The discovery of penicillin in 1928 by Alexander Fleming was one of the greatest revolutions in the history of medicine. Since then, multiple molecules with antibiotic properties have been identified and the use of antibiotics has become generalized. But even though they can certainly save lives, antibiotics can also have serious adverse effects.

Most of those side-effects are widely known: allergic reactions, fever, nausea, or diarrhea, for example, the latter resulting from a disruption of the bacterial composition of the intestinal flora. The gut microbiota is an obvious secondary target of antibiotics, and the gut microbiota has been increasingly recognized as an important regulator of brain functions through the gut-brain axis, having been associated with the development of a number of neurological and mental diseases.

Therefore, it is possible that antibiotics, by unbalancing the gut microbiota, may also have an indirect impact on brain function, since a link between neurodegenerative diseases, neuropsychiatric disorders, neuroinflammation, and gut microbiota dysregulation has been established.

Adult neurogenesis in the hippocampus is also a key process for a regular function of the brain. It has an essential role in brain plasticity and cognitive function, particularly in memory and learning. The hippocampus is involved in many neurological and mental diseases, with decreased neurogenesis being a key element in many pathologies. Decreases in hippocampal neurogenesis can be induced by such factors as social isolation or chronic stress, for example, leading to mental disorders or neurodegenerative diseases. An improvement in neurogenesis, on the other hand, can be achieved through physical or cognitive activity.

But is there a connection between these processes? Can the gut microbiota influence neurogenesis in the hippocampus? If so, can antibiotics also affect neurogenesis though their effects on the gut microbiota? The answer to these questions is what a study recently published in Cell Reports set out to find.

Antibiotics, the gut microbiota and the brain

The gut microbiota has an important influence on the immune system and in our body’s response to infection or inflammation. This effect is not restricted to the gut – immune responses in other organs, namely in the brain, can also be regulated by the gut microbiota. Using mice treated with antibiotics, the authors of this work aimed to determine the impact of gut flora dysregulation on hippocampal neurogenesis. Results showed that antibiotic treatment could indeed decrease neurogenesis in the hippocampus, leading to deficits in memory retention.

Aiming to determine whether those deficits were reversible, and since exercise is known to potentiate neurogenesis, the effects of exercise on mice treated with antibiotics were evaluated. Furthermore, and given that the administration of probiotics can balance gut microbiota composition, treatment with probiotics was also tested.

Interestingly, when the normal content of the gut flora was restored, the deficits in neurogenesis were not completely reversed unless the mice also engaged in physical activity in a running wheel or received probiotics. Since the restoration of a normal intestinal flora per se was unable to restore neurogenesis levels, it is most likely not exclusively the lack of gut flora that determines neurogenesis levels; additional factors may also come into play. But the fact that probiotics can have a similar effect to that of exercise is a clear indication of the importance of the gut microbiota in the modulation of neurogenesis.

This study also investigated the potential role of Ly6Chi monocytes, a type of cell of the immune system, as messengers between the gut and the brain, as well as the effect of antibiotic-induced dysregulation of the gut microbiota on these cells. Antibiotics did indeed decrease the levels of monocytes. Furthermore, the elimination of these cells decreased neurogenesis. But the replenishment of monocytes to these mice was able to restore neurogenesis after antibiotic treatment. Importantly, both exercise and probiotic administration led to an increase in Ly6Chi monocytes in the brain, indicating that these cells may serve as a communication system between the gut and the brain, contributing to the stimulation of neurogenesis induced by probiotics in antibiotic-treated mice.

Nevertheless, these effects in mice treated with antibiotics can be driven by other mechanisms besides the levels of Ly6Chi monocytes. Neuronal progenitor cells may receive additional signals involving other mediators or other types of cells, including glial cells or neurons. Still, data indicates that Ly6Chi may have a crucial involvement in hippocampal neurogenesis. This establishes a new messaging system between the gut and the brain through the immune system, and again underlines the importance of the gut in brain function.

This study also highlights the detrimental effects that antibiotics can have on the brain. On the bright side, probiotic supplementation and exercise can counteract the devastating side effects of prolonged antibiotic treatment, which is actually good news.

References

Bercik P, & Collins SM (2014). The effects of inflammation, infection and antibiotics on the microbiota-gut-brain axis. Advances in experimental medicine and biology, 817, 279-89 PMID: 24997039

Deng, W., Aimone, J., & Gage, F. (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature Reviews Neuroscience, 11 (5), 339-350 DOI: 10.1038/nrn2822

Möhle, L., Mattei, D., Heimesaat, M., Bereswill, S., Fischer, A., Alutis, M., French, T., Hambardzumyan, D., Matzinger, P., Dunay, I., & Wolf, S. (2016). Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis Cell Reports, 15 (9), 1945-1956 DOI: 10.1016/j.celrep.2016.04.074

Petra, A., Panagiotidou, S., Hatziagelaki, E., Stewart, J., Conti, P., & Theoharides, T. (2015). Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation Clinical Therapeutics, 37 (5), 984-995 DOI: 10.1016/j.clinthera.2015.04.002

Schwartz, M., Kipnis, J., Rivest, S., & Prat, A. (2013). How Do Immune Cells Support and Shape the Brain in Health, Disease, and Aging? Journal of Neuroscience, 33 (45), 17587-17596 DOI: 10.1523/JNEUROSCI.3241-13.2013

Spalding, K., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H., Boström, E., Westerlund, I., Vial, C., Buchholz, B., Possnert, G., Mash, D., Druid, H., & Frisén, J. (2013). Dynamics of Hippocampal Neurogenesis in Adult Humans Cell, 153 (6), 1219-1227 DOI: 10.1016/j.cell.2013.05.002

van Praag, H. (2008). Neurogenesis and Exercise: Past and Future Directions NeuroMolecular Medicine, 10 (2), 128-140 DOI: 10.1007/s12017-008-8028-z

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