By Randall Eck
Every human has a unique collection of bacteria living in their gut, like a fingerprint. Collectively, these bacteria are called the gut microbiome. The exact number and types of bacteria that make up your microbiome depend on your genetics, environment, diet, and the people you interact with (Dill-McFarland et al., 2019; Falony et al., 2016; Goodrich et al., 2014; Rothschild et al., 2018; Zhernakova et al., 2016). These bacteria feed on your leftovers, but they are not freeloaders. They are critical to your health and well-being. The microbiome helps to break down the food you cannot, releasing additional nutrients, and also strengthens your immune system against disease. (Consortium, 2012; Koh, De Vadder, Kovatcheva-Datchary, & Bäckhed, 2016; Lubin et al., 2023).
The microbiome helps to break down the food you cannot, releasing additional nutrients, and also strengthens your immune system against disease
Your gut microbiome can communicate with your brain too. Scientists call this interaction the gut-brain axis (Morais, Schreiber, & Mazmanian, 2021). The human brain is connected to the gut by neurons, a specialized cell that sends electrical signals throughout the body. The brain uses these pathways to control gut digestion. Information about the gut and the microbiome is also carried back to the brain. Gut bacteria send signals by releasing chemicals, such as oxytocin, that activate neurons (Morais et al., 2021). In mice, these signals influence anxiety, hunger, and social behaviors (Sgritta et al., 2019; Zheng et al., 2016). Many questions remain about the microbiome’s impact on human behavior, and scientists are getting increasingly creative to answer them.
One of these new strategies is to study honeybees. Beyond producing honey and pollinating plants, honeybees make an ideal model to study the impact of each gut bacterial species on behavior, a nearly impossible task in humans or mice, because of their simple microbiome. While the human microbiome is composed of hundreds of species of bacteria, only five bacteria make up 92% of the honeybee’s microbiome (Bobay, Wissel, & Raymann, 2020; Gill et al., 2006). Like humans, though, each individual honeybee has a unique microbiome – influenced by social ties and diet – that helps break down food and fight off infection (Raymann & Moran, 2018; Vernier et al., 2020).
… honeybees make an ideal model to study the impact of each gut bacterial species on behavior, a nearly impossible task in humans or mice, because of their simple microbiome
Throughout their lives, honeybees learn to associate the smells and colors of flowers with their sweet, sugary nectar. Honeybees form a memory of these associations so they can seek out the same types of nectar. To study this behavior in a controlled environment, researchers in the lab of Dr. Wei Zhao in Jiangsu, China, repeatedly released individual honeybees into a room with ten colored platforms. Five of these colored platforms contained a sugary reward, while the other five contained an extremely bitter drink. Over time, a cohort of 29 honeybees learned to associate the color of the platform with its contents and visited the platforms that contained sugar more often (Li et al., 2021). Among the 29 honeybees studied, some learned and remembered these associations faster and more accurately. By dissecting the guts of each honeybee and sequencing the DNA from the bacteria in their gut, Dr. Zhao and his team reconstructed the number and species of bacteria in each honeybee’s microbiome. They found that the abundance of one bacterial species, Lactobacillus apis, was greater in honeybees with better memory. Supplementing the honeybee diet with Lactobacillus apis increased its abundance in the microbiome and also directly improved memory in honeybees (Li et al., 2021).
With this study, Dr. Zhao’s team showed that manipulating the gut microbiome influences honeybee behavior. But, where does this link between gut and brain come from? The molecular pathway linking Lactobacillus apis to the brain was uncovered by a second group of researchers working in the lab of Dr. Hao Zheng in Beijing, China. Instead of simply increasing the amount of Lactobacillus apis, Dr. Zheng and his team made sure Lactobacillus apis was the only bacterial species in the microbiome. In the sterile environment of a lab, scientists raised honeybees that lacked a microbiome, entirely free of gut bacteria. By feeding these honeybees a single kind of bacterium, like Lactobacillus apis, they could study the bacterial species’ individual effect on learning and memory (Zhang et al., 2022). Here, honeybees were trained to associate an odor, rather than a color, with a sugar reward. After ten training sessions, honeybees with a complete microbiome correctly anticipated a sugary reward and stuck out their tongues about 30% of the time in response to the odor. However, honeybees without a microbiome never successfully learned or remembered the odor. Honeybees with only a microbiome of Lactobacillus apis successfully learned, too, but their ability to learn was dependent on two factors: tryptophan and the aryl hydrocarbon receptor. Honeybees with Lactobacillus apis learned better when their diet included tryptophan, a core amino acid or building block of proteins. Lactobacillus apis breaks down tryptophan into other products that act as messengers in the honeybee body, binding to receptors that carry signals all the way to the brain. In this case, one of these receptors was absolutely necessary for honeybee learning: the aryl hydrocarbon receptor (AhR). When researchers blocked the honeybee’s AhR with a drug, the honeybees with Lactobacillus apis and tryptophan failed to learn to associate the odor with a sugar reward (Zhang et al., 2022). Altogether, these results trace a pathway from the gut to the brain: Lactobacillus apis breaks down tryptophan into products that bind AhR, initiating a cascade of signals that change the activity of cells in the brain, enabling the development and maintenance of learning and memory.
… these experiments show that learning and memory in honeybees – and, likely, in humans – require a community of gut bacteria working together in a complex, interconnected network
This story, as is much of science, is still incomplete. Where can honeybees acquire tryptophan? What changes happen in the honeybee brain when AhR are activated? Do other bacteria in the microbiome also contribute to learning and memory? A forthcoming study from the lab of Dr. Philipp Engel in Lausanne, Switzerland, helps to answer some of these questions. His team of researchers created an artificial honeybee gut microbiome, called BeeCom, by feeding five core bacteria to bees without a microbiome. Honeybees with BeeCom learned to associate an odor with a sugar reward faster than those without a microbiome or a microbiome containing a single bacterial species (Cabirol et al., 2023). While Lactobacillus apis is important, these experiments show that learning and memory in honeybees – and, likely, in humans – require a community of gut bacteria working together in a complex, interconnected network.
Taken together, these honeybee studies suggest that the human microbiome may play an important role in your ability to learn and remember throughout life. Untangling these relationships in the human brain will prove much more difficult. So far, scientists have linked the human microbiome to Alzheimer’s disease, a devastating neurodegenerative disease that results in dementia. Scientists in Japan and the United States have found that Alzheimer’s patients have significant differences in their gut microbiome compared to healthy older adults (Chandra, Sisodia, & Vassar, 2023; Saji et al., 2020; Vogt et al., 2017). While the impact of these changes is still unknown, scientists do know that, in mice, gut bacteria can both worsen or improve models of Alzheimer’s disease. For example, some bacteria in the microbiome of mice release short-chain fatty acids, a byproduct of breaking down fibrous food. These fatty acids increase the formation of toxic amyloid plaques in the brains of an Alzheimer’s mouse model (Colombo et al., 2021). On the other hand, the gut microbiome can protect the mouse brain from swelling and inflammation by controlling the expression of key signaling molecules in the immune system (Sanmarco et al., 2021; Seo et al., 2023).
Future research in humans and model organisms, like honeybees, will provide new insights into how your microbiome affects your brain and behavior as you grow and age. Maybe one day, scientists will engineer microbiomes to reduce your risk of disease or boost your learning and memory. In honeybees, scientists have already constructed a custom microbiome that improves honeybee survival after an infection (Leonard et al., 2020).
Written by Randall Eck
Illustrated by Vidya Saravanapandian
Edited by Zoe Dobler, James Cole, and Liza Chartampila
Bobay, L. M., Wissel, E. F., & Raymann, K. (2020). Strain Structure and Dynamics Revealed by Targeted Deep Sequencing of the Honey Bee Gut Microbiome. mSphere, 5(4). doi:10.1128/mSphere.00694-20
Cabirol , A., Schafer , J., Neuschwander , N., Kesner , L., Liberti , J., & Engel, P. (2023). A defined community of core gut microbiota members promotes cognitive performance in honey bees. BioRxiv. doi:10.1101/2023.01.03.522593
Chandra, S., Sisodia, S. S., & Vassar, R. J. (2023). The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored. Mol Neurodegener, 18(1), 9. doi:10.1186/s13024-023-00595-7
Colombo, A. V., Sadler, R. K., Llovera, G., Singh, V., Roth, S., Heindl, S., . . . Liesz, A. (2021). Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition. Elife, 10. doi:10.7554/eLife.59826
Consortium, H. M. P. (2012). Structure, function and diversity of the healthy human microbiome. Nature, 486(7402), 207-214. doi:10.1038/nature11234
Dill-McFarland, K. A., Tang, Z. Z., Kemis, J. H., Kerby, R. L., Chen, G., Palloni, A., . . . Herd, P. (2019). Close social relationships correlate with human gut microbiota composition. Sci Rep, 9(1), 703. doi:10.1038/s41598-018-37298-9
Falony, G., Joossens, M., Vieira-Silva, S., Wang, J., Darzi, Y., Faust, K., . . . Raes, J. (2016). Population-level analysis of gut microbiome variation. Science, 352(6285), 560-564. doi:10.1126/science.aad3503
Gill, S. R., Pop, M., Deboy, R. T., Eckburg, P. B., Turnbaugh, P. J., Samuel, B. S., . . . Nelson, K. E. (2006). Metagenomic analysis of the human distal gut microbiome. Science, 312(5778), 1355-1359. doi:10.1126/science.1124234
Goodrich, J. K., Waters, J. L., Poole, A. C., Sutter, J. L., Koren, O., Blekhman, R., . . . Ley, R. E. (2014). Human genetics shape the gut microbiome. Cell, 159(4), 789-799. doi:10.1016/j.cell.2014.09.053
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016). From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell, 165(6), 1332-1345. doi:10.1016/j.cell.2016.05.041
Leonard, S. P., Powell, J. E., Perutka, J., Geng, P., Heckmann, L. C., Horak, R. D., . . . Moran, N. A. (2020). Engineered symbionts activate honey bee immunity and limit pathogens. Science, 367(6477), 573-576. doi:10.1126/science.aax9039
Li, L., Solvi, C., Zhang, F., Qi, Z., Chittka, L., & Zhao, W. (2021). Gut microbiome drives individual memory variation in bumblebees. Nat Commun, 12(1), 6588. doi:10.1038/s41467-021-26833-4
Lubin, J. B., Green, J., Maddux, S., Denu, L., Duranova, T., Lanza, M., . . . Silverman, M. A. (2023). Arresting microbiome development limits immune system maturation and resistance to infection in mice. Cell Host Microbe, 31(4), 554-570.e557. doi:10.1016/j.chom.2023.03.006
Morais, L. H., Schreiber, H. L., & Mazmanian, S. K. (2021). The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol, 19(4), 241-255. doi:10.1038/s41579-020-00460-0
Raymann, K., & Moran, N. A. (2018). The role of the gut microbiome in health and disease of adult honey bee workers. Curr Opin Insect Sci, 26, 97-104. doi:10.1016/j.cois.2018.02.012
Rothschild, D., Weissbrod, O., Barkan, E., Kurilshikov, A., Korem, T., Zeevi, D., . . . Segal, E. (2018). Environment dominates over host genetics in shaping human gut microbiota. Nature, 555(7695), 210-215. doi:10.1038/nature25973
Saji, N., Murotani, K., Hisada, T., Kunihiro, T., Tsuduki, T., Sugimoto, T., . . . Sakurai, T. (2020). Relationship between dementia and gut microbiome-associated metabolites: a cross-sectional study in Japan. Sci Rep, 10(1), 8088. doi:10.1038/s41598-020-65196-6
Sanmarco, L. M., Wheeler, M. A., Gutiérrez-Vázquez, C., Polonio, C. M., Linnerbauer, M., Pinho-Ribeiro, F. A., . . . Quintana, F. J. (2021). Gut-licensed IFNγ. Nature, 590(7846), 473-479. doi:10.1038/s41586-020-03116-4
Seo, D. O., O’Donnell, D., Jain, N., Ulrich, J. D., Herz, J., Li, Y., . . . Holtzman, D. M. (2023). ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science, 379(6628), eadd1236. doi:10.1126/science.add1236
Sgritta, M., Dooling, S. W., Buffington, S. A., Momin, E. N., Francis, M. B., Britton, R. A., & Costa-Mattioli, M. (2019). Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron, 101(2), 246-259.e246. doi:10.1016/j.neuron.2018.11.018
Vernier, C. L., Chin, I. M., Adu-Oppong, B., Krupp, J. J., Levine, J., Dantas, G., & Ben-Shahar, Y. (2020). The gut microbiome defines social group membership in honey bee colonies. Sci Adv, 6(42). doi:10.1126/sciadv.abd3431
Vogt, N. M., Kerby, R. L., Dill-McFarland, K. A., Harding, S. J., Merluzzi, A. P., Johnson, S. C., . . . Rey, F. E. (2017). Gut microbiome alterations in Alzheimer’s disease. Sci Rep, 7(1), 13537. doi:10.1038/s41598-017-13601-y
Zhang, Z., Mu, X., Cao, Q., Shi, Y., Hu, X., & Zheng, H. (2022). Honeybee gut Lactobacillus modulates host learning and memory behaviors via regulating tryptophan metabolism. Nat Commun, 13(1), 2037. doi:10.1038/s41467-022-29760-0
Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., . . . Xie, P. (2016). Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry, 21(6), 786-796. doi:10.1038/mp.2016.44
Zhernakova, A., Kurilshikov, A., Bonder, M. J., Tigchelaar, E. F., Schirmer, M., Vatanen, T., . . . study, L. c. (2016). Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science, 352(6285), 565-569. doi:10.1126/science.aad3369