Antibiotic-induced Dysbiosis of Gut Microbiota Increases Food Motivation and Anticipatory Activity Under a Time-restricted Feeding Protocol

Abstract

Newly emerging evidence underscores the crucial role of the gut microbiota in regulating various aspects of mammalian physiology and behavior, including circadian rhythms. These rhythms, fundamental to behavioral and physiological processes, are orchestrated by a circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Extra-SCN oscillators have been identified in brain regions beyond the SCN and in peripheral tissues temporizing wide physiological functions. Under a 12 h light: 12 h dark cycle (12:12 LD), restriction of food access to hours of light in nocturnal animals in a time-restricted feeding (TRF) protocol increases locomotor activity preceding the scheduled daily meal, so-called food anticipatory activity (FAA). This circadian behavior is independent from the SCN and controlled by a food-entrainable oscillator (FEO) dependent on reward-related signals. It is known that signals from the gut microbiota regulate behaviors such as motivation oriented by food reward. Thus, we hypothesized a physiological link between gut microbiota and FEO activity by studying the circadian FAA behavior under TRF and assessing food-oriented motivational behavior. For that aim, C57BL/6J mice treated with antibiotics for generating gut microbiota dysbiosis were subjected to a 3 h TRF protocol at zeitgeber time (ZT) 4-7. Mice treated with antibiotics exhibited greater FAA, lower time for its consolidation, and greater motivation levels for food reward. Moreover, tyrosine hydroxylase (TH) levels were increased in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of antibiotic-treated mice. Finally, changes in the gut microbiota composition-including bacterial diversity and the abundance of certain genera-were observed. These results suggest that gut microbiota has a regulatory role in the circadian motivational output for food reward controlled by the FEO. Understanding this role is important for potential chronotherapeutics targeting gut microbiota in reward-related alterations such as addictions and eating disorders.

Keywords: circadian system; food anticipatory activity; gut-brain axis; nucleus accumbens; reward-related behaviors.