When Systems Collide
Safety Assessment
Rana Samadfam, PhD

When Systems Collide

Trying to understand the bone's newfound connection to immune system and microbiome. It's a marathon not a sprint.

The microbiome is a beehive of activity. The organisms in this mostly bacterial environment outnumber the human cells in our body 10 to 1 and they are constantly on the move. Different species comingle, sharing nutrients and feeding on each other. Apparently, these interactions change quite drastically in diseased states.

Yet until recently, the microbiome was mainly a preoccupation of microbiologists. Not anymore. The microbiome is finally getting the attention it rightfully deserves.

Recent findings are shedding light on the complexity of this forgotten system and its crucial role in homeostasis and immune modulation, and organ development, metabolism and morphogenesis.

Harmful bacteria is now being linked to a wide range of diseases—from periodontitis and rheumatoid arthritis to multiple sclerosis, obesity, diabetes and inflammatory bowel disease (IBD), a poorly understood condition afflicting millions worldwide.

The increased fracture risk and low bone mass associated with IBD raised the potential for "cross talk" between the microbiome and bones, and researchers confirmed this in a mouse model that produces a weak microbiome. Mice injected with low doses of antibiotics—which reduces the microbiome population—demonstrated lower bone density associated with increased bone resorption.

Yet oddly enough, the complete absence of a microbiome did not seem to have the same or worse effect in mice raised in a germ-free environment. In fact, the germ-free mice demonstrated increased  bone density, which was attributed to fewer osteoclasts (which break down bones), and less bone resorption. Scientists associated the decrease in osteoclasts with decreases in osteoclast precursors and CD4+ T cells in the bone marrow.

The number of osteoclast reduced bone resorption were normalized by colonization of germ-free mice with mice raised in a conventional environment. In other words, germ-free mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with mice raised in a conventional environment.

Precisely why mice with immature immune systems and no microbiome might end up with greater bone mass is more complicated, though. The paradoxical results are likely related to the immune system, and the microbiome's influence on maturation (or abnormal maturation) of different cells of the immune system.

Different cells in the immune system directly or indirectly regulate bone density, and an imbalance in this regulation is manifested in diseases such as arthritis, cancer and osteoporosis. Like many other regulations, the cross talk between bone and the immune system is reciprocal, meaning that bone cells (osteoclasts, osteoblasts and osteocytes) also critically control the differentiation and maturation of the immune cells from the inside bone matrix by regulating the hematopoietic stem cell niche. These regulations are complex and involve endocrine (PTH), paracrine (PGE2) and neural (sympathetic- β-adrenergic nerve cell) systems.

The marathon to explore the interactions among different organs/biological systems (including the microbiome, bone and immune system) has only just begun. Clearly there is a long road ahead before a better picture emerges of these interactions. Along the way (or upon completion of this marathon), medicine and drug development will definitely change.

In the meantime, we're going to have to redefine the "target organ" in toxicology studies, and we'll need to be thinking a lot about what the microbiome is doing in our body, what the long term use of antibiotics is doing to the microbiome, and how we can modify the colonies populating the microbiome in order to optimize function of each biological system, including the immune system and bone.

Perhaps the microbiome holds the key to multiple diseases with minimum intervention. In the meantime, the complexity of the cross talk between different biological systems underscores the need to include a more comprehensive assessment of different biological systems in toxicological and efficacy studies.