Identified an immune cellular link between the gut microbiota and the brain

For a while, new evidence has been accumulating linking the gut microbiota to brain function. A new paper published recently in Cell Reports¹, shows that the intermediary is a type of white blood cell, evidencing as well the relationship between the brain and the immune system.

While the crosstalk between the peripheral immune system and the central nervous system has been clearly established, it is still unknown if the gut microbiota can affect the peripheral immune system, under normal conditions since they have been shown to modulate immune responses during infection, inflammation, and autoimmunity. Monocytes are a fundamental leukocyte subset of the innate immune system and contribute to the immune surveillance and host defense upon infections and inflammation. In this work, the authors wanted to investigate the role of monocytes as an effector linking gut flora imbalance to hippocampal neurogenesis. As a countermeasure, in this study, the authors included voluntary exercise and probiotics and examined the effects on neurogenesis and brain function.

After a 7-week antibiotic treatment, the quantification of neuronal proliferation in the hippocampus in treated animals showed a significant decrease in neurogenesis. During 10 days of treatment, animals could exercise and a subgroup of treated animals received a fecal transplant to repair the damage to the gut flora produced by the antibiotic treatment. The analysis of the different animal subgroups showed that, as expected, exercise promoted neurogenesis but that this effect was reduced in animals with a damaged flora, while in those which received a fecal transplant the extent of the benefit over hippocampal neurogenesis was as broad as in control animals. On the other hand, running did not have an effect on the gut flora, the effects were restricted to adult neurogenesis, without having an impact on gut microbial repopulation.

To be able to discern whether restoration of gut flora could alone restore neurogenesis, after antibiotic treatment some animals received a fecal transplant, which had little effect on restoring neurogenesis while others received probiotics. In this group of animals, neurogenesis levels were restored to baseline levels. In control animals, however, probiotics did not increase further neurogenesis rates. Moreover, analysis of the gut flora of probiotic-treated mice showed that the recolonization after antibiotic treatment was more extensive than with the fecal transplant.

Impairment of adult neurogenesis in the dentate gyrus has been shown to affect spatial and memory recognition in rodents. In a novel object recognition task, probiotics and an exercise regimen were able to rescue the impaired performance of the antibiotic-treated mice, but they do not enhance the baseline control level.

Finally, to be able to determine if innate immune cells are the link between the brain, gut and exercise, the authors of the work analyzed the immune populations from a brain hemisphere of antibiotic-treated mice and found that the proportions of Ly6C^hi monocytes had significantly decreased compared to the naive SPF group, and that this effect was maintained over a long time, even after the end of the antibiotic treatment. In a next step they assessed the effects of fecal transplant, probiotics and exercise on leukocyte filtration to the brain finding that while a fecal transplant did not affect the decreased numbers of Ly6C^hi monocytes after antibiotic treatment, both probiotics and exercise could reverse the low monocyte numbers produced by the antibiotic treatment. To test the link between this immune cell type and neurogenesis, they depleted Ly6C^hi monocytes and measured neurogenesis finding decreased rates in the absence of these immune cells. To strengthen the evidence supporting the involvement of Ly6C^hi monocytes in neurogenesis, they injected these cells into antibiotic-treated mice and measured neurogenesis, finding an increase in the formation of new neuronal precursors. Moreover, co-culture of Ly6C^hi monocytes with primary neuronal precursors showed that their role in the facilitation of neurogenesis could be mediated by diffusible factors.

In summary, the evidence from this work identifies a link among the gut microbiota, the immune system, and the brain, and offers a rational ground for the recommendation of probiotics and exercise to restore immune homeostasis and brain plasticity after a prolonged antibiotics treatment.