal ILC3s and formation of postnatal intestinal lymphoid tissues, offering protection against enteric pathogens.
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Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Linfocitos/inmunología , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Animales , Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Interleucinas/análisis , Tejido Linfoide/citología , Tejido Linfoide/crecimiento & desarrollo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR/biosíntesis , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Tretinoina/metabolismo , Péptido Intestinal Vasoactivo/genética , Interleucina-22RESUMEN
Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are highly influenced by changes in the microbiota and of microbiota-derived metabolites, including short chain fatty acids, bile acids, and tryptophan derivatives. This review will discuss the effects of microbiota-derived metabolites on neuroinflammation driven by central nervous system-resident cells and peripheral immune cells, and their influence on outcomes of EAE and MS.
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Bacterias/metabolismo , Microbioma Gastrointestinal , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/microbiología , Animales , Bacterias/clasificación , Bacterias/aislamiento & purificación , Sistema Nervioso Central/inmunología , Ácidos Grasos Volátiles/metabolismo , HumanosRESUMEN
BACKGROUND: Due to the chronic and incurable nature of the autoimmune disease multiple sclerosis (MS), some people with MS will seek out alternative therapeutic approaches. Helminth immunotherapy, the deliberate inoculation with helminthic parasites as an intervention to prevent, delay, or minimize progression of autoimmune disorders, is one such approach gaining traction in academic research and with the public. Herein, we explored the perspectives of people with MS regarding helminth immunotherapy and its use in disease management. METHODS: Interpretive description, a qualitative research approach, was applied to data extracted from online forums. Multiple investigators independently identified, extracted, and analyzed data to develop preliminary codes. Inductive thematic analysis and triangulation were then used to collaboratively establish themes. RESULTS: Four main themes were generated: experience of living with MS, influential factors in contemplating helminth immunotherapy, logistics of helminth immunotherapy, and concerns about helminth immunotherapy. CONCLUSIONS: There was a general consensus in publicly available online forums that conventional therapies do not provide meaningful improvement for some people with MS. These people may seek alternative therapies such as helminth immunotherapy. Information on helminth immunotherapy from internet resources (eg, blogs and social media forums) can contain biased and scientifically unsupported opinions. Messages of efficacy and improved quality of life are readily available and may influence people with MS considering helminth immunotherapy as an alternative therapy. Although some people with MS are seeking helminth immunotherapy, clinical trial data do not currently support its use for people with MS.
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Helminthic worms are ancestral members of the intestinal ecosystem that have been largely eradicated from the general population in industrialized countries. Immunomodulatory mechanisms induced by some helminths mediate a "truce" between the mammalian host and the colonizing worm, thus allowing for long-term persistence in the absence of immune-mediated collateral tissue damage. This concept and the geographic discrepancy between global burdens of chronic inflammatory diseases and helminth infection have sparked interest in the potential of using helminthic worms as a therapeutic intervention to limit the progression of autoimmune diseases such as multiple sclerosis (MS). Here, we present and evaluate the evidence for this hypothesis in the pre-clinical animal model of MS, experimental autoimmune encephalitis, in helminth-infected MS patients and in clinical trials of administered helminth immunotherapy (HIT).
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Helmintiasis , Helmintos , Esclerosis Múltiple , Animales , Ecosistema , Helmintiasis/terapia , Humanos , Inmunoterapia , Esclerosis Múltiple/terapiaRESUMEN
Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.
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Inmunoglobulina A/metabolismo , Interleucina-10/metabolismo , Intestinos/inmunología , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Inmunoglobulina A/inmunología , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Neuroinmunomodulación/inmunología , Células Plasmáticas/metabolismoRESUMEN
B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.
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Basófilos/inmunología , Galectinas/inmunología , Receptores de Hialuranos/inmunología , Inmunoglobulina D/inmunología , Células Th2/inmunología , Animales , Basófilos/metabolismo , Línea Celular Tumoral , Células Cultivadas , Galectinas/genética , Galectinas/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Inmunoglobulina D/metabolismo , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-4/metabolismo , Ratones Endogámicos BALB C , Unión Proteica , Células Th2/metabolismoRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1005684.].
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Mammalian evolution has occurred in the presence of mutualistic, commensal, and pathogenic micro- and macro-organisms for millennia. The presence of these organisms during mammalian evolution has allowed for intimate crosstalk between these colonizing species and the host immune system. In this review, we introduce the concept of the 'multibiome' to holistically refer to the biodiverse collection of bacteria, viruses, fungi and multicellular helminthic worms colonizing the mammalian intestine. Furthermore, we discuss new insights into multibiome-host interactions in the context of host-protective immunity and immune-mediated diseases, including inflammatory bowel disease and multiple sclerosis. Finally, we provide reasons to account for the multibiome in experimental design, analysis and in therapeutic applications.