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The Microbiome [Gut] and Musculoskeletal Conditions of Aging: A Review of Evidence for Impact and Potential Therapeutics
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......The microbiome is a highly plausible target for modulation of diseases of aging owing to its close relationship with the innate and adaptive immune systems.
"Prebiotics are ingredients in fruits and vegetables, such as complex carbohydrate fibers, that alter the composition or activity of the microbiome in a way that may confer health benefits to the host"
"up to 70% of human inflammatory cells are present in the gut-associated lymphoid tissue" "Identifying high-risk patients with low-diversity microbiome could plausibly lead to simple and safe dietary or therapeutic interventions."
Journal of Bone and Mineral Research Feb 2016
Recently, we have begun to realize that the billions of microorganisms living in symbiosis with us have an influence on disease. Evidence is mounting that the alimentary tract microbiome, in particular, influences both host metabolic potential and its innate and adaptive immune system. Inflammatory states characterize many bone and joint diseases of aging. This prompts the hypothesis that the gut microbiome could alter the inflammatory state of the individual and directly influence the development of these common and burdensome clinical problems. Because the microbiome is easily modifiable, this could have major therapeutic impact. This perspective discusses evidence to date on the role of the microbiome and the highly prevalent age-related disorders of osteoporosis, osteoarthritis, gout, rheumatoid arthritis, sarcopenia, and frailty. It also reviews data on the effects of probiotics and prebiotic interventions in animal and human models. Despite suggestive findings, research to date is not conclusive, and we identify priorities for research to substantiate and translate findings
The term gut microbiome (GM) describes the genetic material of the myriad microorganisms (often referred to as a community) within an animal intestine. Recent advances in genome sequencing technology reveal its remarkable complexity and point to its involvement in numerous traits and diseases. Collectively, gut microorganisms encode 150-fold more unique genes than the human genome.[1] Hence, the GM may be conceptualized as an additional organ undertaking a vast amount of metabolic reactions,[2] which influence normal physiology and host metabolism.[3] Humans and their microbiome have co-evolved over millennia and live intimately to mutual benefit.[4, 5] The human GM starts developing at birth, is modulated by infant and adult diet, and may be disrupted by antibiotic administration (reviewed in Cox and Blaser[5]). The host inflammatory response is both educated and driven by interaction with gut microorganisms[6] and neonatal animals reared in sterility do not develop normal immunity or normal size.[7, 8]
A wide range of diverse diseases and conditions lying outside the gut have been demonstrated to be associated with an abnormal or dysfunctional microbiome. Such conditions include type 2 diabetes mellitus (T2D),[9] obesity,[10, 11] and cardiovascular disease.[12] This article reviews the current evidence on microbiota associations with musculoskeletal diseases of aging. Many of the clinical problems reviewed are associated with inflammatory change—either specific to disease or associated with age. Alterations in the microbiota provide plausible candidate mechanisms for driving both inflammation and altering the immune response and host metabolism, which in turn may modulate the development of musculoskeletal problems and frailty (defined below). Studies in these areas are challenging and have to be carefully planned to minimize confounding by factors such as host genetics,[13] age,[14] diet,[15] and the condition itself, as these factors are also important in shaping the gut microbiome. In addition, microbes may behave differently in different environments and geography. Thus, answering the tricky question of cause and effect in disease–microbiome associations remains to be answered unequivocally for many conditions, although transplanting beneficial human microbes into germ-free animal models has had successes in some traits like obesity.[13]
Frailty is the age-related loss of reserve capacity in multiple systems simultaneously, which results in reduced resistance to stressors at increasing age.
Many older individuals with bone and joint disease are also frail Frailty has been associated with alterations in the microbiome, in particular core butyrate producing commensals.
There is now good evidence that frailty is associated with low-grade chronic inflammation, especially in women,[34] contributed to by the age-related increase in systemic inflammation ("inflamm-aging"[35]). Seventy percent of the body's lymphocytes reside in the gut-associated lympoid tissue,[36] and, owing to its folded structure, the alimentary tract constitutes the largest interface with the external world at 30 to 40 m2,[37] a magnitude larger than the skin surface (∼2 m2). Therefore, alterations in the GM could play a role in the development of frailty.
Elevated inflammatory markers, such as high-sensitivity C-reactive protein (CRP), have been consistently associated with low bone mineral density, elevated bone resorption, bone loss, and increased fracture risk.[47-50] Furthermore, numerous inflammatory diseases are associated with osteoporosis,[51] including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In both conditions, bone loss is regulated by pro-inflammatory cytokines.[51, 52] Immune system alterations may also contribute to the loss of bone mass seen in postmenopausal women, where withdrawal of estrogen results in increased formation and prolonged survival of bone-resorbing osteoclasts (OCs).[53]
Muscle wasting occurs in several other pathological conditions, such as cancer, chronic heart failure, chronic infection, and malnutrition. Inflammation and inappropriate nutritional state are postulated to be important common mechanisms
One recent animal study suggests a relationship between muscle wasting and alterations in the gut microbiome. Muscle wasting induced by a model of acute leukemia in mice was reduced by orally supplementing the mice with specific Lactobacillus species.[44] The Authors suggest that gut microbiota may influence muscle physiology through altering amino acid bioavailability; influencing metabolites such as bile acids; and modulating production of pro-inflammatory cytokines.[42]
The gut microbiome provides an attractive target for therapeutic intervention because it may be manipulated relatively easily. For example, it has been well established that antibiotics alter the delicate balance of microorganisms, and changes can be stable and long lasting.[16, 17] Clinical applications of this method include use of the nonsystemic broad-spectrum antibiotic rifaxamin in hepatic encephalopathy, diverticulosis, and irritable bowel disease.[18, 19] Dietary manipulations, such as energy restriction,[20] high meat/fat diet,[21] and changes in fiber also modulate the microbiome. Effects are generally transient, but some longer-term influence may be possible if diet is sustained.[22]
Another method of altering the microbiome is through the use of pro- and prebiotics. A probiotic is a living organism found in food and dietary supplements that may improve the health of the host beyond its inherent basic nutritional content.[23] Prebiotics are ingredients in fruits and vegetables, such as complex carbohydrate fibers, that alter the composition or activity of the microbiome in a way that may confer health benefits to the host.[24]
  Two substances currently meeting the criteria for classification as a prebiotic (Box 1) are inulin and trans-Galacto-oligosaccharides,[24] and more are anticipated.[25] Such prebiotics can be found in naturally occurring fruits and vegetables and produced artificially. Inulin, for example, is found in onions, leeks, asparagus, Jerusalem artichokes, chicory root, and bananas. The underlying mechanisms behind any health-promoting effects of probiotics and prebiotics are not yet proven but are likely to include alterations in the gut flora influencing metabolites produced, releasing short-chain fatty acids, and modulating the immune system; increased solubility and absorption of minerals; and enhanced barrier function.[26]
There is much scope for further investigation of the impact of the human microbiome on bone and joint disease found at older age, particularly the gut microbiome. The microbiome is a highly plausible target for modulation of diseases of aging owing to its close relationship with the innate and adaptive immune systems. It should not be considered in isolation because of the recognized influence of host genetics,[13] geography, diet, and other factors.
To date, some of the best data relating the microbiome to bone disease is in osteoporosis and RA. Other diseases, in particular osteoarthritis, have received little attention to date, despite some promising suggestive findings. Clearly, there is room for well-planned studies in these areas. However, even in the best cases, studies are limited by three main issues. First, the methodology of microbiota research is still a work in progress, and the optimal methods for gaining clinically relevant samples and how they should be sequenced and assigned are yet to be established. Compositional (taxonomic) approaches used in most of the studies reviewed here do not take full account of the functional capacity of microbiota, which may have more biological significance. Few studies to date make use of comprehensive but expensive metagenomic (shotgun) data, which identifies around 80% of all species of microorganism (including fungi, archea). Most published studies use primers for one highly variable gene, the 16SrRNA, which is used for bacterial identification. Taxonomic assignation is only as good as the library used and predicted functions rely on accurate and relevant reference sequences. Metatranscriptomic analyses of intestinal mucosal samples are needed to inform on which genes are actually being expressed and microbiome metabolomics is also in its infancy.
The second issue is that most studies to date have focused on the microbiome of the distal large intestine as revealed by stool samples. This focus stems from the fact that up to 70% of human inflammatory cells are present in the gut-associated lymphoid tissue,[36] and feces are relatively easy to collect. However, there may be significant differences between microbiota along the course of the intestine[116] from the mouth to the colon and at the mucosal interface compared with the lumen.[117]
The third issue is to what extent studies in model animals translate to humans. So far, most of the evidence for a benefit of probiotics is in rodents. In humans, probiotic studies have only shown evidence in randomized controlled trials in very old or young populations or the severely ill. Moreover, the rodent natural microbiota are very different from that of a human, and many studies attempting to "humanize" the murine microbiome have only limited success for short periods, underlining the power of the host to determine its own microbiota. Human variability and underlying genetic variance will make comprehensive clinical studies essential to perform in humans.
Despite these issues, microbiome markers are likely to form part of future multi-omics panels to predict disease risk and indicate prognosis (Box 9). Identifying high-risk patients with low-diversity microbiome could plausibly lead to simple and safe dietary or therapeutic interventions.
Box 9. : Critical questions for the future
Do specific microbiome alterations moderating bone and joint disease and sequelae in animal studies translate to humans?
How can they be modified in a sustained manner required in chronic diseases?
How do individual differences in the microbiota alter the therapeutic responses to common drugs and nutritional interventions used in bone and joint disease?
Should we be prescribing prebiotic foods and probiotics in frail patients?
Should we be routinely testing our patients for disordered gut microbiota?
Although more trials in humans are needed, because of the tight relationship between host and microbe and wide variability, these will be problematic and underpowered until we understand the impact of specific host genotypes on the microbiota, and integrate "omic" wide analyses of the impact on metabolomics and immunophenotyping. Despite the lack of large-scale human data and our current limited understanding of the gut microbiome, the example of how fecal transplants have rapidly become mainstream life-saving treatments in C. Diff infections shows the potential for pragmatic use of gut microbes as agents for good. This is a fast-moving field and has great potential in improving the health of elderly populations with bone and joint conditions.

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