The gut microbiome and immune systems influence bone growth after mild TBI

New research from the  Monash Trauma group indicates that weakening of the gut microbiome with antibiotic treatment and repetitive mild traumatic brain injury each individually stunted bone growth and volume.

by Ms Kerrui Wong, Ms Marissa Sgro (pictured, left to right) and Dr Loretta Piccenna

Adolescence is a sensitive period for bone development. Changes during this critical period may lead to significant long-term complications, for example osteopenia and osteoporosis later in life. New research from the Monash Trauma group in the Department of Neuroscience at the Central Clinical School indicates that weakening of the gut microbiome with antibiotic treatment and repetitive mild traumatic brain injury each individually stunted bone growth and volume, and did so in a sex-dependent manner during adolescence.

The gut-brain-immune axis is an important physiological pathway enabling communication between the nerve cells of the brain, the gut bacteria or microbes and immune cells of the body. The gut microbiome maintains a balance and appropriate function of the gastrointestinal tract (intestinal homeostasis), together with the immune and nervous system to regulate the inflammatory response.

Environmental and external insults can change these normal conditions and influence other systems within the human body, for instance bone growth, development and remodelling, in particular in the long-term. Mild and repetitive mild traumatic brain injuries are one type of external insult that can trigger an inflammatory response that alters the gut-brain-immune axis. Further, several preclinical and clinical research models have demonstrated that independently mild traumatic brain injury and dysregulation of the gut microbiome disrupt both bone formation and bone resorption. The Monash Trauma group has previously shown bone loss in an animal model of moderate traumatic brain injury.

Mild and repetitive traumatic brain injury occur in adolescents due to falls and sports-related activities and are more common than in any other times during life. Bone mass develops and reaches its peak in adolescence. The combination of a disruption to the gut microbiome and repetitive mild traumatic brain injury on bone growth during adolescence remains unknown. By understanding the combined effect of these insults to bone development during adolescence, it may help health professionals to identify adolescents who may have an increased tendency for deleterious effects on bone health and long-term bone complications.

In order to study gut microbiome dysregulation, lead authors Ms Kerrui Wong and Ms Marissa Sgro, PhD students from the Monash Trauma Group, used an antibiotic cocktail given to an adolescent animal model. They also used an adolescent animal model of repetitive mild traumatic brain injury.

“We learnt many things from doing this study and uncovered some things that we do not really know why they happened. For example, when we looked at the gut microbiome depletion and repetitive mild traumatic brain injury both on their own, they reduced bone growth but when we combined the two different conditions together there was no further effect. We also found that the combination reduced bone growth in the male adolescent model but not in the female indicating a sexually dimorphic effect,” commented Kerrui.

“Given the large number of adolescents who experience repeated mild traumatic brain injuries and microbiome dysbiosis, we feel that these findings may have important implications for clinical practice regarding bone development, and therefore require further investigation to prevent long-term complications in adulthood,” commented Marissa.

Senior author of the study, Professor Richelle Mychasiuk, said that their focus now is to explore the mechanisms underlying the changes they observed, specifically inflammation (systemic and within the brain), the role of short chain fatty acids and sex hormones, regulation of the growth hormone/insulin growth factor-1 axis, and nutrient absorption within the gut, to find targets for treatment.

The group hope that the findings from this study, can contribute to further studies looking at how diet may be a potential therapeutic avenue to improve bone development and health following mild traumatic brain injury in adolescents.

“Given that dietary manipulations, such as supplementation with specific bacterial strains, probiotics, and/or prebiotics, have been shown to modulate the gut microbiota and restore microbiome dysbiosis, diet or probiotic administration may be an easy therapeutic avenue to improve bone health following repeated mild traumatic brain injury in adolescence and improve their bone density throughout the lifespan.”

Reference

Wong, K. R., Sgro, M., Yamakawa, G. R., Li, C., McDonald, S. J., Sun, M., ... & Mychasiuk, R. (2021). Gut microbiome depletion and repetitive mild traumatic brain injury differentially modify bone development in male and female adolescent rats. Bone Reports, 15, 101123 https://doi.org/10.1016/j.bonr.2021.101123.