Understanding how environmental microbiomes shape animal sensation

Animals have had to contend with a microbe covered world since their evolutionary emergence ~800 million years ago. We now appreciate that microbes play vital roles in directing host development, digestion, decision making, and disease, making microbes relevant to studies in interoception and exteroception. Yet, the identity of the specific chemical effectors and molecular receptors that confer these interkingdom interactions are often unknown, resulting in uncertainty as to exactly how microbes sculpt animal biology. Deciphering the general rules underlying how animals and microbes sense one another will inform how microbes define the animal experience, drive evolution, and influence health and disease. This proposal spans molecular and organismal tiers of biology to ask how animals respond to their microbial world. Since bacteria accumulate on surfaces in an environment-dependent manner and secrete metabolites in a growth-dependent fashion, I test the hypothesis that bacteria create perceptible surface- and state-dependent chemical cues that drive animal behavior. Here, I will exploit octopus chemotactile sensation as a uniquely suited system to establish a paradigm for how animals sense and interact with environmental microbes. The octopus uses specialized chemotactile receptors (CRs) on its arms to explore surface-affixed molecules along the seafloor. How does the octopus discriminate behaviorally meaningful surfaces from the rocks and crevices it explores? Recently, I found that octopuses use CRs to detect distinct secreted molecules from prey-specific microbes that drive behavior. In this proposal, I will profile the microbial chemical ecology of seafloor surfaces, octopus eggs, prey, and other behavioral relevant substrates to define natural chemical cues that activate diverse octopus CRs (Aim 1). This effort will define the function of numerous orphan CRs and reveal general rules regarding chemosensory cues from environmental microbiomes. I will then use structural biology and molecular evolution to characterize how octopus CRs have evolved to sense distinct microbial cues ranging from secreted metabolites to altered environmental pH (Aim 2). Finally, I will take advantage of the unusual octopus nervous system that facilities autonomous arm behavior by combining electrophysiology, neurophysiology and behavioral assays to define how polymodal microbial cues integrate to drive behavior (Aim 3). Critical training provided through the K99/R00 will not only enable me to establish and scale this approach for discovering interkingdom interactors in the well-suited octopus system, but it will also give me the expertise needed to deploy this framework at other animal-microbe interfaces and create an independent, innovative, and successful research program. When applied across the tree of life, this framework will uncover how the intertwined past of animals and microbes defines the sensory experience of animals and drives animal nervous system evolution. Altogether, these studies will illuminate how unidirectional cues transition into the bidirectional messages that orchestrate host-microbe symbioses and have sweeping implications for how we assess and address host-microbe interactions in health and disease. Project Number: 1K99GM164645-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Rebecka Sepela | Institution: HARVARD UNIVERSITY, CAMBRIDGE, MA | Award Amount: $125,000 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 F02B-H (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11351542