The gut–memory connection is the relation between the gastrointestinal tract and memory performance. The phenomenon of the gut–memory connection is based on and part of the idea of the gut-brain axis, a complex communication network, linking the central nervous system to the gut. The gut-brain axis first gained significant momentum in research and formal recognition in the 20th century with advancements in neuroscience and gastroenterology. The idea of a connection between the gut and emotion has been hinted at in various ancient traditions and medical practices for centuries.
As a vital conduit for the communication between gastrointestinal tract and the brain, the gut-brain axis influences a variety of physiological processes. A prominent example of the gut–memory connection is the effects that alterations in the gut microbiome can have on the pathogenesis of neural diseases like Alzheimer's.
Understanding the connections between the gut microbiome and cognitive health could aid researchers in developing novel strategies for slowing down cognitive decline in neurodegenerative diseases.
Origins The gut-brain axis is a two-way communication network within human systems that correlates the gut microbiome and the brain, encompassing immune, endocrine and neural connections. There is an evident association between the gastrointestinal tract and enteric microbiota with functional changes highlighted in the nervous system evidenced in vivo and vitro studies. This relationship plays a role in maintaining brain health as a result of resident microbes in the GI tract, influencing pathophysiology and mental behaviours. This can be accomplished through neuronal function directly or indirectly via vitamins, neurotransmitters and metabolites. The exact biochemical pathway for this has yet to be determined, while some experimental data may suggest afferent sensory neurons travel via neuroimmune and endocrine systems traveling over the vagus nerve. This demonstrates a commensalistic relationship between bacteria that exist in the human GI tract reaping from a diverse source of nutrients while providing indigestible nutrients available to the host.
It has also been hypothesized that IBS can originate as a result of brain-to-gut or gut-to-brain syndrome as well which emphasizes the importance of the gut-brain axis. Neurological disorders could also be a result of microbiota factors explaining why the intestine is known as the second brain as opposed to having neural origin. This uncovers the link to discovering mental and neurological disorders such as depression and anxiety with gut microbiota health. While not much of the ancestral origin of these interactions is not well known, this has a long history based on the coevolution and ecological interactions between vertebrates and bacteria, tightly coupled in animal evolution. This can also be evidenced by observing the role of bacteria such as the Hydra holobiont in contractile behaviour necessary for gut motility, demonstrating the product of ancient interaction between bacteria and emerging metazoans.
The ancestral mammalian gut likely harboured a diverse array of microbes that played essential roles in metabolism, digestion and immune response, and as a result, has evolved and adapted in response to selection and dietary pressures. With the development of the vertebrate nervous system, the coordination of digestive processes in the gastrointestinal tract with external stimuli would've allowed communication.
Neuroanatomical basis The anatomical basis of the gut–memory connection includes the gastrointestinal tract (GIT), which has its own intrinsic nervous system, called the enteric nervous system (ENS). The ENS controls intestinal function and can theoretically operate independently from the central nervous system (CNS).Ian Miller. (2018). The gut-brain axis: historical reflections. Microbial Ecology in Health and Disease, 29(2). https://doi.org/10.1080/16512235.2018.154292 More than 100 million efferent neurons are present in the human ENS. They are connected to the brain through the vagus nerve, which seems to be the main mediator of gut-brain communication.Furness, J. B. (2008). The enteric nervous system: normal functions and enteric neuropathies. Neurogastroenterology & Motility, 20, 32–38. https://doi.org/10.1111/j.1365-2982.2008.01094.x Around 90% of the vagus nerve fibers connecting the brain and the ENS are afferent, meaning that the brain receives more information from the digestive system than it sends out.Furness, J. B., Callaghan, B. P., Rivera, L. R., & Cho, H. J. (2014). The enteric nervous system and gastrointestinal innervation: integrated local and central control. Microbial endocrinology: The microbiota-gut-brain axis in health and disease, 39-71. Afferent vagus nerve fibers have cell bodies in the nodose ganglia that synapse with the CNS. The signals are then relayed to the medial nucleus of the solitary tract (NTS), which in turn relays them to various brainstem and forebrain regions, including the hippocampus and the amygdala.Suarez, A.N., Hsu, T.M., Liu, C.M. et al. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun 9, 2181 (2018). https://doi-org.mu.idm.oclc.org/10.1038/s41467-018-04639-1Liu, J., Fang, J., Wang, Z., Rong, P., Hong, Y., Fan, Y., Wang, X., Park, J., Jin, Y., Liu, C., Zhu, B., & Kong, J. (n.d.). Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression. Journal of Affective Disorders, 205, 319–326. https://doi.org/10.1016/j.jad.2016.08.003
Signals from the GIT can activate the hippocampus, which was shown by directly stimulating the vagus nerve in human participants.Wang, G.-J., Yang, J., Volkow, N. D., Telang, F., Ma, Y., Zhu, W., Wong, C. T., Tomasi, D., Thanos, P. K., & Fowler, J. S. (2006). Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry. Proceedings of the National Academy of Sciences, 103(42), 15641–15645. https://doi.org/10.1073/pnas.0601977103 The connection between the hippocampus and the medial NTS does not appear to be direct. Instead it seems to involve the locus coeruleus (LC) and the medial septum (MS), making the connection indirect.Castle, M., Comoli, E., & Loewy, A. D. (2005). Autonomic brainstem nuclei are linked to the hippocampus. Neuroscience, 134(2), 657–669. Studies have shown increased memory retention in both humans and rodents, following direct vagus nerve stimulation.Clark, K. B., Krahl, S. E., Smith, D. C., & Jensen, R. A. (1995). Post-training unilateral vagal stimulation enhances retention performance in the rat. Neurobiology of Learning and Memory, 63(3), 213–216.Clark, K. B., Smith, D. C., Hassert, D. L., Browning, R. A., Naritoku, D. K., & Jensen, R. A. (1998). Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat. Neurobiology of Learning and Memory, 70(3), 364–373.Clark, K. B., Naritoku, D. K., Smith, D. C., Browning, R. A., & Jensen, R. A. (1999). Enhanced recognition memory following vagus nerve stimulation in human subjects. Nature Neuroscience, 2(1), 94–98.
There are noradrenergic projections from the nucleus of the solitary tract to the amygdala, which is often associated with emotional learning. Direct Vagus nerve stimulation increases the release of noradrenaline in the amygdala and has been linked to increased fear depletion and positive outcomes of preclinical treatments of major depressive disorder (MDD).Hassert, D. L., Miyashita, T., & Williams, C. L. (2004). The Effects of Peripheral Vagal Nerve Stimulation at a Memory-Modulating Intensity on Norepinephrine Output in the Basolateral Amygdala. Behavioral Neuroscience, 118(1), 79–88. https://doi.org/10.1037/0735-7044.118.1.79Peña, D. F., Childs, J. E., Willett, S., Vital, A., McIntyre, C. K., & Kroener, S. (2014). Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala. Frontiers in Behavioral Neuroscience, 8. https://doi.org/10.3389/fnbeh.2014.00327Liu, J., Fang, J., Wang, Z., Rong, P., Hong, Y., Fan, Y., Wang, X., Park, J., Jin, Y., Liu, C., Zhu, B., & Kong, J. (n.d.). Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression. Journal of Affective Disorders, 205, 319–326. https://doi.org/10.1016/j.jad.2016.08.003
Other factors that can indirectly influence memory function, include the immune system and hormonal processes. The ENS mediates HPA-axis function via gastrointestinal hormones, cytokines and neuropeptides. Through the same pathways the HPA-axis can influence the ENS. Therefore, the gut can indirectly influence hippocampal functioning and other cortical structures related to memory, via the HPA-axis.Jody A. Rusch, Brian T. Layden, & Lara R. Dugas. (2023). Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis. Frontiers in Endocrinology, 14. https://doi.org/10.3389/fendo.2023.1130689
Probiotics
Probiotics and memory function Probiotics, living bacteria with health benefits, are emerging as a potential tool to influence the microbiota-gut-brain axis and improve mental well-being. This axis is a complex communication network linking the gut and the brain, primarily mediated by the vagus nerve and the production of neuromodulators, which influence nerve activity and brain function.Kandpal, M., Indari, O., Baral, B., Jakhmola, S., Tiwari, D., Bhandari, V., Pandey, R. K., Bala, K., Sonawane, A., & Jha, H. C. (2022). Dysbiosis of Gut Microbiota from the Perspective of the Gut-Brain Axis: Role in the Provocation of Neurological Disorders. Metabolites, 12(11), 1064. https://doi.org/10.3390/metabo12111064 Although the exact molecular mechanisms are still unclear, the gut microbiota has been demonstrated to influence behaviour and brain functions, including pain perception, stress response, prefrontal myelination, and brain biochemistry.
Experimental manipulation of the gut microbial community composition has been shown to modify the host's neural function. For instance, long-term consumption of a probiotic Lactobacillus strain by BALB/c mice changed gamma-aminobutyric acid (GABA) expression in brain regions related to emotional processing. This alteration was associated with reduced anxiety and depression-like behaviour. A study found that consuming probiotics for 4–6 weeks altered neural activity in brain regions responsible for the central processing of emotion and sensation in healthy women, even without changes in gut microbial composition.
Given the evidence that gut microbiota influences emotional processing and the connections between emotion, memory, and decision-making, researchers hypothesized that probiotic ingestion could impact brain mechanisms related to such contexts. Their study demonstrated that administering a multi-strain probiotic significantly impacts behavioural scores and fMRI measures in brain regions involved in emotional decision-making and memory.
Probiotics contribute to the reduction of oxidative stress, a cellular process that can damage brain cells. Accordingly, probiotics may protect brain cells in the hippocampus, a region important for memory storage and retrieval while promoting a healthy gut lining.