Review Article

Have we Reached a Time that Therapeutic Application of Gut Microbiota & Metabolites is Feasible for Avoidance & Therapy of Osteoarthritis & Bone Correlated Diseases: A Narrative Review

Kulvinder Kochar Kaurz¹*, Gautam Nand K Allahbadia² and Mandeep Singh³

¹Scientific Director Kulvinder Kaur Centre for Human Reproduction Scientific Director cum Owner, India

²Scientific Director, Ex-Rotunda-A Centre for Human Reproduction Mumbai, India

³Consultant Neurologist, Swami Satyanand Hospital, Jalandhar, India

Submission: January 09, 2023; Published: April 20, 2023

*Corresponding author: Kulvinder Kochar Kaurz, Scientific Director Kulvinder Kaur Centre for Human Reproduction Scientific Director cum Owner, Punjab, India

How to cite this article: Kulvinder Kochar Kaurz*, Gautam Nand K Allahbadia and Mandeep Singh. Have we Reached a Time that Therapeutic Application of Gut Microbiota & Metabolites is Feasible for Avoidance & Therapy of Osteoarthritis & Bone Correlated Diseases: A Narrative Review. Curr Trends Biomedical Eng & Biosci. 2024; 21(3): 556064. DOI:10.19080/CTBEB.2024.21.556064

Abstract

Osteoarthritis(OA) represents a frequent chronic degenerative disease where bone articular cartilage is implicated in case of middle aged in addition to older subjects that might lead to joint pain as well as impairment which further might end causing joint deformity. OA, over time with escalated event of ageing worldwide OA has assumed considerable importance in view of public health problem all over world. Getting insight regarding its etiopathogenesis is key in the generation of newer beliefs for better treatment options to be planned . Earlier we had reviewed the part of gut microbiota (GM)as etiological factors in obesity , type2 Diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), GM, bone health and vascular calcification in Chronic Kidney Disease (CKD), role of probiotics and prebiotics in their treatment .In the last decade GM has been considered to be an organ possessing multiple functions, that is intricately correlated with numerous immune, metabolic along with inflammatory functions. Here we conducted a narrative review utilizing search engine pubmed, google scholar; web of science; embase; Cochrane review library utilizing the MeSH terms like; GM: Osteoarthritis; extraintestinal manifestations of OA;IBD;SLE;RA; mineral along with bone disorders (MBD); immune modulation; TMAO; beneficial bacteria; short chain fatty acids(SCFAs); vitamin generation; role of estrogen on bone metabolism; Parathyroid hormone; microbial - associated molecular patterns (MAMP); damage - associated molecular patterns(DAMP); Probiotics; Prebiotics; from 2000 till 2022 till date. We found a total of 400 articles out of which we selected 124 articles for this review. No meta-analysis was done. Greater human along with animal information has been updated that has pointed to the presence of gut- bone axis in addition to pointed that GM along with its metabolites are intricately correlated with the pathogenesis of generation of OA that might assume the probability of becoming a therapeutic target. Here we outline the modes implicated in GM along with its metabolites impacting OA regarding intestinal mucosal barrier manipulation, intestinal metabolites manipulation, immune modulation along with approaches for avoidance or therapy of OA with this acceptance of pathogenesis of GM along with its metabolites in OA, opening newer avenues for treatment of OA.

Introduction

Osteoarthritis(OA) represents a frequent chronic degenerative disease where bone articular cartilage is implicated in case of middle aged in addition to older subjects that presents in the form of propagating breakdown of articular cartilage, subchondral sclerosis along with hyperplasia, periosteophyte generation besides synovial injuries which can cause joint pain along with impairment or result in joint defiguration or instability [1]. With the escalated event of global aging, OA has assumed a status of considerable public health problem all over world with enhancing social medical expenditure for basically middle aged in addition to older subjects [2]. As per a study by 2020 OA has assumed the 4th maximum prevalent disease throughout the world [3]. In the meantime in view of high prevalence as well as robust ensuing sequelae for patients of OA has become an issue of considerable importance regarding further research [4]. in the form of a complicated chronic degenerative disease there is no clarification regarding its etiopathogenesis with restricted treatment options. Currently approaches regarding treatment are inclusive of drug therapies ,physical strategies along with surgical options. Thus a greater insight regarding the mode of generation of OA is key for the avoidance in addition to production of OA. Moreover greater corroboration has pointed that Gut Microbiota (GM) along with its metabolites possess a crucial part in the generation along with propagation of OA [5]. in view of the human intestine possesses large quantities of microorganisms, the gut works in the form of a huge storage house for large genome, which is 150 fold greater in contrast to the quantity of human genes. Hence GM is believed to be the second gene bank for humans thus it can’t be separated from the human body [6]. Furthermore, GM possesses a key part regarding host health right from birth along with crosstalk amongst intestinal epithelial cells, microorganisms as well as their metabolites being the crucial modulators amongst intestinal epithelium along with other cell kinds [7]. This crosstalk further aids in intestinal epithelium maturation, intestinal nervous system, intestinal vascular system, as well as innate immune system [8]. Additionally, GM impacts the physiological function of the host (like digestion, absorption, energy metabolism, immune defense) via neuromodulation, immunomodulation as well as endocrine modulation regarding sustenance of homeostasis of the internal milieu [9].

Recently numerous investigators besides pointing regarding decontrolling of GM as well as its metabolites is implicated in the etiopathogenic events of intestinal diseases(like inflammatory bowel disease (IBD), Crohn’s disease (CD) as well as colonic cancer) in addition to that further the imbalance regarding intestinal homeostasis might stimulate different osteoporosis extraintestinal immune along with metabolic diseases(like osteoporosis, psoriasis, systemic lupus erythematosus(SLE), as well as Osteoarthritis [10]. In this context, Sheth et al. [11], illustrated that about 10-40% patients with IBD might be afflicted by a minimum of an extraintestinal involved with maximum common being musculoskeletal injuries (like OA as well as osteoporosis).In a cohort study of patients with IBD in Switzerland, Schule et al. [12], found that 57% of them had correlated osteopenia, while 20% with osteoporosis, whereas rest were associated with OA .Therefore, the intricate association amongst GM in addition to taking place along with propagation is getting recognition of therapeutic implications. Regarding intricate association of gut-bone axis [13], the objective of this review is to detail the modes of GM along with its metabolites impacting OA from the point of view of intestinal mucosal barrier manipulation, as well as approaches for avoidance or treatment of OA dependent on the idea of GM in addition to its metabolites thus acknowledgement of its recognition. Having reviewed earlier the), role of gut microbiota (GM )in obesity, Type2 Diabetes mellitus (T2DM), non alcoholic fatty liver disease (NAFLD) regarding correlation of GM in CKD besides the association with bone health and utilization of probiotics for their treatmentof CKD with its association with bone mass complications, normal physiology of bone [14-25] we decided to conduct a narrative review regarding correlation of GM in CKD besides the association with bone health and mineral metabolism (Figure 1 & 2) [26].

Methods

Here we conducted a narrative review utilizing search engine pubmed, google scholar; web of science; embase; Cochrane review library utilizing the MeSH terms like; GM: Osteoarthritis; Extraintestinal manifestations of OA;IBD;SLE;RA; mineral along with bone disorders (MBD); immune modulation; TMAO; beneficial bacteria; short chain fatty acids(SCFAs); vitamin generation; role of estrogen on bone metabolism; Parathyroid hormone; microbial –associated molecular patterns(MAMP); damage-associated molecular patterns (DAMP); Probiotics; Prebiotics; from 2000 till 2022 till date.

Results

We found a total of 400 articles out of which we selected 124 articles for this review. No meta-analysis was done.

The intricate association amongst osteoarthritis, gut microbiota along with obesity

Gut Microbiota (GM)is key factor regarding activation along with sustenance of intestinal physiological function , as well as possesses an inerasable part regarding sustenance of host’s health in addition to its homeostasis. Under natural situations GM is implicated in sustenance of dynamic balance with the host as well as external milieu [27]. Furthermore, it is in general appreciated that the first colonizers are the microorganisms present in the vaginal canal or the milieu which babies come in relation with at the time of birth. At the initiation of babies birth its intestine possesses plenty of oxygen, basically in view of colonization of partial bacteria with greater requirement of oxygen like Escherichia Coli (E.Coli), as well as Staphylococcus [28]. Once there is reduction of oxygen with time, as well as reduction of pH takes place, certain anaerobic bacteria like Bifidobacterium as well as Bacteroides start colonizing. With the escalation of babies age , different bacteria are in the event of correlative impact. Not prior to 2 years of age an adult kind GM structure with stability is achieved [29]. Once old age approaches reduction of GM variations might be correlated with lifestyle alterations .Reduction in advantageous bacteria like Lactobacillus, as well as Bifidobacterium decreased in numbers losing their dominance [30]. These factors further aid in the imbalance of as well as intestinal microecology, as well as the link amongst escalated age associated chronic diseases like heart disease, Alzheimer’s as well as Parkinson’s diseases [31].

GM are in a symbiotic association with the host impacting key associations like nutritional ingestion, food digestion, systemic metabolism, immune system generation , sustenance of physiological functions as well as building of disease defense for the human bodies [32]. In the meantime in particular in the recent past greater human as well as animal studies have pointed to the presence of gut-bone axis apart from intricate association of pathogenic event of OA, that time might assume a probable target of considerable significance for therapeutic interference [33]. Dependent on this Gleason et al. [34] highlighted the part of gut-joint axis regarding the pathogenic event of OA, besides acknowledging regarding correlation, implicating GIT microbiome, immune along with inflammatory reaction whose induction takes place by them as well as total joint health. In the meantime gut is believed to be an interesting in addition to innovative target regarding the treatment of OA, besides dietary manipulation or supplementation of fibers, Probiotics as well as Prebiotics might yield a positive impact on the gut- joint axis [35].

Obesity is of considerable importance regarding OA induction. Canonically the escalated joint wear secondary to enhanced stress locally in the obese joints is the basic etiology of OA. Nevertheless, greater investigators have pointed that escalated joint does not possess the capacity of offering reasons, regarding association amongst obesity along with OA [36]. Moreover, obesity possesses the capacity of escalating the prevalence of OA in joints which are not body weight bearing like hand joints [37]. It is the observation that non mechanical factors are implicated in the pathological event of obese OA [38]. In this event the loss of balance of GM along with its metabolites is key factor regarding triggering of escalated inflammation quantities as well as takes part in the generation of OA in obese people. Collins et al. [39], illustrated that the quantities of intestinal Lactobacillus reduced in obese rats along with enrichment of this particular bacteria possessed a negative association amongst the quantities of inflammatory factors in the blood, synovial fluid in addition to Mankins score of joints. This study further pointed that this loss of balance of GM as well as escalated intestinal permeability led to the escalated quantities of lipopolysaccharides (LPS) in the blood along with the inflammatory reaction stimulated by LPS might be implicated in the pathogenesis of OA. Li et al. [40], further highlighted the crucial importance of evaluation of part of nutrients- GMbacterial metabolites axis in the pathogenesis of OA from various angles like obesity, aging as well as sex. From the point of view of obesity, the metabolic inflammation, insulin resistance (IR), along with other associated diseases secondary to the conditions whose etiology is GM along with its metabolites, which might aggravate the pathological event of OA.

Regarding human work it is well acknowledged that both prevalence as well as robustness of OA is considerably greater in case of women in contrast to men besides the incidence along with robustness of OA in women subsequent to menopause is greater significantly in contrast to prior to menopause [41]. In this event GM might manipulate the immune reaction by impacting the sex hormones. Like Clostridium possesses the capacity of transforming glucocorticoids into androgens along with the variation in addition to abundance of bacteria species(spp)are positively associated with the quantities of serum androgens [42]. In view of GM being implicated in the excretion along with circulation events of sex hormones, the belief of ‘’microgenderome’’ pointed to the part of sex hormone on the GM has been posited over time [43] see figure 3for role of estrogen on bone loss [44].

In the mean time GM further undergoes a dynamic alterations in the body along with kinds of GM apart from advantageous bacteria escalate in infants. On bodies undergoing regression with age, both GM enrichment along with variation reduce as well as inimical bacteria escalate [45]. Xiangya OA group [46] conducted a population dependent study inclusive of1388 middle aged men as well as older subjects, which illustrated that the changes in the GM arrangement were found amongst those who took part in the study possessed the symptomatic hand OA with lesser comparative enrichment of Roseburia, however greater comparative enrichment of Bilophila as well as Desulfovibrio at genus level was commonly seen in case of symptomatic hand OA. In another population dependent study, Rushing, et al. [47], illustrated that in cases of patients with knee along with hand OA, unique faecal microbiome possessing the properties of escalated products of proteolysis, disturbance in leukotriene metabolism along with alterations in the microbial metabolites in contrast to healthy controls occurred. Chen et al. [48], conducted assessment of GM in 57 patients with OA with equivalent healthy controls documented that the enrichment along with variations of GM inpatients with OA were correlated with significantly decreasing quantities of Bifidobacterium longum along with Faecalibacterium whereas there was escalated quantities of Clostridium. Wang et al. [49], conducted a prospective study that was inclusive of 182 stool samples from overweight OA (n=86 )besides overweight normal individual (n=96) along with observed reduction of variations of GM along with enrichment in overweight OA patients. As per the observations 9 branches in addition to 87 genera varied significantly amongst overweight OA patients along with overweight normal individuals. Lee, et al. [50], documented that the Firmicutes: Bacteroides ratio can be believed to be the probable pointer for the anticipation of generation of Rheumatoid Arthritis (RA) however, if other genera or particular spp could further possess an anticipator part needs future examination. With all the publications regarding GM along with OA agreed to the accumulating proof is there for GM taking part regarding pathological manipulation of OA [51] along with illustrated variations in makeup, enrichment as well as arrangement in variable quantities. Apart from sex, age, dietary consumption, lifestyle factors might have considerable association amongst GM along with OA.

Additionally, investigations conducted in animals by Guan et al. [52], illustrated that in mice with damage stimulated OA, the loss of balance of GM stimulated by antibiotics possessed the capacity of decreasing quantities of LPS along with inflammatory reaction ,thus escalated improvement of OA subsequent to joint damage [52]. Collins et al. [39], examined the association amongst GM, systemic LPS quantities along with local inflammatory status as well as OA in a fat rich sucrose rich diet stimulated obese rat model along with invented an intricate crosstalk association amongst GM in addition to adiposity obtained inflammation along with metabolic OA. Ulici et al. [53], saw that in contrast to particular pathogen free (PPF) mice with damage stimulated OA, the Germ Free (GF) mice possessed greater advantageous synovial scores besides articular cartilage structure pointing to factors associated with GM facilitated the generation of OA subsequent to joint damage. Furthermore, Hahn et al. [54], contrasted the early reaction to damage stimulated OA in the canonical in addition to GF mice along with documented that the variations in GF mice in contrast to canonical mice had an association with metabolic pathways which manipulated the inflammation correlated with the innate immune system (Figure3) With the animal studies that Liu et al. [55] had summarized slowly a direct gut-bone connection gets proven over time thus chance of generating innovative evaluation of pathogenesis of OA with subsequent probable new therapeutic strategies for OA.

The implications of intestinal mucosal barrier manipulation

The intestinal barrier comprises of mechanical barrier, chemical barrier in addition to biological barrier.

a. The mechanical barrier is made up of intestinal mucosal epithelial cells, intercellular tight junctions as well as bacterial studies have pointed to the presence of avoidance of inimical substances like bacteria along with endotoxins gaining entry from the intestinal mucosal [55].

b. The chemical barrier comprises of mucus liberated by epithelium, digestive juices, as well as anti- bacterial constituents generated by parasitic bacteria [56].

c. The immune barrier is constituted of intestinal mucosal lymphoid tissues(mesenteric lymph nodes as well as intraepithelial lymphocytes) could produce local mucosal immune reaction along with particular liberating secretory immunoglobulin (sIgA) In the context of avoidance of pathogenic antigens [57]. The biological barrier is constituted of the microspatial structure generated amongst the normal parasitic flora of intestinal tract besides that of host intestinal tissue [58]. Hernandez et al. [59], illustrated that the GM along with its metabolites possessed the capacity of resulting in aberrant intestinal mucosal barrier function by changing intestinal nutrients absorption, stimulating the alteration of intestinal immune function in addition to aberrant intestinal endothelial transport function, thus stimulating the formation along with propagation of disease like OA as well as osteoporosis .

The intestinal permeability in general aids the substances possessing a molecular weight> 150KD regarding easy passage via the intestinal epithelium to gain entry into the circulation [60]. Herein the permeation mechanisms of intestinal epithelial permeability inclusive of transepithelial pathway along with the paracellular pathway.

i) The transepithelial pathway is made up of nutrients absorption occurring from the intestinal cavity via the intestinal epithelium gaining entry into the circulation , whereas selective limitation of inimical substances passage like endotoxin as well as inflammatory factors [61].

ii) The paracellular pathway is composed of the passive diffusion that takes place at the time of intestinal molecules passage via the epithelial space which is regulated by tight junctions amongst the epithelial cells that modulates the passing of intestinal products of microflora besides other macromolecules [62]. The alterations of intestinal mucosal permeability are correlated with different factors inclusive of exogenous factors like nutritional, variable types of cytokines along with actions of immune cells. These changes of GM possess the capacity of impacting the absorption of Vitamin B, VitaminC, VitaminD, VitaminK, tetrahydrofolate, carbohydrate as well as fats, the formation of Short Chain Fatty Acids (SCFA),hence impacting the growth along with propagation of intestinal mucosal cells. At the time of this event the primary concentration of metabolites basically inclusive of SCFA,5-hydroxytryptamine (5HT), tryptophan associated metabolites etc.

Significantly SCFA are the basic constituents obtained subsequent to resistant starch fermentation besides that of polysaccharides(the basic constituents of dietary fiber [63]. Once there is interference with this GM, their might be considerable alterations in the quantities of SCFA in the intestine].

Various investigators have corroborated the implications of altered acetate ,propionate as well as butyrate in bone metabolism [64]. Collins et al. [39], documented that High Fat Diet (HFD), possessed the capacity of significantly decreasing the quantities of Lactobacillus besides the generation of SCFA in the intestine, thus resulting in reduction of energy supply for the intestinal cells, along with bacterial enrichment was intricately correlated with the quantities of inflammatory factors in the blood besides the synovial fluid of the rat models with OA. In view of considerable importance of the constituents of the intestinal mucosal barrier ,there exists a susceptibility for decreasing of tight junctions protein zonula occludens 1(ZO1) by HFD along with changes in the intestinal permeability might change as well lead to large quantities of LPS gaining entry into the systemic circulation [65]. Furthermore, HFD further stimulates large quantities of saturated fat gaining access to the intestines, escalated the quantities of activated macrophages, hence liberating extra proinflammatory modulators along with adipokines that directly causes augmentation of inflammatory reaction as well as exacerbates clinical results of OA [66]. Dependent on this LPS is broadly present in the outer membrane of the intestinal gram negative bacteria that possess the capacity of stimulating inflammatory reaction as well as its escalated translocation into the circulation may work in the form of a factor which makes one prone to formation of OA. Moreover, LPS can result in activation of innate immune system, like macrophages along with neutrophils, besides form proinflammatory cytokines (like Tumor necrosis factor alpha[TNFα] as well as interleukin-1β[IL-1β]etc) leading to secondary inflammation in different joints right through body [51].

Additionally, 5 HT might interfere with the dynamic balance amongst bone generation as well as bone resorption thus impacting the sustenance of bone mass. GM possesses the capacity of generation of 5 HT along with prior studies have further pointed that GM might stimulate the chromaffin cells for generation of 5 HT with GM possessing the capacity of controlling gastrointestinal motility through the neural mode which gets activated by toll like receptors ( TLRs) [67]. Furthermore, 5 HT possesses double actions on bone metabolism . In the form of a hormone, intestinal obtained 5 HT can hamper bone generation, along with as a neurotransmitter, it can facilitate the brain obtained 5 HT, can facilitate bone generation via a cascade of pathways [68]. Tryptophan represents an aromatic amino acids that might work in the form of a biogenerational precursor for some microorganisms along with host metabolites ,hence manipulating bodily functions [69]. Tryptophan metabolism takes place in the intestine with the utilization of these pathways i)enterochromaffincells generate maximum of the 5 HT in circulation through tryptophan hydroxylase 1(TPH1)ii)partial metabolites can facilitate indoleamine 2,3 dioxygenase (IDO1) can facilitate metabolism of tryptophan to kynurenine iii)via GM actions tryptophan might be directly transformed to indole along with work as aromatic hydrocarbon receptor ligand [70,71] (Figure 5).

Additionally, GM might modulate as well as hamper dietary inflammatory reaction generated in the food ingestion every day that possess a key part in the immune system [72]. In the form of a transmembrane transporter, the microbial-associated molecular patterns(MAMP)might impact physiological functions of far off organs along with tissues subsequent to access into the systemic circulation. As per Kim et al. [73], the MAMPs had the capacity of directly impacting the bone remodelling by stimulation of innate immune receptors present on osteocytes inclusive of manipulation of balance amongst osteoblasts along with osteoclasts .On MAMPs translocation ,the alive bacteria might cross the intestinal mucosal barrier ,with immediate clearance by the immune cells along with those bacteria not getting clearance gain access with MAMPs into the systemic circulation. Subsequent to induction of demise by immune cells within the limit of the barrier. Moreover, once MAMPs in circulation arrive at far off organs along with tissues like various joints of limbs. MAMPs possess the capacity of activation of immune reaction as well as generate local inflammation [74]. Partial bacteria that gain access via the intestinal mucosal barrier possess the capacity of invasion of natural cells along with survival ,hence learn to avoid the effect of inflammatory reaction [75] .In general it has been acknowledged regarding the alterations in intestinal mucosal permeability as well as the of GM associated metabolites across the intestinal mucosal barrier might impact the generation as well as the propagation of OA to some degree.

The role of immune modulation

An intricate association amongst GM along with intestinal mucosal immune system as well as the extent of alterations in intestinal microecology ascertains the stability regarding intestinal mucosal immune system in addition to systemic immune system .The direct touching amongst GM, its metabolites along with immune cells stimulate the immune reaction of intestinal mucosal barrier [76]. The immune cells (like T cells along with dendritic cells[DCs]) possess the capacity of crosstalk amongst GM along with migration to lymph node for activation of proinflammatory or anti-inflammatory reactions.In the meantime these cells can further liberate soluble proinflammatory or antiinflammatory mediators/ cytokines into the systemic circulation along with take part systemic bone remodelling [77]. Besides this TLRs further work in the form of a bridge amongst intestinal mucosal barrier, GM along with the innate immune system, possessing a key part in the generation of GM. There is enrichment of dietary along with microbial antigens with the human immune system possessing the requirement of tolerating these antigens for formation of situations regarding survival of GM. TLRs is part of a significant immunosensors meant for sustenance of balanced of GM right through body [78]. TLRs is present in various innate immune cells like macrophages ,DCs along with intestinal epithelial cells that could recall the microorganisms, thus affecting the generation of anti- bacterial substances for modulating immune reactions [79]. A key association further exists amongst the innate immune reaction along with cartilage injury, that impacts the formation of OA. Articular cartilage with basic etiology comprising of numerous factors like ageing along with obesity, might stimulate the liberation of autoantigens along with damage-associated molecular patterns(DAMP),hence activation of innate immune reaction(i.e. activation of immune cells,(like immune cells , activation of complement cascade, along with liberation of anti cartilage constituents of the immune complexes) leading to formation of sterile inflammation along with further injury to the cartilage with generation of a vicious cycle [80] in the form of a broadly documented immunomodulator GM basically stimulate the host intestinal wall for collecting lymph nodes via the bacteria itself or cell wall constituents along with produce immune reactions to bacteria [71,81]. At the time of this event, the lymphocytes activation transfers the immune reactions to the full intestinal mucosal along with then generates secretory immunoglobulin(sIgA) for layering the full mucosal surface. IgA represents the maximum quantities of immunoglobulin liberated by body that might lead to avoidance of adhesion of pathological microorganisms in the intestine from gaining attachment to mucosal surface, neutralization of bacterial toxins along with possess a synergistic bactericidal part with complement along with isozyme [82]. Furthermore, GM might directly modulate immune cells, like Prevotella capri might result in facilitating the generation of Foxp3 + regulatory T(Treg)cells as well as CD4+T cells (Th17cells) in the intestine, besides Tregs might facilitate the generation of retinoic acid -related orphan receptor γ(RORγt+)-for further facilitating the differentiation of CD4+RORγt+Foxp3- (Th17 cells) [72,83, 84] (Figure 6).

Dependent on this GM possesses the capacity of manipulating type II hypersensitivity via Th17cells along with Tregs, for balancing immune reaction on the intestinal mucosal surface [85]. Furthermore, Ivanov et al. [86], pointed that the segmented filamentous bacteria(SFB) possessed the capacity of inducing differentiation of intestinal Th17 cells as Bacteroides fragilis as well could facilitate the differentiation of Th1 cells as well as Tregs. Atarashi et al. [87],posited that once the GM subsets(like SFB, Citrobacter, Escherichia Coli 0157 along with some extracellular pathogens colonized along with become adherent with the intestinal epithelial cells, hence intestinal Th17 cells gets induced in addition to accrued together. More recently, DuTeil Espina et al. [88], observation in the study conducted by them was that of the etiologies of RA, the changes of oral bacteria besides oral diseases (like periodontitis) might lead to aberrant GM conditions, with its variations as well as enrichment might be decreased , whereas the generation of neutrophils along with biofilm possesses the inerasable part in this event.Apart from that intestinal citrullinated proteins oral modulation by oral pathogens (Porphyromonas gingivalis as well as Actinobacillus) can facilitate the generation of anticitrullinated protein antibodies. [89, 10rev by us in ref 26]. At the time of this event, the GM overgrowth might power theTh1cells reaction besides further hamper the Tregs activation by hampering the growth of B.fragilis resulting in immune balance loss in addition to RA formation, besides its propagation [90]. Thus it gets acknowledged that deep evaluation regarding immune modulation secondary to changed along with dyscontrolled GM offers an attractive target regarding intervening as well as avoidance besides treatment of OA.

The approaches regarding avoidance/ treatment of osteoarthritis dependent on knowledge acquired from gm along with its metabolites

At the time of the event of continued investigations the researchers, inadvertently noticed that while attempting treatment of intestinal or extraintestinal diseases secondary to microecological conditions, partial patients of OA illustrated that they had got relieved of joint pains along with enhancement of capacity of exercise with further advances regarding treatment [91], that yielded an innovative knowledge besides greater issue regarding basic research in addition to utility in clinical therapy of OA. regarding this, the intestine represents the basic are of absorption of nutrientsin case of humans, as well as the dietary ingestion along with supplementation of miscellaneous substance /day exerts a considerable along with dynamic influence on the constitution as well as function of GM [92]. Diets possess a considerable impact on the shaping of the structure along with functional ability of GM, besides GM initiates various signal molecules via host receptors by carrying out metabolism of food obtained SCFAs along with signaling molecules like trimethylamine-N-oxide(TMAO)in a direct or indirect fashion impacting the organs at a distance(like bone, Kidney, skin, brain etc.) [93,rev by us in ref 25].The advantageous metabolites of particular foods aid in enrichment of advantageous bacteria to have a positive part regarding modulation of body homeostasis [94]. Thus this structure along with functional ability of GM can be manipulated with utilization of Probiotics as well as Prebiotics. Prebiotics, besides restoring bone depletion secondary to hypogonadism or ovariectomy,further act in enhancement of inflammatory bone correlated diseases [95].

Diet is intricately correlated with pathogenesis of OA along with magnesium, selenium as well as Vitamins [96]. Furthermore, Diets possessing escalated quantities of glucose along with HFD is directly correlated with OA. Glucose possesses a significant part in the growth along with generation of articular cartilage, besides any situation with involvement of glucose metabolism might exacerbate generation along with propagation of OA [97]. With escalation of studies illustrating that GM possess controlling action regarding glucose metabolism along with quantities of Akkermansia muciniphilia are significantly decreased in case of mice with type2 Diabetesmellitus (DM) or obesity . Nevertheless,on feeding these mice with polyphenol enriched canberry extract,a significant escalation of A. muciniphilia quantities took place that was correlated with enhancement of glucose tolerance along with insulin sensitivity based on quantities of escalated A. muciniphilia [98,99]. Akin to that ingestion of escalated quantities of HFD might lead to changes in the GM . Moreover, Nguyen et al. [100], documented Lactobacillus plantarius PH04 supplementation had the capacity of efficaciously decreasing cholesterol along with triglycerides quantities of mice with hypercholesterolemia.In a pilot study Ramasamy et al. [101], pointed that Parabacteroides, Butyricimonas, Pseudobutyrivibrio ,Odribacter, Gardinobacter reflected the commonest bacteria in Vitamin D deficient patients with or without knee Osteoarthritis, along with these outcomes observed a non -minimal association amongst GM, Vitamin D, knee OA. Hence it is acknowledged that diet- GM axis is intricately correlated with the glucose along with lipid metabolism of body, as well as changing the dietary nutritional consumption might work out to be an efficacious strategy for ameliorating OA.

Regarding clinical scenario, the appropriate supplementation of microecological controllers is common tendency regarding rectification of microecological abnormalities as well as sustenance of homeostasis modulation. At present , the Probiotics and Prebiotics are in use broadly inclusive of in Clinical scenario along with day to day life [102]. The definition recognized by Food and Agricultural Organization of the United Nations (FAO) and world health organization (WHO) working group experts is that probiotics are live strains of strictly selected microorganisms, which once administered in adequate amounts, give a health benefit to the host . Probiotics supplementation in enough quantities aiding in the advantageous bacteria that might enhance the resistance of the host against pathogenic bacteria like Escherichia Coli (E.Coli) Salmonella enteridis, Klebsiella pneumoniae simultaneously, manipulate the working of intestinal mucosal barrier,make the intestinal milieu ideal along with sustenance of immune balance of body [103]. Tyagi et al. [104], found that supplementation of Lactobacillus rhamnosus GG possessed the capacity of escalating butyrate generating bacteria in the intestine, which facilitated formation of butyrate followed by escalating Wnt 10B along with enhance the bone mass via T regulatory cells(Tregs) expression to take part in manipulation of bone metabolism (Figure 3b). Pan et al. [105], documented that Lactobacillus Casei possessed the capacity of correcting GM disbalance along with restoration of enrichment of Lactobacillus gasseri, Lactobacillusreuteri along with Lactobacillus vaginalis to normal quantities besides escalated quantities of Lactobacillus Acidophilus,hence avoid of bone breakdown in adjuvant induced arthritis(AIA)rats. Henrotin et al. [106], carried out oral administration of freeze dried inactivated cultureof Bifidobacterium longum CBi0703 in a spontaneous model of OA in guinea pigs, of OA besides saw that structural cartilage damage along with breakdown of type II collagen that had occurred as a result of OA got significantly decreased observing that the probability of avoiding /treating . Sim et al. [107], further fed tyndalized Clostridium butyricum to rats for treatment or ameliorating OA, with experimental outcomes illustrating that quantities of inflammatory pointers along with markers of bone metabolism in serum got significantly decreased, whereas the quantities of interferonγ (IFN-γ) as well as glucosaminoglycans were significantly escalated. Thus this efficaciously conferred protection to cartilage along with synovium of knee joint along with decreased the generation of fibrosis. Additionally, contrasting actions of Probiotics possessing capsules inclusive of Lactobacillus rhamnosus,Ssaccharomyces cerevisiae (boulardii) in addition to Bifidobacterium animalis ssp lactis along with placebo capsules without Probiotics to those enrolled for OA. Taye et al. [108], observed that despite the reduction of pain scores associated with Probiotics treatment was comparatively lesser, in clinical scenario its application might possess a considerable impact on the pain relief for patients with OA. Furthermore in the form of a newly discovered bacterium in human milk TC1633 (Streptococcus. Thermophilus) possesses the capacity of generating hyaluronanate in gastrointestinal tract(GIT). Lyu et al. [109], enrolled 80 patients with knee OA, conducted a randomized double blind, placebo controlled clinical study with TC1633 along with placebo, with outcomes illustrating that TC1633 might postpone propagation of kneeOA .

Conversely, Prebiotics represent a kind of indigestible food constituents which might possess an advantageous part in the host by changing the constitution of GM along with action of partial bacteria, or getting fermented by partial bacteria, along with possesses the capacity of stimulating along with activating intestinal Probiotics [110]. Prebiotics, are believed to be miscellaneous substances for bacterial growth facilitation that get protected from activity of hydrolytic enzymes along with variable kinds of proteases in addition to get transformed to SCFA subsequent to getting fermented by GM [111]. Schott et al. [112], found that Bifidobacterium in the intestine of obese rats got significantly decreased, besides changes of GM led to the accrual of systemic inflammatory downstream signals in addition to macrophages of synovium of joints, that exacerbated the propagation of OA. Nevertheless, by restoring GM by Fructoligosacchharides (FOS), supplementation resulted in reduction of systemic quantities of inflammation along with relieved the painful symptoms of OA. Hence the mode that might be applicable is that FOS supplementation possesses the capacity of escalating Lactobacillus hence sustenance of intestinal mucosal barrier along with avoidance of bacterial endotoxins or translocation of LPS as well as hampering the proliferation of Enterobacteriaceae. Tanabe et al.[113], on greater evaluation of the actions of Prebiotics on bone metabolism of ageing mice found that both FOS along with Glucomannans possessed the capacity of hampering bone resorption along with enhance bone metabolism of ageing mice awa further validate the objective of enhancing femoral calcium quantities basically in view of escalating quantities of Lactobacillus, Clostridium along with Bacteroides. Moreover absorption of FOS does not take place with ease in humans, with resistance to digestive juices of intestine thus reaching colon subsequent to consumption, act in the form of growth matrix for facilitation of ideal GM as well as indirectly possess parallel actions on human [114]. Wu et al. [115], further pointed that directly oral consumption of FOS possesses the capacity of relieving inflammatory reactions in mouse pups without changing kind ,levels along with enrichment of GM in mice. These outcomes pointed that Prebiotics might be possessing direct part regarding immunomodulation without participation of GM. Thus in particular for obesity correlated OA(basically in the form of an inflammatory response event) that is correlated with obesity associated dyscontrolling of GM might cause rectification of healthy microecological milieu by utilization of FOS fibers. FOS possesses the capacity of induction of changes of enrichment of crucial microorganisms in case of obese subjects, reduces the reaction properties of colonic macrophages, result in reduction of systemic along with local joint inflammation, confers protection to articular cartilage along with relieve OA propagation [116]. Hence accumulation of publications have corroborated that supplementation of Probiotics along with Prebiotics might decrease the expression of proinflammatory cytokines along with factors that result in cartilage in various joint tissues, escalate generation of anti-inflammatory factors as well as production of cartilage matrix cytokines for hampering both inflammation along with cartilage breakdown along with relieve the generational event of OA.

Moreover, in the last decade investigators have concentrated on Faecal microbiota transplantation(FMT) that implies transplantation of bacteria from the faeces of a human donor to a recipient by intragastric /oral delivery ,thus changing the makeup, structure along with enrichment of GM in recipient [117]. At the time of this event FMT could realter the architecture of intestinal micromilieu, cause improvement of inflammation along with immunity, besides metabolism of recipient’s gut , hence provision of innovative strategy for numerous intestinal along with systemic diseases [118]. Huang et al.[119], pointed that FMT from a human donor that was metabolically compromised to a recipient possessed the capacity of exacerbating the event of OA in mice along with the alterations of Fusobacterium, Faecalibacterium, along with Ruminooccaceae were illustrated to have a key part of these specific microbiota in accelerating OA. In addition to that Glucosamine, as well as chondroitin sulfate-proteoglycans dependent nutraceuticals. In theory their consumption has the capacity of stimulating chondrocytes for generating new collagen as well as proteoglycans, hence aiding body in cartilage healing injured by OA [120]. Nevertheless, partial studies illustrated that these substances could in general decrease pain taking place secondary to OA, along with heal articular cartilage in some wks to mths of initiation of therapy [121]. Hence despite greater patients at present are utilizing it globally ,even now larger randomized controlled Clinical trial are required regarding confirming safety besides efficaciousness of Glucosamine, as well as chondroitynsulfate in OA. Moreover, nonsteroidal antiinflammatory drugs(NSAID)is used in general in the form of therapy for OA along with prior documented part of NSAID in the control of OA from the point of view of GM. Boer et al. [122], pointed that NSAID delivery can impact the composition of GM along with some association amongst enrichment of particular groups along with pain intensity of knee OA. Vitetta et al. [123], documented that Pharmacologic agents used for therapy for OA might interfere with intactness of intestinal mucosal barrier along with cause intestinal inflammation. Usually patients who require NSAID for relief of OA correlated pain, the GM abnormalities having the properties of aberrant proliferation of gram negative bacteria can stimulate aberrant intestinal mucosal immune reaction that can lead to intestinal inflammation along with intestinal damage whereas Probiotics along with rifaximin can significantly relieve damage caused by NSAIDs [124].

Conclusion

Thus, to summarize greater insight regarding OA greater accumulation of proof pointed to that GM along with its metabolites are intricately correlated with OA pathogenesis in addition to presence of gut- bone axis. Despite, the precise mode of the association amongst are still ill understood besides under massive assessment one can forecast that this association of GM along with its metabolites might assume the probability of becoming a great diagnostic along with therapeutic target besides for avoidance of generation of OA or other bone associated diseases. Figure 7 summarizes the functional association amongst GM along with its metabolites with OA.

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