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1. Nod‐like receptors are critical for gut–brain axis signalling in mice

   https://doi.org/10.1113/JP278640  

   Pusceddu, Matteo M. ; Barboza, Mariana ; Keogh, Ciara E. ; Schneider, Melinda ; Stokes, Patricia ; Sladek, Jessica A. ; Kim, Hyun Jung D. ; Torres‐Fuentes, Cristina ; Goldfild, Lily R. ; Gillis, Shane E. ; et al ( November 2019 , The Journal of Physiology)

   Nucleotide binding oligomerization domain (Nod)‐like receptors regulate cognition, anxiety and hypothalamic–pituitary–adrenal axis activation.

   Nod‐like receptors regulate central and peripheral serotonergic biology.

   Nod‐like receptors are important for maintenance of gastrointestinal physiology.

   Intestinal epithelial cell expression of Nod1 receptors regulate behaviour.

   Gut–brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut–brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)‐like receptors (NLR), Nod1 and Nod2, as novel regulators for gut–brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress‐induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic–pituitary–adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell‐specific deletion of Nod1 (VilCre⁺Nod1^f/f), but not Nod2, increased susceptibility to stress‐induced anxiety‐like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut–brain communication and may serve as potential novel therapeutic targets for the treatment of gut–brain disorders.

    

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2. Microfluidic compartmentalization of rat vagal afferent neurons to model gut-brain axis

   https://doi.org/10.1186/s42234-023-00140-3  

   Girardi, Gregory ; Zumpano, Danielle ; Raybould, Helen ; Seker, Erkin ( December 2024 , Bioelectronic Medicine)

   Vagal afferent neurons represent the key neurosensory branch of the gut-brain axis, which describes the bidirectional communication between the gastrointestinal system and the brain. These neurons are important for detecting and relaying sensory information from the periphery to the central nervous system to modulate feeding behavior, metabolism, and inflammation. Confounding variables complicate the process of isolating the role of the vagal afferents in mediating these physiological processes. Therefore, we developed a microfluidic model of the sensory branch of the gut-brain axis. We show that this microfluidic model successfully compartmentalizes the cell body and neurite terminals of the neurons, thereby simulates the anatomical layout of these neurons to more accurately study physiologically-relevant processes.

   We implemented a primary rat vagal afferent neuron culture into a microfluidic platform consisting of two concentric chambers interconnected with radial microchannels. The microfluidic platform separated cell bodies from neurite terminals of vagal afferent neurons. We then introduced physiologically-relevant gastrointestinal effector molecules at the nerve terminals and assessed their retrograde transport along the neurite or capacity to elicit an electrophysiological response using live cell calcium imaging.

   The angle of microchannel outlets dictated the probability of neurites growing into a chamber versus tracking along chamber walls. When the neurite terminals were exposed to fluorescently-labeled cholera toxin subunit B, the proteins were taken up and retrogradely transported along the neurites over the course of 24 h. Additionally, mechanical perturbation (e.g., rinsing) of the neurite terminals significantly increased intracellular calcium concentration in the distal soma. Finally, membrane-displayed receptor for capsaicin was expressed and trafficked along newly projected neurites, as revealed by confocal microscopy.

   In this work, we developed a microfluidic device that can recapitulate the anatomical layout of vagal afferent neurons in vitro. We demonstrated two physiologically-relevant applications of the platforms: retrograde transport and electrophysiological response. We expect this tool to enable controlled studies on the role of vagal afferent neurons in the gut-brain axis.

    

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3. High-fat diet, microbiome-gut-brain axis signaling, and anxiety-like behavior in male rats

   https://doi.org/10.1186/s40659-024-00505-1  

   de Noronha, Sylvana I. S. Rendeiro ; de Moraes, Lauro Angelo Gonçalves ; Hassell, Jr., James E. ; Stamper, Christopher E. ; Arnold, Mathew R. ; Heinze, Jared D. ; Foxx, Christine L. ; Lieb, Margaret M. ; Cler, Kristin E. ; Karns, Bree L. ; et al ( May 2024 , Biological Research)

   Obesity, associated with the intake of a high-fat diet (HFD), and anxiety are common among those living in modern urban societies. Recent studies suggest a role of microbiome-gut-brain axis signaling, including a role for brain serotonergic systems in the relationship between HFD and anxiety. Evidence suggests the gut microbiome and the serotonergic brain system together may play an important role in this response. Here we conducted a nine-week HFD protocol in male rats, followed by an analysis of the gut microbiome diversity and community composition, brainstem serotonergic gene expression (tph2,htr1a, andslc6a4), and anxiety-related defensive behavioral responses. We show that HFD intake decreased alpha diversity and altered the community composition of the gut microbiome in association with obesity, increased brainstemtph2,htr1aandslc6a4mRNA expression, including in the caudal part of the dorsomedial dorsal raphe nucleus (cDRD), a subregion previously associated with stress- and anxiety-related behavioral responses, and, finally, increased anxiety-related defensive behavioral responses. The HFD increased the Firmicutes/Bacteroidetes ratio relative to control diet, as well as higher relative abundances ofBlautia, and decreases inPrevotella. We found thattph2,htr1aandslc6a4mRNA expression were increased in subregions of the dorsal raphe nucleus in the HFD, relative to control diet. Specific bacterial taxa were associated with increased serotonergic gene expression in the cDRD. Thus, we propose that HFD-induced obesity is associated with altered microbiome-gut-serotonergic brain axis signaling, leading to increased anxiety-related defensive behavioral responses in rats.

    

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4. Microbiome-Gut-Brain Axis as a Biomolecular Communication Network for the Internet of Bio-NanoThings

   https://doi.org/10.1109/ACCESS.2019.2942312  

   Akyildiz, Ian F. ; Chen, Jiande ; Ghovanloo, Maysam ; Guler, Ulkuhan ; Ozkaya-Ahmadov, Tevhide ; Pierobon, Massimiliano ; Sarioglu, A. Fatih ; Unluturk, Bige D. ( January 2019 , IEEE Access)
5. Microbiome-Gut-Brain Axis as a Biomolecular Communication Network for the Internet of Bio-NanoThings

   Akyildiz, Ian F. ; Chen, Jiande ; Ghovanloo, Maysam ; Guler, Ulkuhan ; Ozkaya-Ahmedov, Tevhide ; Pierobon, Massimiliano ; Sarioglu, A. Fatih ; Unluturk, Bige ( January 2019 , IEEE access)