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intestinal microbiota is highly associated with various aspects of metazoan physiology , such as development , metabolism , and immunity , and is decidedly involved in the pathogenesis of various metazoan diseases , such as inflammatory bowel disease , obesity , and cancer [ 1 , 2 ] . even for some invertebrates that have a relative simple of intestinal microbiota , such as caenorhabditis elegans ( one bacterial species ) and drosophila melanogaster ( 520 species ) , the intestinal microbiota still has profound influence in host physiology , like host longevity .
the influence of gut microbiota on host physiological functions and pathogenesis of diseases may result from activity of the microbiome and its metabolic products .
although these years have witnessed a compelling progression on the involvement of dysbiosis of intestinal microbiota in rheumatoid arthritis , the roles of intestinal microbiota or its metabolic products in the pathogenesis of osteoarthritis ( oa ) remain to be known .
the exact etiology of oa is still unknown , but various risk factors have been reported , including person - level factors , such as age , sex , obesity , and diet , and joint - level factors , including injury , malalignment , and abnormal loading of the joints [ 46 ] .
regarding person - level factors , a number of explanations have been proposed to explain the involvement of person - level factors in oa ; however , most of these hypotheses have not been demonstrated experimentally , and even some have been challenged by later observational studies and clinical trials . in this paper , we try to explain the involvement of some person - level factors in oa from aspect of intestinal microbiota and try to highlight the importance of intestinal microbiota or its metabolic products in the pathogenesis of oa .
age is regarded as the main predictor of oa ; however , the underlying mechanisms behind the increased prevalence and incidence of oa with age remain to be known .
although a number of explanations , including oxidative damage , thinning of cartilage , muscle weakening , and a reduction in proprioception , have been proposed to explain the involvement of age in oa , none of these hypotheses have been demonstrated empirically .
with cell culture - dependent and culture - independent studies , older people show significant difference in gut microbiota from that of younger adults , such as lower diversity of gut microbiota , greater proportion of bacteroides spp . , and distinct abundance pattern of clostridium groups [ 7 , 8 ]
. the alteration of gut microbiota may regulate the age - related physiology , such as immune responses , cognitive function , and organ disorders [ 7 , 8 ] .
for example , dysbiosis of intestinal microbiota highly precedes and predicts age - onset intestinal barrier dysfunction in drosophila , while targeting of the aging - related dysbiosis of intestinal microbiota alleviates these age - related dysfunctions and increases life span in drosophila [ 9 , 10 ] .
thus , it is utterly possible that the aging - related dysbiosis of intestinal microbiota contributes to age as a risk factor for oa .
it is an interesting observation that the prevalence and severity of oa in hip , knee , and hand are higher in women than in men , and they also increase around menopause .
for example , with one study with 4733 subjects in alberta , canada , the prevalence of knee oa is 6.3% for males and 8.9% for females , while the prevalence of hip oa is 4.4% for males and 7.6% for females .
this discovery suggests presence of sex difference in oa prevalence and incidence , with females generally at a higher risk .
this compelling investigation results in a hypothesis that hormonal factors , like oestrogen , have role in the development of oa . however , later conclusions from observational studies and clinical trials challenge this hypothesis [ 13 , 14 ] , and other explanations have been proposed for the discrepancy between men and women in oa , such as differences in volume of cartilage , bone strength , and muscle strength .
male mice have more bacteria overall in the feces compared to female mice ; however , female mice show more significant diurnal oscillation in intestinal microbiota than that of male mice , indicating that gender has remarkable influence on intestinal microbiota .
indeed , gender - dependent influence in intestinal microbiota has been observed in various animal models , such as fish , mice , and human .
for example , with 16s dna sequencing of intestinal microbiota in fecal samples of 39 men and 36 postmenopausal women with similar dietary background and age , the abundance of bacteroides genus and the abundance of bilophila are lower in men than in women , while higher presence of veillonella and methanobrevibacter genera is observed in men compared to women .
thus , the difference in intestinal microbiota may be responsible for the higher risk of oa in women . similarly , female mice have higher incidence ( 1.34.4 times ) of type 1 diabetes ( t1d ) , compared to male mice [ 18 , 19 ] .
similar to estrogen therapy which has little effect on oa [ 13 , 14 ] , the protection of males against t1d does not correlate with blood androgen concentration .
however , germ - free ( gf ) mice lack the gender bias , while colonization of gf mice with some lineages of overrepresented microbiota in male mice ( i.e. , enterobacteriaceae family ) restores the gender bias for t1d .
interestingly , transplantation of gut microbiota from adult males to immature females alters the recipient 's microbiota , leading to elevated testosterone , reduced islet inflammation and autoantibody production , and finally increased t1d protection .
these results show that intestinal microbiota regulates disease fate in individuals ; thus it is possible that intestinal microbiota contributes to gender as a risk factor for oa .
one of the well - known risk factors for oa is obesity [ 20 , 21 ] .
c57bl/6j male mice fed a high - fat diet ( hfd ) for 12 weeks have greater body weight and also exhibit features consistent with knee oa , compared to the control mice . with 1,764,061 observed subjects , for a median ( interquartile range ) of 4.45 ( 4.19 to 4.98 ) years
, overweight or obesity increases the risk of oa at knee , hip , and hand , especially at the knee : overweight and ( grades i and ii ) obesity increase knee oa risk 2- , 3.1- , and 4.7-fold , respectively . with one study with 4733 subjects in alberta , canada , obesity ( bmi > 30 
kg / m ) is remarkably associated with the prevalence of knee and hip oa .
the link between obesity and oa was contributed to excessive joint loading as a result of increased body weight ; however , a more complex aetiology for obesity - induced oa has been indicated , such as disturbed lipid metabolism , low - grade inflammation , and adipokines on joint tissues .
it is well known that intestinal microbiota is associated with the establishment and development of obesity .
obesity is associated with phylum - level changes in the microbiota ( i.e. , ratio of firmicutes / bacteroidetes ) , reduced bacterial diversity , and altered representation of bacterial genes and metabolic pathways [ 24 , 25 ] . in genetically obese ob / ob mice and obese people ,
ratio of firmicutes to bacteroides is augmented , which promotes production of biologically active metabolites , such as short chain fatty acids ( scfas ) , including acetate , propionate , and butyrate , from soluble dietary fibers ( i.e. , fructans ) and resistant starch , leading to higher energy extraction from indigestible carbohydrates and to adipogenesis in the liver [ 24 , 25 ] . as the dysbiosis of intestinal microbiota contributes to obesity and to other obesity - related conditions including insulin resistance and systemic inflammation , it is reasonable that intestinal microbiota is associated with pathogenesis of oa .
several dietary factors have been reported to be involved in pathogenesis of oa , such as vitamins , amino acids , and magnesium . however , further studies are needed to better define the association between oa and these dietary factors and to better understand the underlying mechanism for these dietary factors to regulate oa .
intestinal microbiota is highly shaped by dietary nutrients [ 7 , 28 , 29 ] .
for example , little amount of single amino acids supplementation ( 0.5% ( w / w ) l - arginine or 1.0% ( w / w ) l - glutamine ) has shown significant influence on intestinal microbiota , such as the ratio of firmicutes / bacteroidetes [ 28 , 29 ] .
the possible reason for nutrient - induced change of intestinal microbiota is that nutrient alters the microenvironment for intestinal microbiota , such as composition and metabolism of intestinal microbiota , and immune responses of host .
glutamine supplementation promotes mouse intestinal secretory iga ( siga ) production and iga plasma cell numbers through t cell - dependent ( e.g. , il-5 , il-6 , and il-13 ) and t cell - independent pathways [ e.g. , transforming growth factor ( tgf- ) , a proliferation - inducing ligand ( april ) , and b cell - activating factor ( baff ) ] of siga induction , which are largely dependent on glutamine 's effect on intestinal microbiota .
although chitosan has little effect on the richness indices of intestinal microbiota in mouse jejunum , ileum , and feces , it highly affects the microbiota diversity in the jejunum , ileum , and feces of mouse .
chitosan also alters the component of intestinal microbiota , including lowering the ratio of firmicutes  :  bacteroidetes , decreasing the bacteroidales in the feces , and increasing the lactobacillalesin the feces .
these interesting investigations indicate that nutrient affects host physiological functions largely dependent on intestinal microbiota .
thus , the nutrients - intestinal microbiota axis may be implicated in pathogenesis of oa .
if so , the manipulation of nutrients - intestinal microbiota axis is auspicious to prevent and treat oa . indeed
, oral supplementation of resveratrol has significant anti - oa effects in hfd - induced oa model in mouse through recovery in joint structure and type ii collagen expression in cartilage and inhibition in the degradation of type ii collagen into c - telopeptide of type ii collagen ( ctx - ii ) and chondrocyte apoptosis .
the intestinal microbiota is profoundly associated with pathogenesis of various diseases , such as inflammatory bowel disease , obesity , and cancer [ 1 , 2 ] . here
we describe the rationale for the hypothesis that intestinal microbiota is a major hidden risk factor for oa and an important explanation for person - level risk factors in oa ( figure 1 ) .
although bacterial lipopolysaccharide has been suggested as hidden risk factor for oa , it is fruitful to explore the oa patient related changes in microbiota composition , bacterial diversity and bacterial genes , and metabolic pathway . the understanding on the association between intestinal microbiota and oa could facilitate the development of new approaches to diagnosing and treating oa . in particular , with the knowledge of intestinal microbiota in pathogenesis of oa , the manipulation of nutrient - intestinal microbiota- bacterial metabolite axis has potentials to prevent and treat oa .
intestinal microbiota is highly involved in host physiology and pathology through activity of the microbiome and its metabolic products . 
 osteoarthritis ( oa ) is a common form of arthritis characterized by articular cartilage destruction and osteophyte formation . although various person - level risk factors , such as age , sex , and obesity , have been proposed for the pathogenesis of oa , the underlying links between these person - level factors and oa are still enigmatic . 
 based on the current understanding in the crosstalk between intestinal microbiota and these risk factors , intestinal microbiota could be considered as a major hidden risk factor that provides a unifying mechanism to explain the involvement of these person - level risk factors in oa .