What Are Your Gut Microbiome and Microglia Saying to Each Other?

“Realize that everything connects to everything else.”

Leonardo da Vinci

“Our work is thus a comprehensive theoretical foundation for studies on the gut-microglia connection in the development of [central nervous system] diseases…”

Yiliang Wang, et. al, “The Gut-Microglia Connection: Implications for Central Nervous System Diseases,” Frontiers in Immunology,  October 5, 2018.

For centuries, philosophers, spiritual leaders, and scientists have explored the concept of the interconnectedness of all things. Now, the concept of interconnectedness is being explored in two fields I follow closely—microbiology and neuroscience. The connections between the microbes that colonize the gastrointestinal tract (the gut microbiome) and the brain are receiving growing attention as disturbances in the “gut-brain axis”(GBA) are implicated in a growing number of neurodegenerative and neuropsychological disorders.

In a previous post, I revealed my love affair with a population of  brain cells called microglia (the resident macrophages of the brain) and discussed the potential involvement of microglia in the neurogenerative disease, Alzheimer’s disease. (See, “Microglia: A Role in Alzheimer’s Disease?,” Germ Gems, December 4, 2024). In this week’s post, I highlight progress in understanding how microglia serve as a connection between the immune system and the nervous system and the implications for human health when this connection is disrupted.

Gut microbiome biology (recap). The gut microbiome is defined as the microbes—bacteria, viruses, fungi, and protists—that colonize the gut. The gut microbiome plays a vital role in human health, affecting immune function, heart function, and weight. Most studies of the gut microbiome have focused on its bacterial inhabitants—roughly 100 trillion of them belonging to more than 3000 species.  

Commensal bacteria that colonize the lower gastrointestinal tract protect us against invasive, disease-causing pathogens, a phenomenon referred to as “colonization resistance.” A major interest of many researchers involved in this field is on the adverse impacts of antibiotics on commensal bacteria.

Research has shown that antibiotic overuse depletes the gut of beneficial bacteria. (Blaser, M., Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues, Picador, 2015). But antibiotics aren’t the only drugs that disrupt the composition of the gut microbiome. Antivirals, antifungals, antiparasitic agents, proton pump inhibitors, nonsteroidal anti-inflammatory drugs, laxatives, antidepressants, statins, chemotherapeutics, and immunosuppressants also cause an imbalance in the composition and function of the gut microbiota, a condition called dysbiosis.  (Paes, E., “How Common Meds Secretly Wreck Your Patients’ Microbiome?,” Medscape Medical News, June 25, 2025).  And, dysbiosis has been implicated in a wide range of diseases including inflammatory bowel disease, obesity, allergic disorders, Type 1 and 2 diabetes, and certain gastrointestinal cancers.

Recently, researchers at the National Cancer Center of Japan discovered that a specific gut bacterial strain significantly enhances the effectiveness of certain cancer immunotherapy drugs. The anti-cancer drugs called checkpoint inhibitorswork by ratcheting up the immune system. The researchers found these checkpoint inhibitors work better when the bacterium Hominenteromicrobium mulieris (designated as strain YB328) is present.  (Lin, N., Fukuoka, S., Nishikawa, H., “Microbiota-driven antitumor immunity mediated by dendritic cell migration,” Nature, July 14, 2025). They found that this microbe stimulates cells in the immune system called dendritic cells, which go on to amplify the effects of the anti-cancer drugs. (In addition to being a beautiful scientific discovery, this study introduced me to a bacterium with the most difficult to pronounce name that I’ve ever encountered.)

Cells in the brain (recap). Several prominent scientists have described the human brain as  “the most complex structure in the known universe.” Quite simply, however, the human brain is comprised of only two types of cells: neurons and glial cells. There are about as many glial cells as there are neurons in the human brain—85 billion glia vs 86 billion neurons.

Neurons—the cells credited with your ability to think and move about—garner most of the attention of neuroscientists.  And within the context of “interconnectedness,” neurons are the most mind-blowing. It is estimated that the human brain has 86 billion neurons which form a vast network of connections, with a total number of synapses (connections between neurons) varying between 100 trillion to 1,000 trillion).

Microglia account for approximately 5% to 15% of all cells in the brain where they function as primary immune cells. As the resident macrophages of the central nervous system, microglia preform maintenance and immune surveillance, ridding the brain not only of damaged cells and debris, but also of unwanted interlopers (invasive microbes).

In addition to the protective functions of microglia, other glial cell types perform key support roles. For example, astrocytes, which comprise 20-40% of brain cells, provide metabolic and structural support, while oligodendrocytes provide the myelin sheath around the axons of neurons.

Until recently, microglia were considered the only immune call type to reside within the healthy brain. Then this May, a team of Yale University scientists identified in the healthy brains of mice and humans special-agent immune cells (T lymphocytes) that carry information about the gut and fat tissue deep into the brain. (Yoshida, T.M., Nguyen, M., Wang, A., “The subfornical organ is a nucleus for gut-derived T cells that regulate behavior,” Nature, May 28, 2025; see also, Conroy, G. “How the brain spies on the gut: with help from newfound immune cells,” Nature News, May 28, 2025). This is the first time T cells have been shown to inhabit the brain under normal conditions. While the function of these resident brain T cells is yet to be defined, preliminary evidence suggests they may have a surveillance function of the gut.

Involvement of the gut microbiome-brain axis (GBA) in neurological and psychological conditions. Once the connection between the gut microbiome and microglia became established, a growing number of researchers provided evidence that disruptions of the GBA are involved in a multitude of neurodegenerative diseases, as well as in various neuropsychological disorders. (See, e.g., Wang, Y., et. al,  “The Gut-Microglia Connection: Implications for Central Nervous System Diseases,” Frontiers in Immunology, October 5, 2018;  Ashique, S., et. al, “Gut-brain axis: A cutting edge approach to target neurological disorders and potential synbiotic application,” Helyion, July 15, 2024; Kilgore, C., “Gut Microbiome Likely Influences Neurodegenerative Disorders,” Medscape, April 2, 2025; Makin, S., “Why nurturing the gut microbiota could resolve depression and anxiety.” Nature Outlook, August 18, 2025).

Future considerations. For at least two decades, it has been known that there is a bidirectional communication between the gut microbiome and the brain (the so called gut-brain axis). But who in these two incredibly complex organ systems is talking to whom is unclear.

The recent research I have cited in this Germ Gems post suggests microglia play a key role in the conversation. The nature of the messages, however, remain unknown as does the role of aberrant messaging in neurodegenerative and neuropsychological disorders.

I must confess that I’ve never cared all that much for solving complex problems. Nonetheless, microglia cells fascinate me. Therefore, I must admit that if I were still doing research, I would be trying to decipher what the “marvelous microglia” and gut microbes are saying to each other. And in the spirit of connectedness, I’d try to connect with one of the Nobel laureates associated with the company Alphabiome to solve the problem. (See, “Alphabiome Launches Groundbreaking AI Technology that Deciphers the Genetic Code of the Microbiome,” PR Newswire, May 6, 2025).