Gut microbiota as a modulator of circadian neural development in the honey bee model

Disruption in gut microbiota during the early postnatal period can disrupt normal neural development and result in long-term behavioral alterations ¹ . Similar to other neural systems, the circadian clock mechanism continues to mature after birth ² , yet how microbial disturbances in the early period influence the onset of circadian rhythms and the development of central clock mechanisms remains poorly understood. Here we studied whether early-life gut dysbiosis affects the ontogeny of behavioral circadian rhythms and the maturation of clock neurons using the honey bee ( Apis mellifera ), a model organism that shares features of postnatal development of behavioral circadian rhythm and clock system ^3-5 with humans ⁶ . Our findings demonstrate that antibiotic-treated and gnotobiotic-reared bees display reduced rhythmicity compared to controls. These treatments also impair the development of the circadian pacemaker, marked by fewer Pigment-Dispersing Factor (PDF)-expressing neurons. Additionally, antibiotic exposure increased the expression of the Insulin-like Growth Factor Binding Protein Acid Labile Subunit ( IGFALS ) in early ages, which stabilizes the IGF-1/2 ⁷ , a hormone important for neurodevelopmental processes ⁴² . Together, these results identify gut microbiota as a modulator of circadian development. Our work provides an understanding of how early-life microbial disruptions influence the development of circadian rhythms, providing information that may extend to other animals, including humans.