Review ArticlePhytochemicals affect T helper 17 and T regulatory cells and gut integrity: implications on the gut-bone axis
Introduction
Worldwide, 8.9 million osteoporotic fractures occur each year, which ultimately afflict 1 in 3 women and 1 in 5 men over the age of 50 years [[1], [2], [3], [4]]. Although genetic influences on peak bone mass are one of the major determinants of overall fracture risk, nutrition plays a critical role in optimizing peak bone mass and the metabolic processes that determine bone quality across the lifespan. For example, dietary protein and calcium, primarily from animal products, combined with the endogenous production of vitamin D, are required to achieve optimal peak bone mass during growth and early adulthood, and they can influence the rate at which age-related bone loss occurs in older adults. Moreover, micronutrients such as copper, zinc, and vitamins C and K are required for collagen cross-linking and mineralization of the protein matrix (i.e., osteoid) during the formation phase of bone metabolism [5,6]. Still other nutrients and components of the diet, especially those from plant-based foods, act to mitigate oxidative stress and inflammatory processes within the microenvironment of bone that can dysregulate bone metabolism.
Plant-based foods are well‐known for serving as an excellent source of nondigestible carbohydrates and phytochemicals, both of which have osteoprotective properties. Some nondigestible carbohydrates (e.g., fructooligosaccharides [FOS] and inulin) increase bone mineral density (BMD) in animal models and human studies, a response that has historically been attributed to enhanced intestinal calcium and magnesium absorption elicited by an increase in microbiota-derived short chain fatty acids (SCFAs) causing a downward shift in luminal pH [[7], [8], [9]]. Furthermore, several different classes of phytochemicals with osteoprotective activity, including flavonoids, organosulfur compounds, and phenolic acids, are potent scavengers of free radicals and suppress pro‐inflammatory cytokine production by immune cells, especially dendritic and T helper (Th) 17 cell populations. Elevated proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-17, and tumor necrosis factor (TNF)-α can promote osteoclast activity while simultaneously suppressing the bone forming capacity of osteoblasts [10]. More recently, there has been a growing appreciation for phytochemicals’ ability to activate immunosuppressive cell populations such as the T regulatory (Treg) and Th2 cells with anti-inflammatory activity [11]. In contrast to Th17 cells that secrete IL-17, Tregs secrete cytokines (e.g., IL-10 and -4) that inhibit osteoclast formation and promote osteoblast differentiation by mediating Wnt family member 10b (Wnt10b) signaling [12,13]. It is these functions of phytochemicals on T lymphocytes—especially Th17 and Treg cells—that are of particular interest relative to bone health given their central role in the bone loss associated with menopause, rheumatoid arthritis (RA), and periodontitis [[14], [15], [16]].
The scientific literature supporting the benefits of the phytochemicals from plant-based foods on bone is substantial, but many questions remain as to the specific target(s) of their activity and how these effects are conveyed. In vitro studies have shown that a number of different phytochemicals directly alter osteoblast and osteoclast activity through bone morphogenetic protein (BMP), mitogen-activated protein kinase (MAPK), and receptor activator for nuclear factor κ-B (RANK) and its ligand (RANKL) signaling [[17], [18], [19], [20]]. However, phytochemicals with phenolic ring structures have low aqueous solubility and are relatively poorly absorbed in the gastrointestinal (GI) tract. These phytochemicals’ bioavailability depends in large part on the extent to which they are metabolized by microorganisms residing within the lumen, which leads to a favorable change in the composition of the microbiota (i.e., inhibiting pathogenic bacteria and stimulating the growth of commensal bacteria). Additionally, the production of secondary metabolites from many phytochemicals (e.g., SCFAs) can contribute to health benefits for the host locally within the gut and at distal sites such as the bone [21]. Consequently, in vitro studies focused on the direct effects of the parent compounds on bone cells only offer a partial explanation of the mechanisms through which phytochemicals influence bone metabolism [22]. Many phytochemicals and their secondary metabolites can also directly alter the activation intestinal epithelial and dendritic cells, which produce cytokines and chemokines that regulate CD4+ T cell differentiation and activation. Thus, it stands to reason that the ability of some of these compounds to regulate the differentiation and activation of CD4+ T cells, and T cells’ ability to traffic from the gut to distal lymphatic tissues, including the bone marrow, would provide novel mechanisms by which phytochemicals benefit bone [23]. In this review, we will provide an overview of how the concept of the gut-bone axis has evolved over time, including recent findings highlighting the role of the microbiota and gut mucosal immunity on bone metabolism, and then examine how some of the major classes of phytochemicals that are known to improve bone health affect key targets linking the gut and bone.
Section snippets
Gut-bone axis as a potential target for phytochemicals
The concept that pathologies involving the GI system have negative implications on bone health is not new. A case report published in the late 1940s [24] provided an account of a female patient diagnosed with steatorrhea and osteomalacia; subsequent radiological findings revealed the patient suffered from whole body osteoporosis. In the early 1950s, bone changes characterized as osteomalacia were also described in patients with celiac disease [25]. Initially, these gut-bone relationships were
Flavonoids
Flavonoids are the largest class of phytochemicals, comprised of more than 6000 compounds divided into 6 subgroups (i.e., flavonols, flavones, flavanones, isoflavones, anthocyanins, and flavanols). Found in the leaves of plants, fruits, vegetables, and legumes, some of the best dietary sources include teas, onions and scallions, citrus fruits, soy and cocoa products, and berries and fruits that are red, blue, and purple in color. These compounds are among the earliest and most extensively
Organosulfur compounds
Organosulfur compounds, including allicin, sulforaphane, and γ-glutamyl cysteine, are found most abundantly in vegetables belonging to the allium (e.g., garlic and onion) and brassica or cruciferous (e.g., cabbage, cauliflower, and broccoli) families. Much of the research on the health benefits of these compounds has been in the areas of cancer and cardiovascular disease prevention because of their effects on cell cycle arrest, apoptosis, and the inhibition of cholesterol synthesis [[130], [131]
Phenolic acids
Phenolic acids are naturally occurring plant metabolites containing 2 distinguishing carbon frameworks: the hydroxycinnamic and hydroxybenzoic structures [159]. Hydroxycinnamic acids in plants include p-coumaric, caffeic, chlorogenic, ferulic, sinapic, and quinic acids, whereas hydroxybenzoic acids include p-hydroxybenzoic, protocatechuic, vanillic, ellagic, and gallic acids. These compounds are abundant in the skin and seeds of fruits, making the content in dried fruits (e.g., blueberries,
Oligosaccharides
Another widely studied class of plant-based compounds that exert positive effects on bone is nondigestible oligosaccharides. Oligosaccharides from soluble corn fiber, FOS, and inulin have been reported to improve bone and calcium homeostasis [[184], [185], [186]]. FOS and inulin can be consumed as supplements or through dietary sources such as onion, chicory root, banana, garlic, and asparagus. However, it is worth noting that several of the fruits rich in flavonoids and phenolic acids (e.g.,
Other phytochemicals
From a review of the literature, it apparent that there are other classes of dietary phytochemicals reported to have favorable effects on one or more aspects of the gut-bone axis. These include the carotenoids, omega-3 fatty acids, and lignans. Because of a lack of evidence or inconsistencies in the literature, there is a less compelling case for these phytochemicals to act via immune T cell–modulating effects on the gut–bone axis at this time. However, it is important that these phytochemicals
Future research
Initially fueled by discoveries from studies using germ-free mice and probiotics, the concept that the gut microbiome and gut-associated lymphoid tissue could serve as novel targets for the prevention of bone loss has emerged. These discoveries have revealed previously unappreciated links between microbiota-derived metabolites, gut barrier function, mucosal immunity, and bone metabolism. As a result, a great deal of interest in the gut-bone axis has been generated, which has significant
Acknowledgments
This work was funded in part by the Oklahoma Agricultural Experiment Station (OKL03105). The authors have no conflicts of interest to disclose.
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