Osteoporosis and your GUT
It was interesting to me to find that the human gut microbiome plays a critical role in the regulation of important biological processes and the mechanisms underlying bone metabolism. As we know the human gut microbiota, the collection of 10 trillion bacteria that colonize the GI tract, play a very important role in human biological processes. It is estimated that over 1000 different microbial species exist in the human gut, accounting for over 450 times the number of genes as the human genome (Chen, Greenbaum, Shen, & Deng, 2017). Accumulating evidence has demonstrated that the gut microbiota is associated with physiological bone metabolism and a range of inﬂammatory or metabolic bone diseases (Xu et al., 2017). A recent study by Chen et al (2017), was able to comprehensively summarize the relationship between the gut microbiota and bone metabolism by describing the regulatory effects of the microbiome on various biological processes. These processes include nutrient absorption and the intestinal mucosal barrier, immune system functionality, the gut–brain axis, and excretion of functional metabolites. In another prospective cohort study, Di Stefano et al. found that bone loss at the site of the lumbar spine and femoral neck was associated with intestinal bacterial overgrowth, indicating overgrowth of the gut microbiota may be an important risk factor in osteopenia/osteoporosis (Chen et al., 2017). Other studies validated these findings which observed that individuals with intestinal bacterial overgrowth had significantly lower bone mineral density (BMD) in the lumbar spine and femoral neck.
Bacterial overgrowth is associated with malabsorption, which can influence the metabolism of various elements needed for bone processes such as calcium, B vitamins and Vitamin K (Chen et al., 2017). Gut microbiota can affect the absorption of skeletal development-related nutrients such as calcium and vitamin D (Xu et al., 2017). Since vitamin D can facilitate calcium absorption, either calcium deficiency or vitamin D deficiency can induce osteoporosis. ). Moreover, various microorganisms play an essential role in the synthesis of vitamin B and vitamin K as well as the metabolism of bile acids, all critical for the regulation of bone health. The effects of probiotics such as Lactobacillus and Bifidobacteria, have been studied in both animal and human models. Interestingly, specific probiotic bacteria such as L. salivarius has been shown to stimulate calcium uptake by enterocytes (Xu et al., 2017). Lactobacillus reuteri was shown to significantly decrease osteoclastogenesis and bone resorption, preventing bone loss in a mouse model. Similar results have also been observed for other Lactobacillus strains, such as Lactobacillus rhamnosus and Lactobacillus paracasei, among others (Chen et al., 2017). An elevated concentration of the probiotics L. reuteri and Bifidobacterium longum in the gut may increase BMD by promoting mineral (calcium, magnesium, and phosphate) absorption. It has also been shown that the composition of the gut microbiota can influence the pH level of the gut, an important factor for nutrient absorption, especially calcium. The microbiota can also aid in the breakdown of macromolecules, another component of nutrient absorption. However, it should be mentioned that the host diet also influences nutrient absorption. “Therefore, it is crucial to maintain a balanced diet and adequate carbohydrate/protein ratio because dietary intake can lead to meaningful alterations in the gut microbiota, thereby influencing bone metabolic processes” (Chen et al., 2017)
Prebiotics also play a role in the process through direct effects on proteins associated with Ca absorption. For example, oligosaccharides (NDO), the dietary prebiotics containing fructooligosaccharides (FOS) and inulin, signiﬁcantly facilitated intestinal calcium absorption and increased skeletal calcium content in growing and adult rats. As the fermentation substrates of gut microbiota, prebiotics affect bone metabolism by producing a variety of beneﬁcial metabolites, such as short-chain fatty acids (SCFA). In addition, both probiotics and prebiotics can influence intestinal epithelium permeability by regulating the tight junction protein expression and distribution, which can underlie the mechanism of prebiotic effects on paracellular Ca transport. In addition, prebiotics can also favorably alter intestinal microenvironment, indirectly modulating bone metabolism. “SCFA generated from prebiotics could lower the intestinal lumen pH and consequently inhibit the formation of calcium complexes, such as calcium phosphates, leading to increased calcium absorption”(Xu et al., 2017). SCFA’s produced but the gut microbiota can also play an important role in bone formation and bone mineralization by influencing the Runx and osteoprotegerin signaling pathways (Chen et al., 2017). Additional studies have discovered that SCFA’s also might indirectly affect BMD by significantly influencing the function of host endocrine factors that are related to bone metabolism, such as peptide YY and glucagon-like peptide 1 (Chen et al., 2017). (“Peptide YY is a gastrointestinal hormone secreted from the endocrine L cells and has been shown to be negatively associated with total body and hip BMD in premenopausal women. Glucagon-like peptide 1, an amino acid hormone that is also secreted from the endocrine L cells, has been shown to act as a regulator of bone metabolism by altering the balance between osteoblast and adipocyte differentiation from bone mesenchymal stem cells”) (Chen et al., 2017)
Other mechanisms associated with regulation of bone metabolism include actions on the immune system and endocrine system. For example, intestinal segmented ﬁlamentous bacteria in mice were shown to promote the production of IL-17 and IFN-γ (Interferon-gamma), both of which played critical roles in the formation of osteoclasts and osteoblasts (Xu et al., 2017). TNF-α is known to stimulate the receptor activator for nuclear factor κB ligand signaling pathway, which may promote bone loss, as well as suppress the differentiation of mesenchymal stem cells into osteoblasts, inhibiting bone formation (Chen et al., 2017). Other studies demonstrate that altered immune status, such as decreased pro-inflammatory cytokines or CD4 T cells, may account for higher bone mass. The gut microbiota also can influence intestinal homeostasis that regulate the immune system. If homeostasis is disturbed, intestinal pathogens intrude through the barrier and can provoke an immune response that may promote bone resorption and continual bone loss.
Hormone are also regarded as an important regulator of bone metabolism. Growth hormone, IGF-1, for example, can promote the differentiation and growth of bone cells, and is involved in the regulation of bone metabolism and growth (Xu et al., 2017). Other hormones such as estrogen and androgens play roles in turnover of bone metabolism. In addition, estrogen levels also regulate and maintain microbial diversity. In fact, in postmenopausal women, the absence of estrogen could alter intestinal microbial composition and structure, leading to decreased microbial diversity and facilitating pathogen reproduction and consequent immune response (Xu et al., 2017). It has been found that estrogen deficiency can reflect a reduction in Firmicutes bacteria that are needed to sustain the immune system. Also, estrogen receptors on the intestinal epithelium are involved in maintaining proteins that are involved in tight junction integrity. When the junction is weak, antigens from intestinal pathogens can initiate an inflammatory cascade across the epithelial barrier, leading to production of pro-inflammatory cytokines such as TNF-a and IFN-gamma. The presence of the inflammatory cytokines can downregulate the tight junction proteins as well, leading to further exacerbate leaky gut. “Hence, estrogen deﬁciency increases intestinal epithelial permeability, facilitating the intrusion of intestinal pathogens and provoking immune reactions, and ultimately resulting in increased osteoclastic bone resorption and continual bone loss” (Xu et al., 2017). Both adequate estrogen levels and intestinal microbial diversity are needed to maintain immune homeostasis.
Here is a good image summarizing the key points discussed
Chen, Y. C., Greenbaum, J., Shen, H., & Deng, H. W. (2017). Association Between Gut Microbiota and Bone Health: Potential Mechanisms and Prospective. J Clin Endocrinol Metab, 102(10), 3635-3646. doi:10.1210/jc.2017-00513
Xu, X., Jia, X., Mo, L., Liu, C., Zheng, L., Yuan, Q., & Zhou, X. (2017). Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res, 5, 17046. doi:10.1038/boneres.2017.46