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 gutmicrobiota in regulating various aspects of mammalian physiology and behavior,including circadian rhythms. These rhythms, fundamental to behavioral andphysiological processes, are orchestrated by a circadian pacemaker located in thesuprachiasmatic nucleus (SCN) of the hypothalamus. Extra-SCN oscillators havebeen identified in brain regions beyond the SCN and in peripheral tissues temporizingwide physiological functions. Under a 12 h light: 12 h dark cycle (12:12LD), restriction of food access to hours of light in nocturnal animals in a timerestrictedfeeding (TRF) protocol increases locomotor activity preceding thescheduled daily meal, so-called food anticipatory activity (FAA). This circadianbehavior is independent from the SCN and controlled by a food-entrainableoscillator (FEO) dependent on reward-related signals. It is known that signalsfrom the gut microbiota regulate behaviors such as motivation oriented by foodreward. Thus, we hypothesized a physiological link between gut microbiota andFEO activity by studying the circadian FAA behavior under TRF and assessingfood-oriented motivational behavior. For that aim, C57BL/6J mice treated withantibiotics for generating gut microbiota dysbiosis were subjected to a 3 h TRFprotocol at zeitgeber time (ZT) 4-7. Mice treated with antibiotics exhibited greaterFAA, lower time for its consolidation, and greater motivation levels for foodreward. Moreover, tyrosine hydroxylase (TH) levels were increased in thenucleus accumbens (NAc) and ventral tegmental area (VTA) of antibiotic-treatedmice. Finally, changes in the gut microbiota composition—including bacterialdiversity and the abundance of certain genera—were observed. These resultssuggest that gut microbiota has a regulatory role in the circadian motivationaloutput for food reward controlled by the FEO. Understanding this role is importantfor potential chronotherapeutics targeting gut microbiota in reward-relatedalterations such as addictions and eating disorders.