Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut-innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, are affected by or involved in the etiology of these debilitating and progressive disorders has been understudied. Studies in recent years have shown how CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other’s functions. These studies underscore the importance of exploring the gut-innervating and gut-brain connecting neurons of the CNS and gut function in health, as well as the etiology and progression of dysfunction in NDs. In this Review, we discuss our current understanding of how the various gut-innervating neurons and gut physiology are involved in the etiology of NDs, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, to cause progressive CNS and persistent gut dysfunction.
Alpana Singh, Ted M. Dawson, Subhash Kulkarni
The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.
Laura Ghezzi, Claudia Cantoni, Gabriela V. Pinget, Yanjiao Zhou, Laura Piccio
Traumatic brain injury (TBI) is a chronic and progressive disease, and management requires an understanding of both the primary neurological injury and the secondary sequelae that affect peripheral organs, including the gastrointestinal (GI) tract. The brain-gut axis is composed of bidirectional pathways through which TBI-induced neuroinflammation and neurodegeneration impact gut function. The resulting TBI-induced dysautonomia and systemic inflammation contribute to the secondary GI events, including dysmotility and increased mucosal permeability. These effects shape, and are shaped by, changes in microbiota composition and activation of resident and recruited immune cells. Microbial products and immune cell mediators in turn modulate brain-gut activity. Importantly, secondary enteric inflammatory challenges prolong systemic inflammation and worsen TBI-induced neuropathology and neurobehavioral deficits. The importance of brain-gut communication in maintaining GI homeostasis highlights it as a viable therapeutic target for TBI. Currently, treatments directed toward dysautonomia, dysbiosis, and/or systemic inflammation offer the most promise.
Marie Hanscom, David J. Loane, Terez Shea-Donohue
The gut microbiota has the capacity to affect host appetite via intestinal satiety pathways, as well as complex feeding behaviors. In this Review, we highlight recent evidence that the gut microbiota can modulate food preference across model organisms. We discuss effects of the gut microbiota on the vagus nerve and brain regions including the hypothalamus, mesolimbic system, and prefrontal cortex, which play key roles in regulating feeding behavior. Crosstalk between commensal bacteria and the central and peripheral nervous systems is associated with alterations in signaling of neurotransmitters and neuropeptides such as dopamine, brain-derived neurotrophic factor (BDNF), and glucagon-like peptide-1 (GLP-1). We further consider areas for future research on mechanisms by which gut microbes may influence feeding behavior involving these neural pathways. Understanding roles for the gut microbiota in feeding regulation will be important for informing therapeutic strategies to treat metabolic and eating disorders.
Kristie B. Yu, Elaine Y. Hsiao
Given the crucial role of the gastrointestinal tract and associated organs in handling nutrient assimilation and metabolism, it has long been known that its communication with the brain is important for the control of ingestive behavior and body weight regulation. It is also clear that gut-brain communication is bidirectional and utilizes both rapid neural and slower humoral mechanisms and pathways. However, progress in understanding these mechanisms and leveraging them for the treatment of obesity and metabolic disease has been hindered by the enormous dimension of the gut mucosa, the complexity of the signaling systems, and lack of specific tools. With the ascent of modern neurobiological technology, our understanding of the role of vagal afferents in gut-brain communication has begun to change. The first function-specific populations of vagal afferents providing nutritional feedback as well as feed-forward signals have been identified with genetics-guided methodology, and it is hoped that extension of the methodology to other neural communication pathways will follow soon. Currently, efficient clinical leveraging of gut-brain communication to treat obesity and metabolic disease is limited to a few gut hormones, but a more complete understanding of function-specific and projection-specific neuronal populations should make it possible to develop selective and more effective neuromodulation approaches.
Hans-Rudolf Berthoud, Vance L. Albaugh, Winfried L. Neuhuber
The gastrointestinal tract comprises a complex ecosystem with extensive opportunities for functional interactions between neoplastic epithelial cells and stromal, immune, neuronal, glial, and other cell types, as well as microorganisms and metabolites within the gut lumen. In this Review, we focus on interactions between gastrointestinal cancers and elements of the central and enteric nervous systems. This previously understudied but rapidly emerging area of investigation has blossomed in recent years, particularly with respect to improved understanding of neural contributions to the development and progression of esophageal, gastric, pancreatic, and colon neoplasia. Cancer neuroscience offers great promise to advance our understanding of how neural-cancer interactions promote alimentary tract neoplasia. The resulting mechanistic insights can be leveraged to identify diagnostic and prognostic biomarkers, and to develop novel therapeutic interventions.
Alyssa Schledwitz, Guofeng Xie, Jean-Pierre Raufman
As part of the centennial celebration of insulin’s discovery, this review summarizes the current understanding of the genetics, pathogenesis, treatment, and outcomes in type 1 diabetes (T1D). T1D results from an autoimmune response that leads to destruction of the β cells in the pancreatic islet and requires lifelong insulin therapy. While much has been learned about T1D, it is now clear that there is considerable heterogeneity in T1D with regard to genetics, pathology, response to immune-based therapies, clinical course, and susceptibility to diabetes-related complications. This Review highlights knowledge gaps and opportunities to improve the understanding of T1D pathogenesis and outlines emerging therapies to treat or prevent T1D and reduce the burden of T1D.
Alvin C. Powers
The tumor microenvironment profoundly influences the behavior of recruited leukocytes and tissue-resident immune cells. These immune cells, which inherently have environmentally driven plasticity necessary for their roles in tissue homeostasis, dynamically interact with tumor cells and the tumor stroma and play critical roles in determining the course of disease. Among these immune cells, neutrophils were once considered much more static within the tumor microenvironment; however, some of these earlier assumptions were the product of the notorious difficulty in manipulating neutrophils in vitro. Technological advances that allow us to study neutrophils in context are now revealing the true roles of neutrophils in the tumor microenvironment. Here we discuss recent data generated by some of these tools and how these data might be synthesized into more elegant ways of targeting these powerful and abundant effector immune cells in the clinic.
Amanda J. McFarlane, Frédéric Fercoq, Seth B. Coffelt, Leo M. Carlin
Treatment resistance leads to cancer patient mortality. Therapeutic approaches that employ synthetic lethality to target mutational vulnerabilities in key tumor cell signaling pathways have proven effective in overcoming therapeutic resistance in some cancers. Yet, tumors are organs composed of malignant cells residing within a cellular and noncellular stroma. Tumor evolution and resistance to anticancer treatment are mediated through a dynamic and reciprocal dialogue with the tumor microenvironment (TME). Accordingly, expanding tumor cell synthetic lethality to encompass contextual synthetic lethality has the potential to eradicate tumors by targeting critical TME circuits that promote tumor progression and therapeutic resistance. In this Review, we summarize current knowledge about the TME and discuss its role in treatment. We outline the concept of tumor cell–specific synthetic lethality and describe therapeutic approaches to expand this paradigm to leverage TME synthetic lethality to improve cancer therapy.
Kevin J. Metcalf, Alaa Alazzeh, Zena Werb, Valerie M. Weaver
Continued thinning of the atmospheric ozone, which protects the earth from damaging ultraviolet radiation (UVR), will result in elevated levels of UVR reaching the earth’s surface, leading to a drastic increase in the incidence of skin cancer. In addition to promoting carcinogenesis in skin cells, UVR is a potent extrinsic driver of age-related changes in the skin known as “photoaging.” We are in the preliminary stages of understanding of the role of intrinsic aging in melanoma, and the tumor-permissive effects of photoaging on the skin microenvironment remain largely unexplored. In this Review, we provide an overview of the impact of UVR on the skin microenvironment, addressing changes that converge or diverge with those observed in intrinsic aging. Intrinsic and extrinsic aging promote phenotypic changes to skin cell populations that alter fundamental processes such as melanogenesis, extracellular matrix deposition, inflammation, and immune response. Given the relevance of these processes in cancer, we discuss how photoaging might render the skin microenvironment permissive to melanoma progression.
Asurayya Worrede, Stephen M. Douglass, Ashani T. Weeraratna
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