The Gut-Brain Axis
By Hilina Woldemichael
The microbiome is the collection of all of the microscopic life that lives in and on the body. In humans, there exist approximately 50 trillion bacterial cells in the gastrointestinal tract alone [2]. Our microbiomes can be influenced by several factors, including but not limited to diet, environment, medication use, and lifestyle [7]. Given the sheer number of cohabitants with which we share our bodies, it is no wonder they have a major impact on our health. Much research has been done in the past two decades to explore this topic, and microbiologists have discovered strong links between microbiome composition and diseases such as diabetes, obesity, inflammatory bowel disease, and cancer [8].
More recently, studies have linked the microbiome to the brain’s function. Scientists have documented a “bi-directional” signaling pathway between the gut—including the microbes that live there—and the brain—appropriately nicknamed the gut-brain axis [4]. Imbalances in this signaling have been associated with the development of a wide host of illnesses, from metabolic to immune to mood disorders [4].
The challenge today lies in finding exactly how and to what extent our microbes can either improve or deteriorate our mental health. A recent paper published in Nature Microbiology sought to get a better sense of the relationship between microbes and mental illness phenotypes—in particular, depression. To begin with, the scientists took samples from the Flemish Gut Flora Project (FGFP), a large-scale effort funded by the Flemish government to gather and analyze a great number of gut microbiome profiles [5]. The researchers focused on the relation between microbial composition and host quality of life and depression in the patients that gave rise to each profile. The quality of life of the FGFP participants was measured using the RAND-36 health-related quality of life survey, a well-accepted health metric, in order to generate the health status of hosts [1]. 11.5% of the individuals in the cohort had “general practitioner-diagnosed depression” and scored generally lower in health than the rest of the cohort [1]. The authors of the paper used both the RAND scores and depression diagnosis of the FGFP in this study and validated findings within the Dutch Lifelines DEEP (LLD) cohort, another project similar to FGFP [1].
When comparing the species found across all individuals, the team found that physician-diagnosed depression and a lower QoL were strongly linked to depletion of two genera, Coprococcus and Dialister [1]. Additionally, they scoured the genomes of human-associated microbes in an attempt to locate specific pathways that had “neuroactive potential”—pathways that had been elucidated in previous studies—both within the samples that they had taken and across other sequenced datasets [1]. In other words, they were looking for the ability of microbes to synthesize or break down neurotransmitters and other compounds important to neurological function. The researchers discovered that there was potential for the synthesis of 3,4-dihydroxyphenylacetic acid, a product of dopamine metabolism, to correlate positively with QoL, which indicates that there is a possible microbial contribution to γ-aminobutyric acid (GABA) host availability [1]. GABA is a neural inhibitor which other studies have documented as depleted in cases of depression [6]. Altogether, they found several neural-related pathways within the microbial genomes, indicating that there is some evidence for a correlation between modulation of gut-brain signaling and prevalence of depressive symptoms.
Before the results of this study can open any doors, there are major hurdles that must first be overcome. The writers stress that, although promising, these results do not yet prove a causal relationship between the microbiota and depression, nor do they indicate the directionality of these gut-brain interactions [1]. In order to do so, merely observing the differences between host microbial communities and quality of life is not enough. To prove this causal relationship, studies that actively manipulate the microbial communities of hosts and monitoring impacts on QoL and depressive symptoms must be conducted. Testing this hypothesis on humans may be ethically unsound and difficult to implement—at least to the extent that scientists need to prove a relationship exists.
Instead, causality can be determined in mouse models—one of the most popular animal models in human biomedical research—but these results are difficult to translate to people [3]. This is due to the small but significant differences in anatomy, physiology, genetics, and digestion between mice and men [3]. Even so, that there is such a strong relationship between the species we find in our gut and our brain chemistry means that future studies have much to build on.
Revolutionary new treatments for depression may lay within the microbiome. These treatments may be much more individualized and efficacious, as they can target the specific compositions of microbes within each patient. Medication focusing on the microbiome also provides a more innovative alternative to current antidepressants, which may aid those who are treatment-resistant. Although the path moving forward with this research is difficult, that does not mean there is no potential to change our therapeutics for the better.
References
The microbiome is the collection of all of the microscopic life that lives in and on the body. In humans, there exist approximately 50 trillion bacterial cells in the gastrointestinal tract alone [2]. Our microbiomes can be influenced by several factors, including but not limited to diet, environment, medication use, and lifestyle [7]. Given the sheer number of cohabitants with which we share our bodies, it is no wonder they have a major impact on our health. Much research has been done in the past two decades to explore this topic, and microbiologists have discovered strong links between microbiome composition and diseases such as diabetes, obesity, inflammatory bowel disease, and cancer [8].
More recently, studies have linked the microbiome to the brain’s function. Scientists have documented a “bi-directional” signaling pathway between the gut—including the microbes that live there—and the brain—appropriately nicknamed the gut-brain axis [4]. Imbalances in this signaling have been associated with the development of a wide host of illnesses, from metabolic to immune to mood disorders [4].
The challenge today lies in finding exactly how and to what extent our microbes can either improve or deteriorate our mental health. A recent paper published in Nature Microbiology sought to get a better sense of the relationship between microbes and mental illness phenotypes—in particular, depression. To begin with, the scientists took samples from the Flemish Gut Flora Project (FGFP), a large-scale effort funded by the Flemish government to gather and analyze a great number of gut microbiome profiles [5]. The researchers focused on the relation between microbial composition and host quality of life and depression in the patients that gave rise to each profile. The quality of life of the FGFP participants was measured using the RAND-36 health-related quality of life survey, a well-accepted health metric, in order to generate the health status of hosts [1]. 11.5% of the individuals in the cohort had “general practitioner-diagnosed depression” and scored generally lower in health than the rest of the cohort [1]. The authors of the paper used both the RAND scores and depression diagnosis of the FGFP in this study and validated findings within the Dutch Lifelines DEEP (LLD) cohort, another project similar to FGFP [1].
When comparing the species found across all individuals, the team found that physician-diagnosed depression and a lower QoL were strongly linked to depletion of two genera, Coprococcus and Dialister [1]. Additionally, they scoured the genomes of human-associated microbes in an attempt to locate specific pathways that had “neuroactive potential”—pathways that had been elucidated in previous studies—both within the samples that they had taken and across other sequenced datasets [1]. In other words, they were looking for the ability of microbes to synthesize or break down neurotransmitters and other compounds important to neurological function. The researchers discovered that there was potential for the synthesis of 3,4-dihydroxyphenylacetic acid, a product of dopamine metabolism, to correlate positively with QoL, which indicates that there is a possible microbial contribution to γ-aminobutyric acid (GABA) host availability [1]. GABA is a neural inhibitor which other studies have documented as depleted in cases of depression [6]. Altogether, they found several neural-related pathways within the microbial genomes, indicating that there is some evidence for a correlation between modulation of gut-brain signaling and prevalence of depressive symptoms.
Before the results of this study can open any doors, there are major hurdles that must first be overcome. The writers stress that, although promising, these results do not yet prove a causal relationship between the microbiota and depression, nor do they indicate the directionality of these gut-brain interactions [1]. In order to do so, merely observing the differences between host microbial communities and quality of life is not enough. To prove this causal relationship, studies that actively manipulate the microbial communities of hosts and monitoring impacts on QoL and depressive symptoms must be conducted. Testing this hypothesis on humans may be ethically unsound and difficult to implement—at least to the extent that scientists need to prove a relationship exists.
Instead, causality can be determined in mouse models—one of the most popular animal models in human biomedical research—but these results are difficult to translate to people [3]. This is due to the small but significant differences in anatomy, physiology, genetics, and digestion between mice and men [3]. Even so, that there is such a strong relationship between the species we find in our gut and our brain chemistry means that future studies have much to build on.
Revolutionary new treatments for depression may lay within the microbiome. These treatments may be much more individualized and efficacious, as they can target the specific compositions of microbes within each patient. Medication focusing on the microbiome also provides a more innovative alternative to current antidepressants, which may aid those who are treatment-resistant. Although the path moving forward with this research is difficult, that does not mean there is no potential to change our therapeutics for the better.
References
- Valles-Colomer, Mireia, Gwen Falony, Youssef Darzi, Ettje F. Tigchelaar, Jun Wang, Raul Y. Tito, Carmen Schiweck, et al. 2019. “The Neuroactive Potential of the Human Gut Microbiota in Quality of Life and Depression.” Nature Microbiology 4 (4): 623–32. https://doi.org/10.1038/s41564-018-0337-x.
- “American Gut – What’s in Your Gut?” n.d. 2020. http://americangut.org/.
- Nguyen, Thi Loan Anh, Sara Vieira-Silva, Adrian Liston, and Jeroen Raes. 2015. “How Informative Is the Mouse for Human Gut Microbiota Research?” Disease Models & Mechanisms 8 (1): 1–16. https://doi.org/10.1242/dmm.017400.
- “Gut-Brain Axis.” 2017. https://www-nature-com.ezp-prod1.hul.harvard.edu/collections/dyhbndhpzv.
- VIB - Vlaams Instituut Voor Biotechnologie.” 2020. https://vib.be/.
- Anisman, Hymie, Zul Merali, and Michael O. Poulter. 2012. “Gamma-Aminobutyric Acid Involvement in Depressive Illness Interactions with Corticotropin-Releasing Hormone and Serotonin.” In The Neurobiological Basis of Suicide, edited by Yogesh Dwivedi. Frontiers in Neuroscience. Boca Raton (FL): CRC Press/Taylor & Francis. http://www.ncbi.nlm.nih.gov/books/NBK107210/.
- Wen, Li, and Andrew Duffy. 2017. “Factors Influencing the Gut Microbiota, Inflammation, and Type 2 Diabetes.” The Journal of Nutrition 147 (7): 1468S-1475S. https://doi.org/10.3945/jn.116.240754.
- “The Microbiome and Disease.” 2020. https://learn.genetics.utah.edu/content/microbiome/disease/.
