Mechanisms underlying microbial modulation of host behavior









1. How do the gut microbiome shape brain gene regulatory networks and behavior?
Growing evidence suggests that the gut microbiome can modulate host behavior and brain function, but the underlying mechanisms remain poorly defined. Using Drosophila, we found that foraging behavior and diet choice vary depending on microbiome status (Wong et al). To understand how the microbiome exerts these effects, we built the first single-cell transcriptomic atlas of the aging Drosophila brain, showing that the microbiome drives cell-type-specific changes in gene expression in an age-dependent manner (Zhou et al). These results raise a central question: how does the microbiome remodel brain gene regulatory networks to control behavior, and which microbial chemical signals mediate this process?

2. How does diet shape microbiome effects on host physiology and behavior?
The interplay between diet and the gut microbiome is fundamental to shaping host physiology and behavior; however, their interactions remain poorly understood. Most studies treat diet as a single-dimensional variable (e.g., high-fat or high-sugar), this oversimplification neglects how diet and microbes function as an integrated system. We recently tested 120 different nutrient-microbiome combinations in Drosophila (Hung et al), systematically varying yeast and carbohydrate levels and microbiome configurations. Our results show that dietary nutrient composition drives body protein and fat storage, whereas the microbiome plays a notable role in glucose metabolism and buffers against excess fat accumulation. Microbial effects on reproduction, locomotion, and sleep depend on diet nutrient composition, and our model reveals specific diet-microbiome patterns driving these outcomes. By treating diet as a dynamic, multidimensional factor, we provide a novel, ecologically relevant framework for understanding how diet and microbiome shape host phenotypes.

3. Sex differences in microbiome-mediated effects on behavior.
Males and females are distinct in their foraging motivation and reproductive investments. In oviparous insects, females make foraging decisions to fulfill both their own nutritional needs (feeding) as well as those of their offspring (oviposition). Females also allocate a large amount of energy and resources to oogenesis, requiring significant nutrient intake from the diet. These male- and female- specific nutritional needs are likely to drive sex-specific patterns of foraging and diet selection behaviors. Given the importance of the microbiome in nutrition and metabolism, we are investigating how sex - microbiome interactions could exert different behavior outcomes, such as foraging and food choices, see our recent publications, e.g., Shu et al.