Picture it: it’s 2.7 billion years ago and the only living things are single-celled organisms—mostly bacteria. One day, one of these bacteria engulfed another and, instead of digesting it, formed the symbiotic relationship we now refer to as Eukaryotic cells: think Pac Man eating a ghost and not losing those sweet ghost powers. Many years later, these cells would give rise to the humans we know today [1]. But don’t think for a minute that we have left bacteria behind: these single-celled organisms play a critical role in human health through several tissues in the body, but especially so through the gut-microbiome. The term “gut-microbiome” refers to the community of bacteria, viruses, and fungi that live within the gut. As this micro-ecosystem develops and evolves over an individual’s lifetime, it influences the development of the brain and plays a role in adult physical and mental health.
In recent years, research on the gut-brain relationship in adults has demonstrated a link between bacteria of the gut and adult mental health, immunological response, and metabolism [2]. Naturally, these findings have led researchers to explore whether these links originate early in development. These scientists discovered that the composition of the gut-microbiome is important for the development of the brain, mind, and behavior [3]. This gut-brain connection begins late in pregnancy (second to third trimester) when the fetus “borrows” some of the mother’s microbiome to start its own microbial garden, an event referred to as seeding. The first two years of life have emerged as being the most critical time to cultivate the microbiome, and two factors stand out as key seeding events with strong ties to neurological and cognitive outcomes: the method in which one is birthed (vaginal or cesarean) and the method in which one is fed (human milk or formula) [4, 5, 6, 7].
Studies using birth cohorts, groups of babies born around the same time and studied as a group, allow researchers to assess different developmental trajectories over an individual's lifespan. These cohorts have an advantage over other longitudinal models in that they tend to have more thorough medical and background information on participants to take into account when drawing conclusions. Two studies at the University of North Carolina, done by Alexander Carlson and Wei Gao respectively, comprised of babies from the same birth cohorts, have greatly expanded our understanding of the neurodevelopmental gut-brain connection in the first two years of life through the analysis of stool samples, cognitive assessments, and fMRI imaging [4, 5]. For those interested in the broken-down-Barney-style version of these methods, stool sample collection is exactly what it sounds like. Cognitive testing involves a researcher playing various games with the infant/toddler, and resting fMRIs are performed by coaxing an unsedated toddler to take a nap in a machine louder than a Metallica concert. Each of these methods provides researchers with puzzle pieces from the microbial, structural, and cognitive levels, allowing a bigger picture to form. These efforts have yielded new evidence that the composition of the infant microbial neighborhood plays a role in nutrient metabolism, brain structure growth, and cognitive performance.
Carlson’s findings from the 89 babies studied show that the group with the greatest proportion of vaginal births and breastfeeding/chestfeeding had some advantages over other groups [4]. This group had increased vitamin metabolism, an increased size of certain brain structures, and higher performance in cognitive testing. At age one, toddlers in this group had a larger occipital gyrus, a brain region associated with object recognition, indicating better progression of neural development. Then, at age two, these same toddlers were found to have larger left and/or right caudate nuclei, areas related to associative learning and connecting visual stimuli to motor responses, which may have contributed to their higher cognitive testing scores in their understanding and production of language. Additionally, this group also had the least amount of alpha diversity in their fecal samples, which is the measure of diversity of microbial species within the microbiome [4]. The lower alpha diversity of an immature gut is a desirable condition in early development, much like the perfect soil is to the springtime gardener.
Gao’s study built off of Carlson’s work and further investigated the correlation between alpha diversity in infancy and neurological development. This group focused on the 39 infants from Carlson’s study who had successfully completed the fMRI portion. Researchers found that less alpha diversity has been positively correlated with greater functional connectivity between the amygdala and the thalamus, a neural pathway involved in fear processing [5]. Greater functional connectivity along this pathway is linked to the ability to more efficiently process emotions, specifically fear. This finding is especially important when considering that other research has linked the gut-microbiome to anxiety in adults [2]. Conversely, investigation of the supplementary motor area and inferior parietal lobule, structures related to processing sensory inputs and language learning, showed a positive correlation between the infant’s alpha diversity and the functional connectivity between the two regions [5]. This finding suggests that there may need to be greater gut maturation (i.e. greater alpha diversity) to increase the brain’s capacity for multi-sensory processes. To summarize: less gut alpha diversity in the first two years of life seems to facilitate stronger connections in the developing brain for emotional processing, and greater gut maturation is likely needed for language learning and multi-sensory processing surrounding vision and movement [5].
But how do alpha diversity shifts and subsequent maturation of the gut contribute to a child's development? This may be where breastfeeding/chestfeeding duration plays a role.
Fredrik Bäckhed, a Swedish researcher, found that alpha diversity was linked to birth and feeding methods, where lowest alpha diversity occurs in babies who were both vaginally birthed and breastfed [7]. Importantly, the duration of breastfeeding/chestfeeding in the first year of life was correlated with alpha diversity in fecal samples, while the cessation of breastfeeding/chestfeeding was correlated with a rapid maturation of the gut, signaled by an increase in alpha diversity [7]. Tying back to the work of Carlson and Gao, these results suggest that breastfeeding/chestfeeding facilitates greater neural development in regions related to emotional processing and building better hand-eye coordination, while cessation of breastfeeding/chestfeeding promotes the gut maturation associated with language learning processes [4, 5].
It is worth noting that the effect of birth and feeding methods on cognitive performance may not be limited to the first two years of life. Research from a Finnish birth cohort suggests that their impact may be lifelong. Rantalainen et al. found that breastfeeding/chestfeeding duration was correlated with better cognitive performance at around the age of 70. Most notably, they observed an increase in verbal reasoning in adulthood if the subject had been breastfed for longer than three months [8]. This is striking, as cognitive decline typically begins at age 70 [9]. While this birth cohort was started before the advent of advanced technology for microbial sequencing and thus had no fecal samples to further this research, we can infer from the findings of Carlson, Gao, Bäckhed, and this study, that the microbial seeding done by breastfeeding/chestfeeding may play a significant role in lifelong neurological health.
Given how polarizing the conversations surrounding birth and feeding methods can be in parenting circles, it is important to acknowledge that a variety of factors can unexpectedly alter parents’ birth plans or feeding goals. Fortunately, these objective differences are not as extreme as Steve Rogers before and after his Captain America transformation, but subtle in their developmental impacts. Recent studies have theorized that there are several critical windows in development where the microbiome is most sensitive to influence. This includes the prenatal period, the first two years of life, and adolescence [6]. Armed with this knowledge, parents can utilize other healthy gut-seeding options, most notably a healthy diet, to stabilize the gut and feed the brain of their child, even post infancy [6].
So what does this mean for the adult who may have been born by cesarean, was combination fed during their first year of life, spent their adolescent years as a latch-key kid binging on dunkaroos and capri-suns, but now is concerned for their long-term gut-brain health?
Researchers have explored several ways to alter the adult microbiome: probiotics, fecal transplants, and diet. Unfortunately, probiotics are likely not the answer. Some probiotic studies have been able to slightly shift the overall composition of the adult gut-microbiome, but these changes were only noted while taking supplements [10]. This option is expensive, not well regulated in the US, and difficult to stabilize for commercial sale. Fecal transplant as a vector to introduce a healthy microbial community to one in dysbiosis, such as those with Irritable Bowel Syndrome or C. Diff infection, has been effective in altering the adult microbiome. However, this approach has risks, is costly, and does not lead to significant long term benefits [11]. Unsurprisingly, the intervention that seems to have the longest-lasting impact on the microbiome is a healthy diet, more specifically the Mediterranean diet, which works by feeding the desired microbes in the gut and helping them to flourish [12]. It is interesting that the method in which we feed ourselves seems to have a direct tie to our gut health, and subsequently our brains, for the duration of our lives.
It’s easy to see why the field of research surrounding the inhabitants of our gut-microbiome is exploding right now; there is much to explore and understand and a huge potential to improve mental and physical health in adulthood. Looking forward, we hope to see more research detailing the locations of the microbial concentrations within the gut in the form of an atlas, understanding their functions, and the development of targeted therapies when dysbiosis occurs to prevent chronic health conditions. In the meantime, we humans need to do what the bacterial cells that came before did: eat well to feed the symbiotic creatures within us. It seems the old adage, “You are what you eat,” is more true today than ever before.
Sagan L. (1967). On the origin of mitosing cells. Journal of theoretical biology, 14(3), 255–274. https://doi.org/10.1016/0022-5193(67)90079-3.
Carabotti, M., Scirocco, A., Maselli, M. A., & Severi, C. (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of gastroenterology, 28(2), 203–209.
Diaz Heijtz R. (2016). Fetal, neonatal, and infant microbiome: Perturbations and subsequent effects on brain development and behavior. Seminars in fetal & neonatal medicine, 21(6), 410–417. https://doi.org/10.1016/j.siny.2016.04.012.
Carlson, A. L., Xia, K., Azcarate-Peril, M. A., Goldman, B. D., Ahn, M., Styner, M. A., Thompson, A. L., Geng, X., Gilmore, J. H., & Knickmeyer, R. C. (2018). Infant Gut Microbiome Associated With Cognitive Development. Biological psychiatry, 83(2), 148–159. https://doi.org/10.1016/j.biopsych.2017.06.021.
Gao, W., Salzwedel, A. P., Carlson, A. L., Xia, K., Azcarate-Peril, M. A., Styner, M. A., Thompson, A. L., Geng, X., Goldman, B. D., Gilmore, J. H., & Knickmeyer, R. C. (2019). Gut microbiome and brain functional connectivity in infants-a preliminary study focusing on the amygdala. Psychopharmacology, 236(5), 1641–1651. https://doi.org/10.1007/s00213-018-5161-8.
Robertson, R. C., Manges, A. R., Finlay, B. B., & Prendergast, A. J. (2019). The Human Microbiome and Child Growth - First 1000 Days and Beyond. Trends in microbiology, 27(2), 131–147. https://doi.org/10.1016/j.tim.2018.09.008.
Bäckhed, F., Roswall, J., Peng, Y., Feng, Q., Jia, H., Kovatcheva-Datchary, P., Li, Y., Xia, Y., Xie, H., Zhong, H., Khan, M. T., Zhang, J., Li, J., Xiao, L., Al-Aama, J., Zhang, D., Lee, Y. S., Kotowska, D., Colding, C., Tremaroli, V., … Wang, J. (2015). Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell host & microbe, 17(5), 690–703. https://doi.org/10.1016/j.chom.2015.04.004.
Rantalainen, V., Lahti, J., Henriksson, M., Kajantie, E., Mikkonen, M., Eriksson, J. G., & Raikkonen, K. (2017). Association between breastfeeding and better preserved cognitive ability in an elderly cohort of Finnish men. Psychological medicine, 48(6), 939–951. https://doi.org/10.1017/S0033291717002331
Harada, C. N., Natelson Love, M. C., & Triebel, K. L. (2013). Normal cognitive aging. Clinics in geriatric medicine, 29(4), 737–752. https://doi.org/10.1016/j.cger.2013.07.002
Tremblay, A., Fatani, A., Ford, A. L., Piano, A., Nagulesapillai, V., Auger, J., MacPherson, C. W., Christman, M. C., Tompkins, T. A., & Dahl, W. J. (2020). Safety and Effect of a Low- and High-Dose Multi-Strain Probiotic Supplement on Microbiota in a General Adult Population: A Randomized, Double-Blind, Placebo-Controlled Study. Journal of dietary supplements, 1–21. Advance online publication. https://doi.org/10.1080/19390211.2020.1749751.
Vrieze, A., de Groot, P. F., Kootte, R. S., Knaapen, M., van Nood, E., & Nieuwdorp, M. (2013). Fecal transplant: a safe and sustainable clinical therapy for restoring intestinal microbial balance in human disease?. Best practice & research. Clinical gastroenterology, 27(1), 127–137. https://doi.org/10.1016/j.bpg.2013.03.003.
Dash, S., Clarke, G., Berk, M., & Jacka, F. N. (2015). The gut microbiome and diet in psychiatry: focus on depression. Current opinion in psychiatry, 28(1), 1–6. https://doi.org/10.1097/YCO.0000000000000117.
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