Do the microbes in your gut affect cognitive and behavioral development?

 Background

Neuronal development is especially critical in adolescent years (Paus, 2005; O’Connor & Cryan, 2014). Consequentially, this time is also when doctors see the onset of mental illness and behavioral abnormalities that include, but are not limited to, anxiety and mood disorders (O’Connor & Cryan, 2014; Paus, Keshavan & Giedd, 2008). The causal relationships of these atypical behaviors that are seen in mental illness have long been debated. Some scholars believe deficient diets lead to cognitive and short-term memory disabilities (Bondi et al, 2014), whereas others suggest that errors in the human genome could affect brain development and induce mental illness (Guo et al, 2009). In recent years, researchers have brought forward the idea that the microbes in our gut could influence the development of our brain.

With little knowledge about the actions of the 100 trillion microbes present in the human body, it is reasonable to hypothesize that they might play a definitive role in brain development (Knight, 2015; Foster & Neufeld, 2013). It has long been known that the human gut communicates with the brain and vice a versa. However, the mechanisms through which it did so remained an intriguing field of study for members of the scholastic community (Foster & Neufeld, 2013). The ensuing studies of germ free mice and the development of their neuronal functions shed a new light on the possibility of intestinal microbes affecting the development of cognitive and behavioral attributes(Kelly et al, 2016; Gareau, 2011). A study performed by Desbonnet et al (2015) that was similar to those with germ free mice showed an equally interesting trend that adds to the evidence of microbial intervention in brain development.

Central Question

The goal of this study was to determine if gradually depleting the microbial diversity in the guts of study mice during adolescence would affect their behavior or brain chemistry by the time they reached adulthood (postnatal day 55-80).

Evidence

Non-germ free mice subjects were colonized with bacteria from birth and in order to study the effects of microbial depletion Desbonnet et al (2015), subjected the mice to high doses of antibiotics through their drinking water. The mice were started on antibiotic treatment at adolescence, which in mice is postnatal day 21. First and foremost, the mice that underwent antibacterial treatment showed compositional changes in their microbial diversity as well as the number of bacteria in their guts. This change in gut microbiota correlated with altered phenotypic expression of neuronal attributes and behavioral characteristics in the mice, which is consistent with a connection between the microbes in the gut and functions of the brain. For instance, in different portions of the brain specific compounds were found to be either reduced or increased. The hippocampus is a portion of the brain that modulates the formation of memories. In the mice treated with antibiotics, levels of brain-derived neurotrophic factor (BDNF) were significantly reduced (Intro to Psychology, 2010). This protein may  be vital in learning, memory, and higher thinking (Nieto et al, 2013). When coupled with the lowered ability of antibiotic treated mice to distinguish between novel and familiar objects, it seems likely that these two would coincide. The hypothalamus, which helps regulate emotional response and the ability to control primitive urges, showed decreased concentrations of both oxytocin and vasopressin, both of which play roles in social behaviors (Intro to Psychology, 2010). These reduced levels most likely contributed to the mice’s inability to interact with their cage mates in predictable ways. Desbonnet et al. also discovered that their antibiotic-treated mice showed increased levels of tryptophan, but reduced levels of kynurenine, which both act as neuromodulator proteins in neuronal signaling. The effects of these fluctuating neurotransmitters can be likened to the effects of a child eating too much sugar and becoming hyperactive. Or a person not eating enough calories in a day and becoming lethargic. These examples displayed in the research findings of Desbonnet et al. (2015) suggest that disturbances to the gut microbiota might play a role in producing or regulating the compounds necessary for underlying physiological health and brain functioning.

My questions

As with any scientific article, when reading one it is important to remain skeptical about the facts and assumptions that are presented. Likewise, here are some questions that poke and prod into the methods and results of this paper.

Do Bacteroidetes and Firmicutes contribute to the metabolism of compounds to form neuropeptides like oxytocin or vasopressin? We are told a countless number of times that correlation does not lead to causation. Desbonnet et al. assumed that the disturbances of the gut microbiota were responsible for the altered behavior and different levels of specific compounds within antibiotic treated mice. Could the authors be making a mistake by assuming that the microbiota are contributing to the decrease in such compounds because they show a positive correlation? A culture-based study measuring the metabolic output of oxytocin and vasopressin precursors from individual bacteria would help answer this question.

Also, how would the consumption of antibiotics affect intestinal conditions in the mice? Would the antibiotics disrupt normal gut functionality (i.e. peristalsis, nutrient absorption, and pH balance), and could disruption of these functions alter behavior?

Further reading

For further reading, the following articles and videos give a broad overview of the article’s topic.

1) Gut—brain axis: how the microbiome influences anxiety and depression: DOI:/10.1016/j.tins.2013.01.005.

The review,  Gut-brain axis: How the microbiome influences anxiety and depression  by Jane Foster and Karen-Anne Neufeld, serves as a wonderful summary of recent findings regarding the gut-brain axis (1).

2) Why do many psychiatric disorders develop during adolescence? DOI: 10.1038/nrn2513.

This review article on why psychiatric disorders develop in adolescence details the vulnerability of the adolescent brain (2).

3) Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat: DOI:10.1016/j.jpsychires.2016.07.019.

The third recommended reading is an article that has a very similar topic to the study discussed above, but a vastly different experimental design. This article will display some of the different approaches to studying microbiota and how they affect the brain (3).

4) Ted Talk: Mind altering microbes by Elaine Hsiao

Lastly, the Ted Talk by  Elaine Hsiao might stimulate further interest in the field of the human microbiome and its effects on human behavior (4).

References

• Bondi, C. O. et al. (2014). Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency. Biological Psychiatry, 75, 38-46. doi: 10.1016/j.biopsych.2013.06.007.
• Desbonnet, L., Clarke, G., Traplin, A., O’Sullivan, O., Crispie, F., Moloney, R. D., Cotter P. D., Dinan, T. G., Cryan, J. F. (2015). Gut microbiota depletion from early adolescence in mice: Implications for brain and behavior. Brain, Behavior, and Immunity, 48, 165-178. https://doi.org/10.1016/j.bbi.2015.04.004.
• Foster, J. A. & Neufeld, K. (2013). Gut—brain axis: how the microbiome influences anxiety and depression. Trends in Neurosciences, 36(5), 305-312.  https://dx.doi.org/10.1016/j.tins.2013.01.005.  
• Gareau, M. G., Wine, E., Rodrigues, D. M., Cho, J. H., Whary, M. T., Philpott, D. J., MacQueen, G.,  Sherman, P. M. (2011). Bacterial infection causes stress-induced memory dysfunction in mice. Gut, 60, 307-317. https://dx.doi.org/10.1136/gut.2009.202515.
• Guo, X., Hamilton, P., Reish, N. J., Sweatt, J. D., Miller, C. A., &  Rumbaugh, G. (2009). Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of schizophrenia. Neuropyschopharmocology, 34(7), 1659-1672. doi: 10.1038/npp.2008.223.
• Hsiao, E. (2013, February 8). Mind-altering microbes: how the microbiome affects brain and behavior. Retrieved from https://www.youtube.com/watch?v=FWT_BLVOASI.
• Introduction to Psychology. (2010). MN: University of Minnesota Libraries Publishing. Retrieved October 6, 2017 from https://open.lib.umn.edu/intropsyc/front-matter/publisher-information/.  
• Kelly, J. R. et al. (2016). Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of Psychiatric Research, 82, 109-118. https://doi.org/10.1016/j.jpsychires.2016.07.019.
• Knight, Rob. (2015).  Follow Your Gut: The Enormous Impact of Tiny Microbes. New York, NY: Simon and Schuster.
• Nieto, R., Kukuljan, M., & Silva, H. (2013). BDNF and schizophrenia: From neurodevelopment to neuronal plasticity, learning, and memory. Frontiers in Psychiatry, 4(45). doi: https://dx.doi.org/10.3389/fpsyt.2013.00045.
• O’Connor, R. M., Cryan, J. F. (2014). Adolescent brain vulnerability and psychopathology through the generations: Role of diet and dopamine. Biological Psychiatry, 75(1), 4-6.  https://doi.org/10.1016/j.biopsych.2013.10.022.
• Paus, T. (2005). Mapping brain maturation and cognitive development during adolescence. Trends in Cognitive Science, 9(2), 60-68. https://doi.org/10.1016/j.tics.2004.12.008.
• Paus, T., Keshavan, M., & Giedd, J. N. (2008). Why do many psychiatric disorders emerge during adolescence? Nature Reviews Neuroscience, 9(12), 947-957. doi: 10.1038/nrn2513.
• [Puzzle pieces connecting gut and microbes and the brain]. Retrieved October 4, 2017 from https://blogs.biomedcentral.com/on-biology/2014/05/29/the-gut-brain-axis-whats-the-relationship-between-our-bowels-and-our-brains/.