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Modeling and Analysis of SCFA-Driven Vagus Nerve Signaling in the Gut-Brain Axis via Molecular Communication

Beyza E. Ortlek, Ozgur B. Akan

TL;DR

This work addresses how gut microbiota metabolites communicate with the brain via the vagus nerve by treating SCFA signaling as an end-to-end molecular communication channel. It develops a coupled model that links SCFA-GPCR binding, GPCR-driven calcium signaling, Hodgkin–Huxley neuron dynamics, and probabilistic neurotransmitter release to map gut conditions to brain signals, with $k_1$ governing GPCR activation. Information-theoretic metrics, including mutual information $I(X;Y)$ and delay, are used to quantify fidelity and timing, and Monte Carlo simulations show that higher GPCR activation rates improve $I(X;Y)$ from $0.0085$ to $0.0110$ bits/bin and reduce mean delay from about $9.40$ s to $7.99$ s. The framework provides a quantitative basis for understanding and potentially tuning gut-brain signaling for neurological and psychiatric applications.

Abstract

Molecular communication (MC) is a bio-inspired communication paradigm that utilizes molecules to transfer information and offers a robust framework for understanding biological signaling systems. This paper introduces a novel end-to-end MC framework for short-chain fatty acid (SCFA)-driven vagus nerve signaling within the gut-brain axis (GBA) to enhance our understanding of gut-brain communication mechanisms. SCFA molecules, produced by gut microbiota, serve as important biomarkers in physiological and psychological processes, including neurodegenerative and mental health disorders. The developed end-to-end model integrates SCFA binding to vagal afferent fibers, G protein-coupled receptor (GPCR)-mediated calcium signaling, and Hodgkin-Huxley-based action potential generation into a comprehensive vagus nerve signaling mechanism through GBA. Information-theoretic metrics such as mutual information and delay are used to evaluate the efficiency of this SCFA-driven signaling pathway model. Simulations demonstrate how molecular inputs translate into neural outputs, highlighting critical aspects that govern gut-brain communication. In this work, the integration of SCFA-driven signaling into the MC framework provides a novel perspective on gut-brain communication and paves the way for the development of innovative therapeutic advancements targeting neurological and psychiatric disorders.

Modeling and Analysis of SCFA-Driven Vagus Nerve Signaling in the Gut-Brain Axis via Molecular Communication

TL;DR

This work addresses how gut microbiota metabolites communicate with the brain via the vagus nerve by treating SCFA signaling as an end-to-end molecular communication channel. It develops a coupled model that links SCFA-GPCR binding, GPCR-driven calcium signaling, Hodgkin–Huxley neuron dynamics, and probabilistic neurotransmitter release to map gut conditions to brain signals, with governing GPCR activation. Information-theoretic metrics, including mutual information and delay, are used to quantify fidelity and timing, and Monte Carlo simulations show that higher GPCR activation rates improve from to bits/bin and reduce mean delay from about s to s. The framework provides a quantitative basis for understanding and potentially tuning gut-brain signaling for neurological and psychiatric applications.

Abstract

Molecular communication (MC) is a bio-inspired communication paradigm that utilizes molecules to transfer information and offers a robust framework for understanding biological signaling systems. This paper introduces a novel end-to-end MC framework for short-chain fatty acid (SCFA)-driven vagus nerve signaling within the gut-brain axis (GBA) to enhance our understanding of gut-brain communication mechanisms. SCFA molecules, produced by gut microbiota, serve as important biomarkers in physiological and psychological processes, including neurodegenerative and mental health disorders. The developed end-to-end model integrates SCFA binding to vagal afferent fibers, G protein-coupled receptor (GPCR)-mediated calcium signaling, and Hodgkin-Huxley-based action potential generation into a comprehensive vagus nerve signaling mechanism through GBA. Information-theoretic metrics such as mutual information and delay are used to evaluate the efficiency of this SCFA-driven signaling pathway model. Simulations demonstrate how molecular inputs translate into neural outputs, highlighting critical aspects that govern gut-brain communication. In this work, the integration of SCFA-driven signaling into the MC framework provides a novel perspective on gut-brain communication and paves the way for the development of innovative therapeutic advancements targeting neurological and psychiatric disorders.
Paper Structure (9 sections, 16 equations, 8 figures, 2 tables)

This paper contains 9 sections, 16 equations, 8 figures, 2 tables.

Table of Contents

  1. Introduction
  2. System Model
  3. SCFA-GPCR Binding and Intracellular Signaling
  4. Neuro-spike Communication
  5. Theoretical Analysis and Simulations
  6. Mutual Information
  7. Delay Analysis
  8. Discussion
  9. Conclusion

Figures (8)

  • Figure 1: Biological Representation of MC System (Created in https://BioRender.com).
  • Figure 2: Illustration of ligand-receptor binding.(Created in https://BioRender.com).
  • Figure 3: Scheme of the MC channel model for SCFA-driven vagus nerve signaling withing GBA.
  • Figure 4: SCFA-driven cytosolic calcium oscillation and membrane potential for changing $k_1$ values.(a) Cytosolic calcium oscillations for $k_1=1.50 \mu M/s$, (b) Membrane potential $(V_m)$ for $k_1=1.50 \mu M/s$, (c) Cytosolic calcium oscillations for $k_1=3.82 \mu M/s$, (b) Membrane potential $(V_m)$ for $k_1=3.82 \mu M/s$,
  • Figure 5: Action potential generation and neurotransmitter release w.r.t changing activation rate.
  • ...and 3 more figures