Mechanisms and consequences of intestinal dysbiosis

The composition of the gut microbiota is in constant flow under the influence of factors such as the diet, ingested drugs, the intestinal mucosa, the immune system, and the microbiota itself. Natural variations in the gut microbiota can deteriorate to a state of dysbiosis when stress conditions rapidly decrease microbial diversity and promote the expansion of specific bacterial taxa. The mechanisms underlying intestinal dysbiosis often remain unclear given that combinations of natural variations and stress factors mediate cascades of destabilizing events. Oxidative stress, bacteriophages induction and the secretion of bacterial toxins can trigger rapid shifts among intestinal microbial groups thereby yielding dysbiosis. A multitude of diseases including inflammatory bowel diseases but also metabolic disorders such as obesity and diabetes type II are associated with intestinal dysbiosis. The characterization of the changes leading to intestinal dysbiosis and the identification of the microbial taxa contributing to pathological effects are essential prerequisites to better understand the impact of the microbiota on health and disease.     

Implication of gut microbiota metabolites in cardiovascular and metabolic diseases

Evidence from the literature keeps highlighting the impact of mutualistic bacterial communities of the gut microbiota on human health. The gut microbita is a complex ecosystem of symbiotic bacteria which contributes to mammalian host biology by processing, otherwise, indigestible nutrients, supplying essential metabolites, and contributing to modulate its immune system. Advances in sequencing technologies have enabled structural analysis of the human gut microbiota and allowed detection of changes in gut bacterial composition in several common diseases, including cardiometabolic disorders. Biological signals sent by the gut microbiota to the host, including microbial metabolites and pro-inflammatory molecules, mediate microbiome–host genome cross-talk. This rapidly expanding line of research can identify disease-causing and disease-predictive microbial metabolite biomarkers, which can be translated into novel biodiagnostic tests, dietary supplements, and nutritional interventions for personalized therapeutic developments in common diseases. Here, we review results from the most significant studies dealing with the association of products from the gut microbial metabolism with cardiometabolic disorders. We underline the importance of these postbiotic biomarkers in the diagnosis and treatment of human disorders.     

Voices from within: gut microbes and the CNS

Recent advances in research have greatly increased our understanding of the importance of the gut microbiota. Bacterial colonization of the intestine is critical to the normal development of many aspects of physiology such as the immune and endocrine systems. It is emerging that the influence of the gut microbiota also extends to modulation of host neural development. Furthermore, the overall balance in composition of the microbiota, together with the influence of pivotal species that induce specific responses, can modulate adult neural function, peripherally and centrally. Effects of commensal gut bacteria in adult animals include protection from the central effects of infection and inflammation as well as modulation of normal behavioral responses. There is now robust evidence that gut bacteria influence the enteric nervous system, an effect that may contribute to afferent signaling to the brain. The vagus nerve has also emerged as an important means of communicating signals from gut bacteria to the CNS. Further understanding of the mechanisms underlying microbiome–gut–brain communication will provide us with new insight into the symbiotic relationship between gut microbiota and their mammalian hosts and help us identify the potential for microbial-based therapeutic strategies to aid in the treatment of mood disorders.     

Immunoregulation by the gut microbiota

The human intestinal mucosa is constantly exposed to commensal microbiota. Since the gut microbiota is beneficial to the host, hosts have evolved intestine-specific immune systems to co-exist with the microbiota. On the other hand, the intestinal microbiota actively regulates the host’s immune system, and recent studies have revealed that specific commensal bacterial species induce the accumulation of specific immune cell populations. For instance, segmented filamentous bacteria and Clostridium species belonging to clusters XIVa and IV induce the accumulation of Th17 cells in the small intestine and Foxp3⁺ regulatory T cells in the large intestine, respectively. The immune cells induced by the gut microbiota likely contribute to intestinal homeostasis and influence systemic immunity in the host.     

Expression and functional importance of innate immune receptors by intestinal epithelial cells

Pattern recognition receptors are somatically encoded and participate in the innate immune responses of a host to microbes. It is increasingly acknowledged that these receptors play a central role both in beneficial and pathogenic interactions with microbes. In particular, these receptors participate actively in shaping the gut environment to establish a fruitful life-long relationship between a host and its microbiota. Commensal bacteria engage Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs) to induce specific responses by intestinal epithelial cells such as production of antimicrobial products or of a functional mucus layer. Furthermore, a complex crosstalk between intestinal epithelial cells and the immune system is initiated leading to a mature gut-associated lymphoid tissue to secrete IgA. Impairment in NLR and TLR functionality in epithelial cells is strongly associated with chronic inflammatory diseases such as Crohn’s disease, cancer, and with control of the commensal microbiota creating a more favorable environment for the emergence of new infections.     

Intestinal epithelial barrier and mucosal immunity

The innate immune system plays a crucial role in maintaining the integrity of the intestine and protecting the host against a vast number of potential microbial pathogens from resident and transient gut microflora. Mucosal epithelial cells and Paneth cells produce a variety of antimicrobial peptides (defensins, cathelicidins, crytdinrelated sequence peptides, bactericidal/permeabilityincreasing protein, chemokine CCL20) and bacteriolytic enzymes (lysozyme, group IIA phospholipase A2) that protect mucosal surfaces and crypts containing intestinal stem cells against invading microbes. Many of the intestinal antimicrobial molecules have additional roles of attracting leukocytes, alarming the adaptive immune system or neutralizing proinflammatory bacterial molecules. Dysfunction of components of the innate immune system has recently been implicated in chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, illustrating the pivotal role of innate immunity in maintaining the delicate balance between immune tolerance and immune response in the gut.     

Molecular dialogue between the human gut microbiota and the host: a Lactobacillus and Bifidobacterium perspective

The human gut represents a highly complex ecosystem, which is densely colonized by a myriad of microorganisms that influence the physiology, immune function and health status of the host. Among the many members of the human gut microbiota, there are microorganisms that have co-evolved with their host and that are believed to exert health-promoting or probiotic effects. Probiotic bacteria isolated from the gut and other environments are commercially exploited, and although there is a growing list of health benefits provided by the consumption of such probiotics, their precise mechanisms of action have essentially remained elusive. Genomics approaches have provided exciting new opportunities for the identification of probiotic effector molecules that elicit specific responses to influence the physiology and immune function of their human host. In this review, we describe the current understanding of the intriguing relationships that exist between the human gut and key members of the gut microbiota such as bifidobacteria and lactobacilli, discussed here as prototypical groups of probiotic microorganisms.     

Selected aspects of the human gut microbiota

The gut microbiota represents a highly complex assembly of microbes, which interact with each other and with their host. These interactions have various implications in terms of health and disease, and this multi-author review issue will address a number of selected aspects pertaining to gut microbiota research.     

Inflammatory bowel disease: is it a primary immunodeficiency?

Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea, bleeding and malabsorption. IBD has been considered a hyperinflammatory state due to disturbed interactions between the immune system and the commensal bacterial flora of the gut. However, there is evidence that Crohn’s disease might be the consequence of a reduced release of pro-inflammatory cytokines and an impaired acute inflammatory response, thereby suggesting that IBD might be an immunodeficiency rather than an excessive inflammatory reaction. This theory has been supported by observations in patients with primary immunodeficiencies such as the Wiskott–Aldrich syndrome and IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In contrary, defects in the anti-inflammatory down-regulation of the immune response as they are seen in patients with Mendelian defects in the IL10 signaling pathway support the hyper-inflammatory theory. In this review, we describe and discuss primary immunodeficiencies associated with IBD and show that the bowel is a highly sensitive indicator of dysregulations, making IBD a model disease to study and identify key regulators required to balance the human mucosal immune system.     

Microbiome–health interactions in older people

Alterations in the composition and function of the gut microbiome have been implicated in a range of conditions and diseases. Culture-dependent and culture-independent studies both showed that older people harbour a gut microbiome that differs in composition from that of younger adults. Detailed analyses have identified discrete microbiota subtypes that characterize intermediates between a high diversity microbiota found in healthy community-dwelling subjects and a low diversity microbiota typical for elderly living in long-term residential care. There are also alterations in the microbiome composition associated with biological age, independent of health status. Even after adjusting for confounding factors such as age and medication, trends in microbiota composition correlate with gradients in clinical metadata particularly frailty and inflammatory status. There are few known mechanisms by which these associations might be causative rather than consequential, and this is a subject of intensive research. The strongest candidate effectors are microbial metabolites that could impact host energy balance, act as signalling molecules to modulate host metabolism or inflammation, and potentially also impact on the gut–brain axis.     

Metallothionein expression in the central nervous system of multiple sclerosis patients

Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS by tissue injury, stress and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In fact, MT-I+II-deficient mice are more susceptible to developing experimental autoimmune encephalomyelitis (EAE), and treatment of Lewis rats with Zn-MT-II reduces EAE severity. We show here that, as in EAE, MT-I+II proteins were expressed in brain lesions of MS patients. Cells expressing MT-I+II were mainly astrocytes and activated monocytes/macrophages. Interestingly, the levels of MT-I+II were slightly increased in the inactive MS lesions in comparison with the active lesions, suggesting that MTs may be important in disease remission.     

The enteric nervous system in gastrointestinal disease etiology

A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut–brain interaction, inflammatory bowel diseases, and colorectal cancer.

     

The CD40/CD154 receptor/ligand dyadRID="†"ID="†" Review

Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines, matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory processes and prevalent human diseases. Received 10 January 2000; revised 16 June 2000; accepted 5 July 2000 RID="†" ID="†" Review RID="*" ID="*" Corresponding author.     

Wnt and lithium: a common destiny in the therapy of nervous system pathologies?

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.     

Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases

Oxidative stress and low-grade inflammation are the hallmarks of the aging process and are even more enhanced in many age-related degenerative diseases. Mitochondrial dysfunction and oxidative stress can provoke and potentiate inflammatory responses, but the mechanism has remained elusive. Recent studies indicate that oxidative stress can induce the assembly of multiprotein inflammatory complexes called the inflammasomes. Nod-like receptor protein 3 (NLRP3) is the major immune sensor for cellular stress signals, e.g., reactive oxygen species, ceramides, and cathepsin B. NLRP3 activation triggers the caspase-1-mediated maturation of the precursors of IL-1β and IL-18 cytokines. During aging, the autophagic clearance of mitochondria declines and dysfunctional mitochondria provoke chronic oxidative stress, which disturbs the cellular redox balance. Moreover, increased NF-κB signaling observed during aging could potentiate the expression of NLRP3 and cytokine proforms enhancing the priming of NLRP3 inflammasomes. Recent studies have demonstrated that NLRP3 activation is associated with several age-related diseases, e.g., the metabolic syndrome. We will review here the emerging field of inflammasomes in the appearance of the proinflammatory phenotype during the aging process and in age-related diseases.     

A central role for calcineurin in protein misfolding neurodegenerative diseases

Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegenerative diseases affecting humans and animals. Dysregulation of calcium (Ca²⁺) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca²⁺ in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca²⁺ storing organelle, ultimately leading to neuronal dysfunction and apoptosis. Calcineurin (CaN), a Ca²⁺/calmodulin-dependent serine/threonine phosphatase, has been implicated in T cells activation through the induction of nuclear factor of activated T cells (NFAT). In addition to the involvement of several other signaling cascades, CaN has been shown to play a role in early synaptic dysfunction and neuronal death. Therefore, inhibiting hyperactivated CaN in early stages of disease might be a promising therapeutic strategy for treating patients with protein misfolding diseases. In this review, we briefly summarize the structure of CaN, inhibition mechanisms by which immunosuppressants inhibit CaN, role of CaN in maintaining neuronal and synaptic integrity and homeostasis and the role played by CaN in protein unfolding/misfolding neurodegenerative diseases.     

Bifidobacteria and the infant gut: an example of co-evolution and natural selection

Throughout the human life, the gut microbiota interacts with us in a number of different ways, thereby influencing our health status. The acquisition of such an interactive gut microbiota commences at birth. Medical and environmental factors including diet, antibiotic exposure and mode of delivery are major factors that shape the composition of the microbial communities in the infant gut. Among the most abundant members of the infant microbiota are species belonging to the Bifidobacterium genus, which are believed to confer beneficial effects upon their host. Bifidobacteria may be acquired directly from the mother by vertical transmission and their persistence in the infant gut is associated with their saccharolytic activity toward glycans that are abundant in the infant gut. Here, we discuss the establishment of the infant gut microbiota and the contribution of bifidobacteria to this early life microbial consortium.     

Epithelial homeostasis and the underlying molecular mechanisms in the gut of the insect model <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Insects mostly develop on decaying and contaminated organic matter and often serve as vectors of biologically transmitted diseases by transporting microorganisms to the plant and animal hosts. As such, insects are constantly ingesting microorganisms, a small fraction of which reach their epithelial surfaces, mainly their digestive tract, where they can establish relationships ranging from symbiosis to mutualism or even parasitism. Understanding the tight physical, genetic, and biochemical interactions that takes place between intestinal epithelia and either resident or infectious microbes has been a long-lasting objective of the immunologist. Research in this field has recently been re-vitalized with the development of deep sequencing techniques, which allow qualitative and quantitative characterization of gut microbiota. Interestingly, the recent identification of regenerative stem cells in the Drosophila gut together with the initial characterization of Drosophila gut microbiota have opened up new avenues of study aimed at understanding the mechanisms that regulate the dialog between the Drosophila gut epithelium and its microbiota of this insect model. The fact that some of the responses are conserved across species combined with the power of Drosophila genetics could make this organism model a useful tool to further elucidate some aspects of the interaction occurring between the microbiota and the human gut.     

Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors

Microglia are key sentinels of central nervous system health, and their dysfunction has been widely implicated in the progressive nature of neurodegenerative diseases. While microglia can produce a host of factors that are toxic to neighboring neurons, NOX2 has been implicated as a common and essential mechanism of microglia-mediated neurotoxicity. Accumulating evidence indicates that activation of the NOX2 enzyme complex in microglia is neurotoxic, both through the production of extracellular reactive oxygen species that damage neighboring neurons as well as the initiation of redox signaling in microglia that amplifies the pro-inflammatory response. More specifically, evidence supports that NOX2 redox signaling enhances microglial sensitivity to pro-inflammatory stimuli, and amplifies the production of neurotoxic cytokines, to promote chronic and neurotoxic microglial activation. Here, we describe the evidence denoting the role of NOX2 in microglia-mediated neurotoxicity with an emphasis on Alzheimer's and Parkinson's disease, describe available inhibitors that have been tested, and detail evidence of the neuroprotective and therapeutic potential of targeting this enzyme complex to regulate microglia.     

Alzheimer’s disease: the impact of age-related changes in reproductive hormones

Two classes of ovarian steroids, estrogens and progestins, are potent in protecting neurons against acute toxic events as well as chronic neurodegeneration. Herein we review the evidence for neuroprotection by both classes of steroids, provide plausible mechanisms for these potent neuroprotective activities and indicate the need for further clinical trials of both estrogens and progestins in protection against acute and chronic conditions that cause neuronal death. Estrogens at concentrations ranging from physiological to pharmacological are neuroprotective in a variety of in vitro and in vivo models of cerebral ischemia and brain trauma as well as in reducing key neuropathologies of Alzheimers disease. While the mechanisms of this potent neuroprotection are currently unresolved, a mitochondrial mechanism is involved. Progestins have been recently shown to activate many of the signaling pathways used by estrogens to neuroprotect, and progestins have been shown to protect against neuronal loss in vitro and in vivo in a variety of models of acute insult. Collectively, results of these animal and tissue culture models suggest that the loss of both estrogens and progestins at the menopause makes the brain more vulnerable to acute insults and chronic neurodegenerative diseases. Further clinical assessment of appropriate regimens of estrogens, progestins and their combination are supported by these data.