NCS-FO: Developing engineering solutions to investigate microbiome-to-neuron communication

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The goal of this project is to create an engineering solution to measure and predict the molecular communication across the gut-microbiome-brain axis. This platform has the potential to facilitate the fundamental understanding of gut microbiome communication with the nervous system. The project will quantify release patterns of key molecules involved in this cross-talk and identify their influence on neural activation and behavior. The gut-microbiome-brain axis, comprising a vast network of nerves innervating the gut and propagating signals to the brain, is a major influencer of behavior and cognition. The neurotransmitter serotonin is a key molecule in this pathway; gut epithelial cells sense luminal conditions and release serotonin to stimulate nearby neurons. The gut microbiome has been shown to mediate this serotonin release, a process that is also linked to the co-occurrence of gastric and neural disorders. The technical underpinnings of this work involve designing and constructing a device that enables researchers to assemble the essential components of the gut-microbiome-neuron tissue interface. The device is fabricated with sensors to obtain information that is currently inaccessible - collecting molecular information at the length and time scales of the cells and tissues under investigation. The data extracted from this platform will enable temporal correlation and prediction of microbial, gut, and neural signaling patterns. This work provides opportunities to bring together researchers and stakeholders from various disciplines including electrical and computer engineering, bioengineering, molecular biology, neuroscience, and data science to develop a system-oriented approach. Further, this project promotes the participation of women, historically underrepresented in engineering, and undergraduates through programs such as Women in Engineering Research Fellowship and First-Year Innovation and Research Experience (FIRE). Multidisciplinary engineering methods are essential to building an in vitro discovery platform capable of directly monitoring chemical transduction patterns along the gut-neuron axis. In TASK 1, electrochemical sensors will be directly fabricated on a porous cell culture substrate, allowing direct access to cellular and molecular mechanisms of an in vitro model gut epithelium. Impedance monitoring of the cell layer will detect physical changes over time (e.g., barrier integrity). Potentiometric monitoring will detect real-time serotonin released from gut cells due to bacterial metabolite stimulation. In TASK 2, the neural effect of gut serotonin signaling will be studied by exposing this cell-released serotonin to an isolated ex vivo crayfish nerve cord with connected and innervated hindgut. Neurobehavioral activation patterns will be recorded during hindgut peristalsis in motor and sensory neurons that bidirectionally connect the central and enteric nervous systems. Machine learning approaches will identify key variables to quantify discrete serotonin release and neuronal activation patterns. In TASK 3, the mucosal layer of the gut epithelium will be colonized with specific gut microbes to assess bacterial influence on barrier integrity, serotonin release patterns, and resulting neuromuscular activation. Classification via machine learning will quantify the wholistic and synergistic effects of different microbial combinations on time-dependent serotonin release profiles and downstream effects. There are multiple novel aspects of this work. First, this is a new platform implementing extensive integrated cell-interfacial sensors for direct access to real-time cell and molecular data. Second, the use of this technology to investigate the interplay between gut and nervous system can give unprecedented insight into the vast and relatively inaccessible gut-brain transduction pathways. Third, machine learning analysis can identify meaningful patterns of serotonergic communication and predict the expected impact of gut bacteria on neural behavior.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.