Research

The gut-brain axis modulates several important aspects of physiology and behavior, and defects in this biological system are linked to a number of diseases of high unmet need. At Kallyope we are taking a systems biology approach, using a highly integrated platform of cutting-edge technologies, to create a comprehensive map of gut-brain circuits. We are identifying circuits involved in physiology and disease and targeting these circuits with gut-restricted molecules. Modulating the brain via the gut is a fundamentally new approach for multiple important diseases for which direct CNS targeting has had limited success.

The Gut-Brain Axis

The gut-brain axis is the bi-directional communication that takes place between the gastrointestinal tract and the brain. This occurs via hormonal and neural circuits. Key components of the gut-brain axis include highly specialized, secretory intestinal cells that release hormones (enteroendocrine cells or EECs), the autonomic nervous system (vagus nerve, enteric nervous system), and the central nervous system. These systems work together in a highly coordinated fashion to modulate physiology and behavior. The microbiome-gut-brain axis includes the role of the gut microbiome in the signaling that takes place between the gut and the brain.

The Gut-Brain Axis and Disease

At Kallyope, we are focused on discovering transformational therapeutics in diseases of high unmet need. The gut-brain axis has clearly established roles in metabolism and gastrointestinal function, and is increasingly implicated in central nervous system (CNS) functions including mood, cognition, and reward. Defects in the gut-brain axis have been linked to diseases including obesity, diabetes, NASH, functional gastrointestinal disorders, inflammatory disorders, depression, autism, and Parkinson's disease. Our initial focus is on metabolic and CNS disorders, although our drug discovery platform has relevance for virtually all disease areas linked to the gut and gut-brain axis.

Our Platform

We are integrating cutting-edge technologies to build a comprehensive map of gut-brain circuits and interrogating the functions of these circuits to identify therapeutic targets that can be modulated with gut-restricted molecules. Components of our state-of-the-art platform include single-cell sequencing, computational biology, circuit mapping technologies. We are also using optogenetics and chemogenetics to elucidate the link between circuits and physiology/disease. Implementation of this platform has led to new insights into gut and gut-brain biology that enable a rationale, well-informed approach to targeting gut-brain circuits.

Water-in-oil droplets are loaded with cells and barcoded beads in order to capture the RNA from thousands of individual cells in parallel

SINGLE-CELL SEQUENCING

Heterogeneity is a ubiquitous feature of biological systems. The gut-brain axis - a network of cells from the gastrointestinal epithelium, enteric nervous system, vagus nerve, and brainstem - consists of many different cell types, each with unique functions. To identify and characterize each of these cell types we rely on single-cell RNA sequencing. Recent advances in technology have made it possible to routinely profile thousands of individual cells and to identify the RNA transcripts present in each single cell. Coupled with computational biology, this allows us to identify the many different cell types of the gut-brain axis and gain insight into their functions.

Single-cell atlas of murine enteroendocrine cells (EECs)

COMPUTATIONAL BIOLOGY

At Kallyope we are using computational biology to rationalize target discovery by applying a convergence of new methods from machine learning, next-generation sequencing, network biology, proteomics, knowledge representation, and artificial intelligence. Working closely with our internal sequencing team, the computational group has constructed a comprehensive understanding of the distinct cell types, and their transcriptional profiles, that comprise the gut-brain axis. To accomplish this, we have used proprietary software that extends the state of the art in the genomic alignment of sequencing reads and the high-dimensional, unsupervised clustering of single cells. To date we have identified several novel cell types and molecular targets with the potential to potently modulate systemic physiology, behavior, and disease.

Virally-labeled nodose ganglia and associated vagal nerve

CIRCUIT MAPPING

Technical advances in the neurosciences over the past decade have dramatically increased our ability to address previously unapproachable questions such as how do individual cell types respond to inputs and how are those cells integrated into circuits? Genetically-encoded activity sensors enable the interrogation of specific cellular responses throughout the body, and trans-synaptic tracers can determine which neurons are interconnected. Kallyope applies these advances to link the activation of components of the gut-brain axis to neural circuits implicated in processes ranging from metabolic regulation to behavioral control.

We activate gut cells using chemogenetics (left) and optogenetics (right) to modulate physiology and behavior

MAPPING CIRCUITS TO FUNCTION

To understand how gut-brain circuits alter behavior and physiology, we are stimulating unique cell types within a gut-brain circuit and observing the physiological responses. We first gain control of a cell type of interest by genetically expressing proteins that can be selectively activated either with light (optogenetics) or with a targeted small molecule (chemogenetics). We can then use these tools to systematically engage each gut-brain circuit, determine its function, and identify promising pathways for treating disease.