Brain - Gut Microbiota Connection

By: Karen Jiang

The process of learning about the human biology generally tends to systematize and separate the body into discrete units and understand their function as disparate parts. This often translates into the clinical world of diagnoses and treatments where diseases are isolated to their corresponding systems—Parkinson’s disease is viewed under a neurodegenerative lens, or patients with irritable bowel syndrome are sent to a gastroenterologist.

Research on the junctions between the nervous system and gastrointestinal system, known as the enteric nervous system (ENS) is gaining traction amongst scientists in neuroscience, microbiology, and gastroenterology. This intermediary system between our brain and our gut has been implicated in further understanding homeostasis, emotions, and gastrointestinal disorders. Greater insight into the connections between the mind and the gut opens avenues for preventative health measures and moderate treatments to alleviate and address pathologies in both systems.

There is an intuitive aspect in thinking about the ways the mind and the gut relate. Sensations of hunger, thirst, and satiety emerge as recognizable system loops that motivate and drive food-directed behavior known as homeostatic emotion (Mayer et al., 2006). The ability to sense the state of visceral structures like the gut, intestine, and bowels are part of the interoceptive system; this system provides feedback to the conscious mind as a status report on the physiological state of the body. Perhaps the “hangry” phenomena where intense hunger initiates a negative, aggressive affective state might actually be more than a cultural byproduct, and serve to demonstrate the innate relationship between these two systems that drive the human system to readjust to a state of equilibrium.

The primary structures that mediate the communication in the gut microbiota- brain axis are the gastrointestinal epithelium, the vagus nerve, and the blood brain barrier (BBB) (Bauer et al., 2016). The gastrointestinal system does not solely consist of tissues and structures that share the same genetic information, as is the case in the rest of the human body. The intestine, which has a surface area that exceeds that of the skin by approximately 100-fold, is unique in that it contains 40,000 species and 100 trillion organism that live in a commensal relationship along the epithelial tissues (Mayer, 2011). This vastly diverse microbial universe with their associated genetic sequences produce biomolecules that create a rich environment within the gut. The vagus nerve is the tenth cranial nerve and mostly contains sensory afferents that convey information about gut immunity, microbial activity, and nutrient levels. A clinical study that performed a truncal vagatomy of the nerve at the base of the abdomen found a decrease in risk for Parkinson’s Disease. The vagus nerve is hypothesized to be the conduit through which microbial infections that originate in the gastrointestinal tract reach the brain (Svensson et al., 2015), but severing this connection in other circumstances would create deficits in maintaining the body’s homeostasis. The BBB seems to be an unlikely structure that connects the brain and the gut, in that its primary function is to be a vigilant barrier for any potential substance that might be toxic or pathogenic. However, high-fat diets in rats led to increases in lipoprotein A, a product of Gram-positive bacteria, which activates an immune response and weakens the BBB, placing the brain in a vulnerable state (Davidson et al., 2013). This potential for high fat diets in mice to subsequently weaken the highly selective defensive protection for the brain warrants careful consideration in humans, especially considering the contents of a modern diet.

Additionally, modern neuroimaging techniques enable the visualization of the changes in neural responses to what is consumed. A recent study by Tillisch et al. studied the effects of Fermented Milk Product with Probiotic (FMPP), or yogurt, in healthy female participants on modulating brain activity. Functional magnetic resonance images (fMRIs) were taken at resting state and during a standardized emotional faces attention task. After consuming FMPP for 4 weeks, the subjects showed significant decrease in Blood Oxygen Level Dependent (BOLD) activity in interoceptive and somatosensory regions, specifically the insula and the sensory cortex. This altered state was attributed to changes in the resting state connectivity centered around the periaqueductal gray (PAG) network with connections to affective, interoceptive, and prefrontal regions. The PAG is responsible for modulating descending pain tracks, which control encephalin-releasing neurons to regulate pain control and analgesia. It is hypothesized the introduction of these micro-organisms from yogurt consumption interact with serotonin containing cells in the gut. The vagus nerve would receive signals from the gut epithelium and transduce the signal through the tract that connects to the PAG (Tillisch et al., 2013). A potential avenue from this research might be creating “mindful” menus featuring prebiotics and probiotics as mechanisms to regulate neural responses in preparation for emotional situations. As modern culture approaches the personalization of medicine, diets too may also be curated in ways that intentionally modify brain regions and reactivity.

The clinical applications engage the ability for bi-directional communication of the mind and gut with interventions at both ends. In patients with IBS, the psychological stress from the condition results in elevated levels of norepinephrine levels in the gut lumen; these higher levels have been reported to result in increased virulence of certain pathogenic bacteria in the gut, exacerbating the condition and creating a feedback loop (Rhee et al., 2009). Brain images of these IBS patients have shown greater cortical thickness and activation in areas associated with response to visceral stimuli, and cognitive behavior therapy interventions led to reduced cerebral blood flow in brain regions associated with anxiety when undergoing rectal distention (Mayer, 2011). On the other end, introducing certain strains of probiotics to stress-induced mice showed improvements in sensitivity to visceral pain, restored GI permeability, and prevented the stress-induced adherence of bacteria to the epithelium (Collins & Bercik, 2009). The clinical aspects of this research still require further investigation, with larger sample sizes in human subjects to counter variability in individuals’ gut environment, and standardized regions of influence in brain imaging to visualize neural changes.

While the majority of focus in western medicine has been symptom-based treatment and identifying loci to target surgically or pharmacologically, research around brain-gut interactions is particularly innovative in the ways that it provides accessible and viable tools to the general population for preventative measures in mind health and gut health. Pharmacological, surgical, and therapeutic treatments are costly and not readily available to all individuals when issues arise in gastrointestinal or mental health. Food, however, is a direct and accessible method for most individuals to actively readjust their gastrointestinal environment and subsequently their mental reactivity in a preventative and life-style directed manner. Increased education in preventative health through changes in diet, backed by rigorous research, has the potential of inducing a cultural shift in food perception as means of promoting health, not only physically but also mentally.

 

 

References

Bauer KC, Huus KE, and Finlay BB. (2016) Microbes and the mind: emerging hallmarks of the gut microbiota-brain axis. Cellular Microbiology. 18 (5): 632-644.

Collins, S. M., & Bercik, P. (2009). The Relationship Between Intestinal Microbiota and the Central Nervous System in Normal Gastrointestinal Function and Disease. Gastroenterology, 136(6), 2003–2014. https://doi.org/10.1053/j.gastro.2009.01.075

Davidson, T.L., Hargrave, S.L., Swithers, S.E., Sample, C.H., Fu, X., Kinzig, K.P., and Zheng, W. (2013) Inter-relation- ships among diet, obesity and hippocampal-dependent cognitive function. Neuroscience 253: 110–122.

Rhee SH, Pothoulakis C, and Mayer EA. (2009) Principles and clinical implications of the brain-gut enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 6(5):

Mayer EA, Naliboff BD, Craig ADB. (2006) Neuroimaging of the Brain-Gut Axis: From Basic Understanding to Treatment of Functional GI Disorders. Gastroenterology. 131(6):1925-1942

Mayer EA. (2011) Gut feelings: the emerging biology of gut-brain communication. Nature Reviews Neuroscience. 12:453-466

Svensson, E., Horváth-Puhó, E., Thomsen, R.W., Djurhuus, J.C., Pedersen, L., Borghammer, P., and Sørensen, H.T. (2015) Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 522–529.

Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, and Mayer EA. (2013) Consumption of Fermented Milk Product with Probiotic Modulates Brain Activity. Gastroenterology. 144(7)