“One cannot think well, love well, sleep well, if one has not dined well.”
— Virginia Woolf, A Room of One’s Own
Every day, it seems, more data accumulates that strengthens the idea of a powerful mind-gut connection. That is, the simple premise that for our minds to function well, our gut must first do the same. Additionally, the latest research continues to underscore that our gut health, including the health of our gut microbiome, is influenced by the food choices we make. As the gut is largest reservoir of our immune system, the gut-brain axis no doubt influences the state of our immunity. The connection between chronic disability and disease, which is fueled at its core by chronic, continuous low-level inflammation, and our food choices continues to be an area of active investigation within this mind-gut-immune system partnership.
However, previous understanding suggested an indirect communication, primarily involving neuroendocrine pathways. That is because among the organs of the body, the brain exists in relative isolation. A physical barrier known as the blood-brain barrier protects the brain, limiting who and what can enter like an ironclad fortress. Within that fortress, the brain has its own security system with specialized immune cells called microglia. Only in the case of severe infection or pathology were the immune cells present in the rest of the body allowed entry into that sacred cerebral space.
This week’s study destroys that theory. For the first time, researchers demonstrated the presence of T cells (a type of adaptive immune system cell) within the brain under normal, non-diseased conditions. Furthermore, these immune cells originate in the gut and are influenced by the gut microbiota before taking up permanent residence in our brains.
- The study utilized a mouse model and confirmatory evidence from 7 human autopsy specimens. Cerebrospinal fluid (CSF), peripheral blood samples, and a duodenal biopsy were provided by a healthy volunteer.
- The T cells originated in the gut, where the gut bacteria prime them.
- From both the gut and white fat cells, the T cells then move and take up permanent residence in the subfornical organ (SFO) of the brain.
- This area of the brain regulates key physiological functions, including the regulation of our feeding, drinking-related behavior, and systemic inflammation.
- Alterations to the gut microbiota or the composition of adipose tissue can modulate the population of these T cells in the brain.
- These T cells secrete interferon gamma (IFN γ) as part of their normal function.
The Caveat:
This research demonstrates, for the first time, that under normal physiological conditions, the immune system originating in our gut, with priming from our gut microbiota, participates in regulating the area of our brain involved in our feeding and drinking behavior, as well as systemic inflammation. The fingerprints of our gut bacteria are present in our brain. These adaptive immune system cells are informed and their numbers modulated by our gut bacteria and our white fat cells. Their numbers are influenced by how we eat, what we eat, how we fast, and the number of white adipose cells in our bodies.
In the course of normal function, these immune cells secrete interferon gamma (IFN γ), a protein crucial in immune signaling. This molecule is involved in immune activation, antiviral and antimicrobial defense, adaptive immunity, and anti-tumor monitoring. It is also crucial in maintaining a balanced immune system.
As a participant in everyday normal cerebral functioning, this study opens a new door regarding the role of the immune system beyond fighting infection. The fact that these gut-derived, bacteria-influenced immune system cells take up permanent residence in our brains demonstrates direct communication (beyond neuroendocrine signaling) from gut bacteria, gastrointestinal, and fat cells to cerebral neurons via an immune system intermediary. In other words, the gut and brain don’t just talk to each other over the phone; they hold face-to-face meetings and physically share information courtesy of the immune system. It suggests a role for the immune system beyond just being the body’s bouncers in fighting infection, or the originators of a ruckus in the setting of autoimmune disease, but also as a vital signaling pathway, like a FedEx service or Amazon delivery, communicating critical physical information throughout the body.
A very interesting finding highlighted how important the gut bacteria – the quality and character which depends on the types of foods we choose to consume – are in this process. Germ-free mice, which are known to exhibit behavioral abnormalities, are mice that lack bacteria in their gut. It turns out that these mice also lacked T cells in their brain.
Because the cells naturally turn over, this method of communication enables immune cells to report the status of the gut to brain cells, where they can act on this information. This provides a depth of information that may be difficult to convey through neuroendocrine pathways.
“This study raises more questions than it answers,” says Dr. Yoshida, the study’s lead author. But, then again, that is the purpose of all good science.
The Study:
Additional Resources:
Collins, N. et al. The bone marrow protects and optimizes immunological memory during dietary restriction. Cell 178, 1088–1101 (2019).
Hindmarch, C. C. & Ferguson, A. V. Physiological roles for the subfornical organ: a dynamic transcriptome shaped by autonomic state. J. Physiol. 594, 1581–1589 (2016).
Omri, B. et al. CD4 expression in neurons of the central nervous system. Int. Immunol. 6, 377–385 (1994).
Pulman, K. J., Fry, W. M., Cottrell, G. T. & Ferguson, A. V. The subfornical organ: a central target for circulating feeding signals. J. Neurosci. 26, 2022–2030 (2006).
Takahashi, Y., Smith, P., Ferguson, A. & Pittman, Q. J. Circumventricular organs and fever. Am. J. Physiol. 273, R1690–R1695 (1997).
Zhang, J. et al. Projections from subfornical organ to bed nucleus of the stria terminalis modulate inflammation-induced anxiety-like behaviors in mice. Sci. Adv. 10, eadp9413 (2024).
Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30, 492–506 (2020).
