A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis

Boles, Jake Sondag; Krueger, Maeve E.; Jernigan, Janna E.; Cole, Cassandra L.; Neighbarger, Noelle K.; Uriarte Huarte, Oihane; Tansey, Malú Gámez

doi:10.1016/j.bbi.2024.02.007

Cited by 5 publications

(3 citation statements)

References 131 publications

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“…Mitochondrial dysfunction is also one of the contributing factors for increased oxidative stress, which can occur as a result of diminished mitophagy and an altered electron transport chain complex. , Environmental and occupational toxins that are known to induce PD, such as paraquat, rotenone, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), predominantly act on the mitochondria and inhibit complex I of the electron transport chain and are frequently thought of as oxidative stressors. , Evidence gathered from animal and human post-mortem suggests that reactive oxygen and nitrogen species (ROS/RNS) are significant contributors in sporadic PD . Furthermore, coming to PNS, the gut epithelium itself induces the generation of ROS via formyl peptide receptors when it comes in contact with disturbed commensal microbiota or harmful bacteria finally causing the leaky gut state. , Additionally, Fasano reported that disrupted gut microbiota can disturb zonulin, which regulates antigen trafficking. As a result, luminal materials cross the epithelium and endothelium barrier, allowing a large inflow of food and microbial antigens that activate T cells.…”

Section: Pathophysiological Aspects: a Concise Overviewmentioning

confidence: 99%

“…36 Furthermore, coming to PNS, the gut epithelium itself induces the generation of ROS via formyl peptide receptors when it comes in contact with disturbed commensal microbiota or harmful bacteria finally causing the leaky gut state. 37,38 Additionally, Fasano reported that disrupted gut microbiota can disturb zonulin, which regulates antigen trafficking. As a result, luminal materials cross the epithelium and endothelium barrier, allowing a large inflow of food and microbial antigens that activate T cells.…”

Section: Pathophysiological Aspects: a Concise Overviewmentioning

confidence: 99%

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Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration–Gut Connection in Parkinson’s Disease

Bhardwaj,

Singh,

Kumar

2024

ACS Chem. Neurosci.

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Parkinson's disease, a classical motor disorder affecting the dopaminergic system of the brain, has been as a disease of the brain, but this classical notion has now been viewed differently as the pathology begins in the gut and then gradually moves up to the brain regions. The microorganisms in the gut play a critical role in maintaining the physiology of the gut from maintaining barrier integrity to secretion of microbial products that maintain a healthy gut state. The pathology subsequently alters the normal composition of gut microbes and causes deleterious effects that ultimately trigger strong neuroinflammation and nonmotor symptoms along with characteristic synucleopathy, a pathological hallmark of the disease. Understanding the complex pathomechanisms in distinct and established preclinical models is the primary goal of researchers to decipher how exactly gut pathology has a central effect; the quest has led to many answered and some openended questions for researchers. We summarize the popular opinions and some contrasting views, concise footsteps in the treatment strategies targeting the gastrointestinal system.

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Section: Pathophysiological Aspects: a Concise Overviewmentioning

confidence: 99%

Section: Pathophysiological Aspects: a Concise Overviewmentioning

confidence: 99%

Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration–Gut Connection in Parkinson’s Disease

Bhardwaj,

Singh,

Kumar

2024

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…This complex network involves the neural, endocrine, and immune systems [13][14][15][16][17]. The intricate information exchanged between the CNS and the gut microbiome is mediated by microbiome-derived products, including serotonin, dopamine, norepinephrine, shortchain fatty acids (SCFAs), glutamate, γ-aminobutyric acid (GABA), secondary bile acids, tryptophan metabolites, and histamine.…”

Section: Introductionmentioning

confidence: 99%

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

De Cól,

de Lima,

Pompeu

et al. 2024

IJMS

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Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain–gut–liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain–gut–liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines.

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RGS10 Attenuates Systemic Immune Dysregulation Induced by Chronic Inflammatory Stress

Jernigan,

Staley,

Baty

et al. 2024

Preprint

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Regulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinson's Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebral spinal fluid (CSF) compared to age-matched healthy controls. However, it is unknown whether CSF-resident peripheral immune cells in individuals with PD also exhibit decreased levels of RGS10. Therefore, we performed an analysis of RGS10 levels in the proteomic database of the CSF from the Michael J. Fox Foundation Parkinson's Progression Markers Initiative (PPMI) study. We found that RGS10 levels are decreased in the CSF of individuals with PD compared to healthy controls and prodromal individuals. Moreover, we find that RGS10 levels decrease with age but not PD progression and that males have less RGS10 than females in PD. Importantly, studies have established an association between chronic systemic inflammation (CSI) and neurodegenerative diseases, such as PD, and known sources of CSI have been identified as risk factors for developing PD; however, the role of peripheral immune cell dysregulation in this process has been underexplored. As RGS10 levels are decreased in the CSF and circulating peripheral immune cells of individuals with PD, we hypothesized that RGS10 regulates peripheral immune cell responses to CSI prior to the onset of neurodegeneration. To test this, we induced CSI for 6 weeks in C57BL6/J mice and RGS10 KO mice to assess circulating and CNS-associated peripheral immune cell responses. We found that RGS10 deficiency synergizes with CSI to induce a bias for inflammatory and cytotoxic cell populations, a reduction in antigen presentation in peripheral blood immune cells, as well as in and around the brain that is most notable in males. These results highlight RGS10 as an important regulator of the systemic immune response to CSI and implicate RGS10 as a potential contributor to the development of immune dysregulation in PD.

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A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis

Cited by 5 publications

References 131 publications

Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration–Gut Connection in Parkinson’s Disease

Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration–Gut Connection in Parkinson’s Disease

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

RGS10 Attenuates Systemic Immune Dysregulation Induced by Chronic Inflammatory Stress

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