Einblick - Computational Biology - # Gut-Brain Axis Signaling in Oxidative Stress Response

Endogenous Hydrogen Peroxide Regulates Intestinal Peptide Secretion to Potentiate the Oxidative Stress Response in C. elegans

Q: How might this gut-brain signaling axis be leveraged to modulate the oxidative stress response in other organisms, including humans?

The gut-brain signaling axis identified in C. elegans, involving the interplay between FLP-2 and FLP-1 peptides, along with the regulation of H2O2 levels, presents an intriguing avenue for potential therapeutic interventions in other organisms, including humans. Understanding the mechanisms by which endogenous H2O2 positively regulates the secretion of FLP-2 from the intestine, which in turn potentiates the release of FLP-1 from neurons to activate the antioxidant response, opens up possibilities for targeted interventions in oxidative stress-related conditions. In humans, oxidative stress is implicated in a wide range of diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. By targeting the gut-brain signaling axis, it may be possible to modulate the oxidative stress response in a more precise and effective manner. For example, developing drugs or interventions that enhance the release of specific peptides involved in antioxidant responses could be a novel approach to combat oxidative stress-related conditions. Additionally, understanding how H2O2 signaling influences peptide secretion could lead to the development of therapies that target this pathway to regulate oxidative stress in a variety of contexts.

Q: What other physiological processes or behaviors could be regulated by this H2O2-FLP-2-FLP-1 signaling pathway in C. elegans?

The H2O2-FLP-2-FLP-1 signaling pathway identified in C. elegans is likely to have broader implications beyond the oxidative stress response. Given the role of peptides in modulating various physiological processes and behaviors, it is plausible that this signaling pathway could influence a range of functions in the organism. Some potential processes and behaviors that could be regulated by this pathway include: Metabolism: Peptides released in response to oxidative stress could impact metabolic pathways, energy balance, and nutrient utilization in C. elegans. Immune Response: The gut-brain axis is known to influence immune responses, and the peptides involved in this pathway could play a role in regulating immune function in the organism. Behavioral Responses: Neuropeptides are often involved in regulating behavior, and the FLP-2-FLP-1 signaling axis could modulate behavioral responses to stress, pathogens, or environmental cues. Developmental Processes: Peptides released in response to oxidative stress may also influence developmental processes, growth, and reproduction in C. elegans. By further investigating the impact of this signaling pathway on these and other physiological processes, a more comprehensive understanding of its role in organismal homeostasis and adaptation can be achieved.

Q: Given the importance of mitochondrial function in aging and neurodegeneration, how might disruptions in this gut-brain axis contribute to age-related diseases?

Disruptions in the gut-brain axis, particularly those affecting the H2O2-FLP-2-FLP-1 signaling pathway and its regulation of oxidative stress, could have significant implications for age-related diseases, especially those associated with mitochondrial dysfunction, aging, and neurodegeneration. Here are some ways in which disruptions in this axis could contribute to age-related diseases: Mitochondrial Dysfunction: The dysregulation of H2O2 levels and peptide signaling in the gut-brain axis could lead to mitochondrial dysfunction, a hallmark of aging and age-related diseases. Impaired H2O2 signaling and peptide release may compromise mitochondrial function, leading to increased oxidative damage and reduced energy production. Oxidative Stress: Age-related diseases are often characterized by increased oxidative stress, which can damage cells and contribute to disease progression. Disruptions in the H2O2-FLP-2-FLP-1 pathway could exacerbate oxidative stress, further accelerating the aging process and increasing the risk of age-related diseases. Neurodegeneration: Given the role of peptides in neuronal function and the impact of oxidative stress on neurodegenerative disorders, disruptions in this gut-brain axis could contribute to neurodegeneration. Impaired peptide signaling and antioxidant responses may lead to neuronal damage and cognitive decline. Inflammation: Oxidative stress and mitochondrial dysfunction are closely linked to inflammation, which is a key factor in many age-related diseases. Disruptions in the gut-brain axis could perturb the balance between pro-inflammatory and anti-inflammatory processes, contributing to chronic inflammation and disease progression. Overall, disruptions in the H2O2-FLP-2-FLP-1 signaling pathway could have far-reaching consequences for mitochondrial function, oxidative stress, and age-related diseases, highlighting the importance of understanding and potentially targeting this axis for therapeutic interventions.

Kernkonzepte

Endogenous hydrogen peroxide (H2O2) produced by mitochondrial and cytosolic superoxide dismutases (SODs) positively regulates the secretion of the intestinal peptide FLP-2, which in turn activates the release of the antioxidant neuropeptide FLP-1 from neurons to potentiate the oxidative stress response in C. elegans.

Zusammenfassung

This study investigates the mechanisms by which the gut-brain axis mediates bidirectional signaling to regulate the activation of the antioxidant response in C. elegans. The key findings are:

The intestinal release of the FMRFamide-like peptide FLP-2 is necessary and sufficient to activate the secretion of the antioxidant neuropeptide FLP-1 from AIY interneurons, which in turn promotes the expression of antioxidant genes in the intestine.
FLP-2 secretion from the intestine is positively regulated by endogenous hydrogen peroxide (H2O2) produced by the mitochondrial matrix superoxide dismutase SOD-3 and the cytosolic superoxide dismutase SOD-1.
The peroxiredoxin PRDX-2 and the thioredoxin TRX-3 negatively regulate FLP-2 secretion by depleting H2O2 levels in the mitochondria and cytosol, respectively.
H2O2-induced FLP-2 secretion is mediated by the activation of the calcium and diacylglycerol-dependent protein kinase C family member PKC-2 in the intestine.
Disruption of this H2O2-FLP-2-FLP-1 signaling axis impairs the activation of the antioxidant response, highlighting the importance of gut-brain communication in regulating organism-wide homeostasis under oxidative stress conditions.

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Statistiken

Juglone treatment led to a two-fold increase in coelomocyte fluorescence of FLP-1::Venus fusion proteins expressed in AIY neurons.
Mutations in aex-5, aex-1, aex-3, aex-4, and aex-6 blocked the juglone-induced increase in FLP-1 secretion.
flp-2 mutants exhibited reduced survival under juglone-induced oxidative stress, similar to flp-1 mutants.
Overexpression of flp-2 in the intestine enhanced juglone-induced FLP-1 secretion and antioxidant gene expression in the intestine.
sod-1 and sod-3 mutants blocked juglone-induced increases in FLP-2 secretion and intestinal H2O2 levels.
prdx-2 and trx-3 mutants exhibited elevated FLP-2 secretion and antioxidant gene expression in the absence of stress.
pkc-2 mutants blocked juglone-induced FLP-2 secretion without affecting H2O2 levels.
egl-8/PLCβ mutants blocked juglone-induced FLP-2 secretion without affecting H2O2 levels.

Zitate

"FLP-2 signaling originating in the intestine positively regulates the stress-induced secretion of FLP-1 from AIY, as well as the subsequent activation of anti-oxidant response genes in the intestine."
"Endogenous H2O2 signaling in the intestine promotes inter-tissue antioxidant signaling through regulated neuropeptide-like protein exocytosis in a gut-brain axis to activate the oxidative stress response."
"H2O2 promotes FLP-2 secretion through the DAG and calcium-dependent protein kinase C family member pkc-2 and by the SNAP25 family member aex-4 in the intestine."

Wichtige Erkenntnisse aus

Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response in C. elegans

by Jia,Q., Youn... um www.biorxiv.org 04-05-2024

https://www.biorxiv.org/content/10.1101/2024.04.03.587937v1

Tiefere Fragen

How might this gut-brain signaling axis be leveraged to modulate the oxidative stress response in other organisms, including humans?

The gut-brain signaling axis identified in C. elegans, involving the interplay between FLP-2 and FLP-1 peptides, along with the regulation of H2O2 levels, presents an intriguing avenue for potential therapeutic interventions in other organisms, including humans. Understanding the mechanisms by which endogenous H2O2 positively regulates the secretion of FLP-2 from the intestine, which in turn potentiates the release of FLP-1 from neurons to activate the antioxidant response, opens up possibilities for targeted interventions in oxidative stress-related conditions.
In humans, oxidative stress is implicated in a wide range of diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. By targeting the gut-brain signaling axis, it may be possible to modulate the oxidative stress response in a more precise and effective manner. For example, developing drugs or interventions that enhance the release of specific peptides involved in antioxidant responses could be a novel approach to combat oxidative stress-related conditions. Additionally, understanding how H2O2 signaling influences peptide secretion could lead to the development of therapies that target this pathway to regulate oxidative stress in a variety of contexts.

What other physiological processes or behaviors could be regulated by this H2O2-FLP-2-FLP-1 signaling pathway in C. elegans?

The H2O2-FLP-2-FLP-1 signaling pathway identified in C. elegans is likely to have broader implications beyond the oxidative stress response. Given the role of peptides in modulating various physiological processes and behaviors, it is plausible that this signaling pathway could influence a range of functions in the organism. Some potential processes and behaviors that could be regulated by this pathway include:

Metabolism: Peptides released in response to oxidative stress could impact metabolic pathways, energy balance, and nutrient utilization in C. elegans.

Immune Response: The gut-brain axis is known to influence immune responses, and the peptides involved in this pathway could play a role in regulating immune function in the organism.

Behavioral Responses: Neuropeptides are often involved in regulating behavior, and the FLP-2-FLP-1 signaling axis could modulate behavioral responses to stress, pathogens, or environmental cues.

Developmental Processes: Peptides released in response to oxidative stress may also influence developmental processes, growth, and reproduction in C. elegans.

By further investigating the impact of this signaling pathway on these and other physiological processes, a more comprehensive understanding of its role in organismal homeostasis and adaptation can be achieved.

Given the importance of mitochondrial function in aging and neurodegeneration, how might disruptions in this gut-brain axis contribute to age-related diseases?

Disruptions in the gut-brain axis, particularly those affecting the H2O2-FLP-2-FLP-1 signaling pathway and its regulation of oxidative stress, could have significant implications for age-related diseases, especially those associated with mitochondrial dysfunction, aging, and neurodegeneration. Here are some ways in which disruptions in this axis could contribute to age-related diseases:

Mitochondrial Dysfunction: The dysregulation of H2O2 levels and peptide signaling in the gut-brain axis could lead to mitochondrial dysfunction, a hallmark of aging and age-related diseases. Impaired H2O2 signaling and peptide release may compromise mitochondrial function, leading to increased oxidative damage and reduced energy production.

Oxidative Stress: Age-related diseases are often characterized by increased oxidative stress, which can damage cells and contribute to disease progression. Disruptions in the H2O2-FLP-2-FLP-1 pathway could exacerbate oxidative stress, further accelerating the aging process and increasing the risk of age-related diseases.

Neurodegeneration: Given the role of peptides in neuronal function and the impact of oxidative stress on neurodegenerative disorders, disruptions in this gut-brain axis could contribute to neurodegeneration. Impaired peptide signaling and antioxidant responses may lead to neuronal damage and cognitive decline.

Inflammation: Oxidative stress and mitochondrial dysfunction are closely linked to inflammation, which is a key factor in many age-related diseases. Disruptions in the gut-brain axis could perturb the balance between pro-inflammatory and anti-inflammatory processes, contributing to chronic inflammation and disease progression.

Overall, disruptions in the H2O2-FLP-2-FLP-1 signaling pathway could have far-reaching consequences for mitochondrial function, oxidative stress, and age-related diseases, highlighting the importance of understanding and potentially targeting this axis for therapeutic interventions.