Abstract:Gut microbes are immunologically tolerated in the gastrointestinal tract but trigger aggressive immune responses upon translocation across the gut barrier. Although oral tolerance, a physiological process that dampens immune responses to food proteins and commensal microbiota, remains poorly defined, significant progress was made during and after the Human Immunodeficiency Virus epidemic in the 1980s and the discovery of regulatory T cells in 1995. Additional insight was gained after the discoveries of innate … Show more
“…In our previous work, we have discussed microbial translocation from the GI tract into the host systemic circulation, suggesting that the pathogenesis of several idiopathic diseases could be explained by the immune responses to extraintestinal microbial proteins [193]. As higher gut and BBB permeability markers, including the soluble form of CD14 (sCD14), were documented in neuropsychiatric illness, this pathology may, at least in part, result from microbial migration through the gut barrier [194][195][196].…”
Section: Microbial Translocation Outside the Gi Tractmentioning
A paradigm shift is currently taking place in the etiopathogenesis of neuropsychiatric disorders as immunometabolism is replacing the earlier neurotransmitter model. According to the new concept, cellular bioenergetics drives information processing in the central nervous system; therefore, neuropathology is conceptualized as a direct consequence of impaired metabolism. Along the same lines, endoplasmic reticulum stress and gut barrier dysfunction are emerging as novel targets in schizophrenia and affective disorders, linking immune responses to cellular distress. Furthermore, microglia, the brain’s innate immune cells, acquire energy through oxidative phosphorylation, while in the resting state, and glycolysis upon activation, contributing to lactate accumulation and reduced brain pH. The same metabolic signature characterizes neuropsychiatric disorders as the central nervous system derives adenosine triphosphate from aerobic glycolysis, upregulating lactate and generating an acidic environment. Although known for over three decades, the link between dysmetabolism and neuropathology was poorly defined until the discovery of brain-resident innate lymphoid cells, including natural killer cells, and lactylation of histone and nonhistone proteins. In this perspective article, we examine three anti-inflammatory microglial systems relevant for neuropsychiatry: lactate, oxytocin, and the aryl hydrocarbon receptor. We also discuss potential interventions for restoring microglial homeostasis.
“…In our previous work, we have discussed microbial translocation from the GI tract into the host systemic circulation, suggesting that the pathogenesis of several idiopathic diseases could be explained by the immune responses to extraintestinal microbial proteins [193]. As higher gut and BBB permeability markers, including the soluble form of CD14 (sCD14), were documented in neuropsychiatric illness, this pathology may, at least in part, result from microbial migration through the gut barrier [194][195][196].…”
Section: Microbial Translocation Outside the Gi Tractmentioning
A paradigm shift is currently taking place in the etiopathogenesis of neuropsychiatric disorders as immunometabolism is replacing the earlier neurotransmitter model. According to the new concept, cellular bioenergetics drives information processing in the central nervous system; therefore, neuropathology is conceptualized as a direct consequence of impaired metabolism. Along the same lines, endoplasmic reticulum stress and gut barrier dysfunction are emerging as novel targets in schizophrenia and affective disorders, linking immune responses to cellular distress. Furthermore, microglia, the brain’s innate immune cells, acquire energy through oxidative phosphorylation, while in the resting state, and glycolysis upon activation, contributing to lactate accumulation and reduced brain pH. The same metabolic signature characterizes neuropsychiatric disorders as the central nervous system derives adenosine triphosphate from aerobic glycolysis, upregulating lactate and generating an acidic environment. Although known for over three decades, the link between dysmetabolism and neuropathology was poorly defined until the discovery of brain-resident innate lymphoid cells, including natural killer cells, and lactylation of histone and nonhistone proteins. In this perspective article, we examine three anti-inflammatory microglial systems relevant for neuropsychiatry: lactate, oxytocin, and the aryl hydrocarbon receptor. We also discuss potential interventions for restoring microglial homeostasis.
Introduction
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition for which no diagnostic biomarkers have been validated, and most treatments globally are limited to managing the symptoms. The technological advantages for complex computational processing, achieved in population cohorts, for the study of cardiovascular diseases and cancer, can offer a potential new avenue for research in ME/CFS.
Methods
Two such digital research approaches are considered here: (1) the potential implementation of digital twins as a dynamic monitoring system and (2) the potential implementation of synthetic data as a way of augmenting available data sets while having the potential to protect the privacy of individual patients’ data.
Results
Utilizing such computational methodologies has the potential to provide novel angles in the investigation of ME/CSF; however, they remain in the early stages of their development, and doing so would be computationally expensive, and would require the training of professional staff in new technologies, as well as the clinical validation of the predictive modelling.
Conclusion
Thus, carefully targeted implementations of these new technologies are anticipated in the immediate future, at least in the biomarker discovery field.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.