19/03/2022
Modulating the Gut-Immune-Bone Axis as Therapeutic & Preventative Strategies Against Immunoporosis: an expansive and comprehensive review of current and historic literature.
“…Discoveries in the last few years have emphasized the existence of an enormous breadth of communication between bone and the immune system in maintaining skeletal homeostasis…”
“…Originally, the discovery of various factors was assigned to the immune system viz. interleukin (IL)-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa B ligand (RANKL), nuclear factor of activated T cells (NFATc1), etc., but now these factors have also been shown to have a significant impact on osteoblasts (OBs) and osteoclasts (OCs) biology…”
“… These discoveries led to an alteration in the approach for the treatment of several bone pathologies including osteoporosis[,]… an inflammatory bone anomaly affecting more than 500 million people globally…”
“…In 2018, to highlight the importance of the immune system in the pathophysiology of osteoporosis, our group coined the term ‘immunoporosis’…”
Building upon this…
“…In the present review, we exhaustively revisit the characteristics, mechanism of action, and function of both innate and adaptive immune cells with the goal of understanding the potential of immune cells in osteoporosis…”
‘We specifically highlight and discuss the emerging Immunoporotic role of the gut microbiota (GM) for the treatment and management of osteoporosis, and discuss whether an immune cell-based strategy to treat and manage osteoporosis is feasible and relevant in clinical settings.’
“…Multiple parameters regulate the development of the immune system, among them Gut-Microbiota (GM) plays a vital role in the development of the host’s innate and adaptive immune system…”
“…[Indeed,] our group, along with others, reported that modification of the GM, via probiotics (a viable micro-organism), could be a potential therapeutic strategy in regulating bone health, ie, Osteomicrobiology…”
“…[For example,] among various immune cells, the intricate balance between Tregs and Th17 plays a vital role in bone homeostasis[, and our group recently]… reported that probiotics administration viz. Lactobacillus acidophilus, Bacillus clausii and Lactobacillus rhamnosus attenuates inflammatory bone loss in an osteoporotic mice model by modulating the Th17/Tregs cell balance…”
“…[Moreover,] under physiological conditions, it has been observed that differentiation of naïve T cells into Tregs and Th17 is further regulated by Regulatory B Cells (Bregs)…”
“…In both mice and human studies, it has been observed that the immunosuppressive phenotype of Bregs is controlled by the expression of the AhR transcription factor[,]… a ligand stimulated transcription factor that perceive signals from microbial, dietary, and metabolic stimuli that binds to the IL10 locus in Bregs…”
“…In search of identifying a suitable stimulus apart from cytokine stimuli that activate AhR in B cells[, researchers have recently]… demonstrated that microbial derived short chain fatty acid (SCFA) viz. butyrate supports Bregs functionality by amplifying the activation of AhR and by reprogramming the differentiation of B cells towards Bregs…”
“…Notably, butyrate promotes Bregs differentiation via enhancing the production of a tryptophan derived metabolite viz. 5-hydroxyindole-3-acetic acid (5-HIAA)…”
“…Markedly, other SCFAs such as acetate and pentanoate also enhanced IL-10 production by B cells… in humans via enhancing the production of acetyl coenzyme A, ultimately fueling the tricarboxylic acid (TCA) cycle for energy metabolism.
“…In addition, a fiber rich diet intervention can also enhance acetate levels and thus B10 Breg differentiation in human peripheral blood mononuclear cells (PBMCs)…”
“… Pentanoate potentiate IL-10 production in CpG stimulated mice B cells by enhancing glycolysis and mTOR activation in B cells…”
“…Activation of Bregs via these metabolites further enhances the downstream differentiation of Tregs along with inhibition of Th17 cells…”
“…These studies along with our own work clearly highlight that modulation of dietary habits could be exploited as a novel, safe, and effective approach in modulating the pivotal “Bregs-Treg-Th17” cell axis in osteoporosis…”
Figure Key: harnessing “GUT-IMMUNE-BONE” axis in bone health.
Gut microbiota (GM) acts on the non-digestible carbohydrates (NDOs) such as fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS) etc. and convert them into various Gut Associate Metabolites (GAMs).
Short chain fatty acids (SCFAs), ie, acetate (C2), propionate (C3), butyrate (C4), pentanoate (C5), and hexanoate (C6).
Moreover, primary bile acids produced by liver such as cholic acid and deoxycholic acid are converted into secondary bile acids (by the GM) such as lithocholic acid (LCA), etc.
These Gut Associate Metabolites can cross the intestinal lining and upon entry into lamina propria modulate Breg, Tregs, and Th17 cells which further regulate bone remodelling after reaching bone marrow (BM).
Also, Gut Associate Metabolites can directly regulate bone remodelling via the peripheral circulation, thereby maintaining bone health.
'Significantly together these studies, in addition to those outlined throughout this review, provides numerous potential checkpoints which can be modulated and selectively targeted in the treatment and management of osteoporosis.’
Full text: https://www.dovepress.com/the-rising-era-of-immunoporosis-role-of-immune-system-in-the-pathophys-peer-reviewed-fulltext-article-JIR
