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Antibiotics through Effects on the Microbiota-Gut-Brain Axis and Inflammatory Monocytes May Reshape Brain Hippocampal Neurogenesis

Antibiotics Gut-Brain Axis Hippocampal Neurogenesis
Antibiotics -microbiota – gut-brain-axis

A new Cell Reports study indicates that ‘inflammatory’ monocytes may represent the missing ‘pathogenic link’ between the antibiotics’ effects on gut microbiota, and the subsequent changes in the brain hippocampal neurogenesis and plasticity.

Antibiotics are applied by millions of people and billions of farm animals worldwide every day. Although their use has saved countless lives, antibiotics also can negatively impact the physiology and psychology of the patients.

Some of these changes have been ascribed to the impact of antibiotics on the gut-brain axis, as the microbiota colonizing the intestinal lumen are thought to affect their host’s vegetative and cognitive functions. In fact, recent research suggests that antibiotics may exert some of their unsolicited side effects through effects on the gut-brain axis.

Soon after birth, the newborn organism is rapidly populated with the gut microbiota. This process contributes to the developmental programming of epithelial barrier function, gut homeostasis and the immune system. It appears that gut microbes are able to reshape the maturation and homeostasis of the brain immune cells such as microglia. Moreover, gut microbiota regulates the immune response in other organ systems and, perhaps, contributes in some cases to the pathogenesis of rheumatoid arthritis.

Importantly, new evidences indicates that gut microbiota also modulates brain development and function, and the gut microbial composition may direct or even trigger immune responses in the brain.

The lifelong production of new neurons, or the adult neurogenesis that takes place in the subgranular zone of the dentate gyrus in the hippocampus has been linked to memory resolution, and its dysfunction to mental disorders, such as major depression, posttraumatic stress disorder and Alzheimer’s disease.

It is unclear whether the gut microbiota can shape the maintenance of the peripheral immune system in the steady state. The selective gateway for leukocyte entry to the central nervous system is the choroid plexus, which mediates important neuro-immunological processes also under steady-state condition.

In the Cell Reports study the authors focused on the potential of monocytes to serve as a messenger between gut and brain and to shape adult hippocampal neurogenesis. Monocytes are a fundamental leukocyte subset of the innate immune system, and they contribute to the immune surveillance and host defense upon infections and inflammation. How monocytes are affected by antibiotics-induced dysbiosis of the gut flora and subsequently shape neurogenesis was the focus of this study.

In the Cell Reports study Luisa Möhle and colleagues from the Institute of Medical Microbiology, University of Magdeburg, Magdeburg, Germany report that treatment of female C57BL/6 wild-type mice with broad-spectrum antibiotics for 7 weeks resulted in decreased adult hippocampal neurogenesis, whereas the use of probiotics restored neurogenesis.

When analyzing the infiltrating immune cell populations in the brain, the authors found the proportions of Ly6Chi monocytes (the ‘inflammatory monocyte subpopulation’ in mice, equivalent to human classic CD14++ CD16cells) had significantly decreased, and this was also evident in the bone marrow and the blood, one week after antibiotics treatment. Elimination of Ly6Chi monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6Chi monocytes rescued neurogenesis after antibiotic treatment.

In summary, the study demonstrates that treatment with antibiotics results in a long-lasting impairment of neurogenesis that can be restored by probiotics and voluntary exercise. Cells of the innate immune system, in particular Ly6Chi monocytes, are critical for the restorative effect.

Thus, the authors suggest that Ly6Chi monocytes are “critical for the restorative effect” and serve as a link or the ‘messenger’ within the gut-immune-brain axis that may play a critical role in the modulation of brain neurogenesis and plasticity, and/or cognitive function.

This study may also raise the question as to whether the frequent use of antibiotics can be linked to this mechanism, and the recent ‘epidemics’ of certain mental disorders, for example Alzheimer’s disease.

Source: Cell Rep, 2016; 15:1945-56. doi: 10.1016/j.celrep.2016.04.074. Epub 2016 May 19.
Read More: Cell Reports