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The trillions of bacteria that inhabit our gastrointestinal tract play an intricate and increasingly appreciated role in human health. Deemed by some as the “forgotten organ” (1), new connections between these microorganisms and our physiology are being discovered all the time.
In recent months, I’ve written extensively about these connections. Check out my other blog articles to learn more about the influence of microbes on your health:
Next up in the series, and yet another reason to protect your gut microbes: bone health! Before we dive in, let’s review a few fundamentals of bone physiology and how we determine bone health.
Bone health: The basics
Bone is not a static structure and is constantly being remodeled. Mature bone tissue is regularly removed from the skeleton by cells called osteoclasts (a process called resorption), and new bone tissue is formed by cells called osteoblasts (a process called ossification). Remodeling helps to reshape bone following fractures and also responds to mechanical loads like exercise (2). An imbalance in bone resorption and formation can result in bone diseases like osteoporosis and arthritis (3).
There are numerous measures of bone health. In humans, researchers often use a DEXA scan to determine bone mineral density. In rodent models, scientists can also measure bone mass, length, volume, and mineral composition to get a more complete assessment of bone structure. In general, higher bone mineral density is associated with reduced risk of fracture and bone disease. However, increased bone mineral density, bone mass, and bone length do not always suggest better bone health (4).
The association between gut microbes and bone
One of the key ways that researchers study the effects of the microbiota on an organ system is using mice that don’t have one at all. Called “germ-free” (GF), these mice are born and raised in sterile incubators. Studies of skeletal health in GF mice have found mixed results. In one type of mice, GF mice had reduced bone mass compared with conventionally raised animals, which have a full consortium of microbes (5). In another type of mouse, the GF environment resulted in increased bone mass, while the conventional environment increased measures of bone turnover (6). Although it is difficult to reconcile these contradictory findings, the key feature of both studies was that the mere presence or absence of a microbiota significantly changed the structure of the bone.
Antibiotic models provide further evidence for an association between gut microbes and bone, and the results are much more translational to humans. One study found that exposing mice to subtherapeutic doses of antibiotics at weaning resulted in a significant increase in bone mineral density after three weeks (7). Another study found that animals treated with tylosin, amoxicillin, or a mixture of both had larger bones and a higher bone mineral content than control mice (8). Low-dose antibiotics have long been used in the agricultural industry in animal feed for this very reason; they influence skeletal growth and make for larger, more profitable livestock.
Bone disease is partly heritable and associated with GI disorders
All that nitty-gritty science in animal models is great, but what about humans? Is there evidence of a gut–bone connection in humans? Epidemiological evidence and observational studies suggest that there is.
In adult humans, bone mineral density is 50 to 80 percent heritable (9). For quite some time, heritable traits were thought to be only passed on from parent to offspring through DNA. We now know that vertical transmission of microbes occurs at birth—as a baby passes through the mother’s birth canal, he or she acquires crucial microbes that shape the composition of their gut microbiota (5). It’s possible that in addition to the heritable traits encoded by our own genetics, additional determinants of our bone health are acquired based on our microbial inheritance.
Bone complications are often seen in individuals with GI disorders. Patients with inflammatory bowel disease (IBD) have an increased risk of osteopenia, osteoporosis, and bone fracture. This has been attributed to malabsorption of calcium, reduced blood levels of vitamin D and K, or bone loss after glucocorticoid treatment (10). Gut and systemic inflammation are also associated with increased production of cytokines that are key contributors to bone loss (11). We’ll discuss this in detail in the next two sections.
Leaky gut and bone health
If you’re an avid reader of my blog, you might be thinking: leaky gut, again? Yep. When the intestinal barrier becomes compromised, microbes or parts of microbes can translocate from the gut lumen to the bloodstream. Your immune system recognizes these bacterial components in the bloodstream and launches a systemic immune response. Indeed, studies have found a strong association between microbial translocation and joint pathologies like rheumatoid arthritis (12, 13).
The most common of the bacterial components include peptidoglycan, lipopolysaccharide, and flagellin. These stimulate various “toll-like” receptors (TLRs) on innate immune cells: peptidoglycan is the primary component of bacterial cell walls and stimulates TLR2; lipopolysaccharide is located in the outer membrane of gram-negative bacteria and stimulates TLR4; and flagellin is the main protein that makes up the filamentous “tail” of bacteria and stimulates TLR5 (14, 15, 16).
Stimulation of innate immune receptors has effects throughout the body, which is why a leaky gut can manifest as a number of different chronic health conditions. In regard to bone health, stimulation of innate immune cells has a direct effect on bone remodeling.
Microbes shape the systemic and mucosal immune system to influence bone remodeling
The microbiota plays a key role in the initial development of the immune system as a child and the maintenance of proper immune responses later in life. This represents yet another pathway by which microbes are connected to bone health, as the immune system is intricately involved in the regulation of bone metabolism and physiology.
Immune cells that are activated by microbes in the gut can migrate to bone and directly regulate bone remodeling via osteoclast-inducing factor, RANKL, and other bone-active molecules (17). Increased levels of activated innate immune cells have been shown to increase expression of the signaling molecule TNFα in bone marrow. TNFα stimulates stems cells in the bone marrow to differentiate into osteoclasts. This tips the normal balance of bone resorption and formation, resulting in higher levels of bone breakdown and lower bone density (18, 19)
Gut microbes regulate the availability of nutrients important for bone health
Healthy bones require a multitude of nutrients, including calcium, phosphorus, vitamin D, vitamin K2, vitamin A, and magnesium. Recent research has also suggested a role of several B vitamins and even vitamins C and E in bone health (20). Animals raised on a nutrient-depleted diet have reduced bone length (21).
Disruption of the microbiota can significantly alter nutrient absorption. Gut dysbiosis has been shown to increase the number of calories absorbed from food (22, 23). Yet it can also result in inflammation of the gut epithelium, the location of nutrient transporters that allow for the absorption of vitamins and minerals. This paradoxically results in individuals that are both overweight and malnourished (24).
In addition to influencing absorption and metabolism, microbes themselves also synthesize some of our vitamins. These include thiamin (B1), niacin (B3), pantothenic acid (B5), biotin (B7), folate, tetrahydrofolate, pyridoxal phosphate, and vitamin K2 (25, 26).
Protect your microbes to support healthy bones
While there are certainly many factors that influence bone health, including genetics, diet, mechanical loading, and other environmental factors, gut health seems to play a crucial role. Below I have compiled a list of ways to support a healthy gut flora and how each might improve bone health.
- Probiotics. Eat your fermented foods! Adult male mice treated with Lactobacilli for four weeks showed increased femoral bone volume, increased bone formation, and a reduction in circulating pro-inflammatory cytokine expression (27). Lactobacilli were also shown to prevent bone loss in a model of type 1 diabetes (28). You can find Lactobacilli in sauerkraut, kimchi, and other fermented vegetables.
- Prebiotics. Prebiotic fibers in dandelion greens, plantains, and other foods promote the growth of beneficial bacteria. Prebiotics have been shown to have a beneficial role in mineral metabolism, enhancing calcium absorption in both rodents and humans (29, 30). This enhanced absorption translates to increased bone density (31). While different fibers have different effects, a study testing eight different prebiotic fibers in young rats showed that most prebiotic fibers had significant effects on bone density measures (32).
- Bone broth. Bone broth supports a healthy gut lining and a healthy microbial community. Homemade broth also provides all of the necessary vitamins and minerals for building bone, as well as the proteins collagen and glucosamine for healthy joints and cartilage.
Now I’d love to hear your thoughts. Did you know about the gut–bone connection? Do you or someone you know suffer from osteoarthritis, osteoporosis, or another bone disorder? Let us know in the comments!