PROBIOTICS: ANAVANT-GARDESTEP INTHE THERAPY OF RHEUMATOID ARTHRITIS

PROBIOTICS: ANAVANT-GARDESTEP INTHE THERAPY OF RHEUMATOID ARTHRITIS

Jeel Manish Shah, Bhavini Vinodkumar Sutar, Vivek Sukant Pradhan, Princy Piyushbhai Patel and Pooja Dineshgiri Goswami *

Babaria Institute of Pharmacy, Vadodara, Gujrat, India.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic progressive inflammatory autoimmune ailment with multifactorial etiology. The human gut is a massive intricate ecosystem where microbiota, nutrients, and host cells interact extensively to uphold gut homeostasis. Gut microbiota acts as a modulator of immunity and dysbiosis has detrimental effects on health by triggering a persistent inflammatory response that may eventually result in disease.  Probiotics are live microorganisms that can normalize gut microbiota and boost the host's health when administered in adequate amounts. Recent research has demonstrated that probiotics have important roles in the makeup of the gut microbiota, which can prevent pathogenic bacteria from colonizing the intestine, support the host in developing a strong intestinal mucosa defensive barrier, and reinforce the host immune system. Probiotics have positive effects on health, including immune system regulation and anti-inflammatory activity by preventing the release of pro-inflammatory cytokines like TNF-. Probiotics may affect NF-kB, proteasome activity, Toll-like receptors, as well as their regulators and stimuli, at various sites along the MAPK pathway. Because of the close association between gut microbiota and human immunity, controlling the gut microbiome with probiotics has proven to be a very efficient strategy to boost human immunity in Rheumatoid arthritis. The preclinical and clinical trials demonstrating probiotics' effectiveness in treating Rheumatoid arthritis are summarized in this review together with the recent information on the interaction between immunology, probiotics, and gut microbiota.

Keywords: Lactobacillus, Inflammation, Dysbiosis, T-reg cells, L. rhamnosus, TNF-α

INTRODUCTION: Rheumatoid arthritis is an autoimmune disease fundamentally affecting the joints of the body. It is a type of arthropathy characterized by chronic inflammation of synovial joints, bones, and cartilage ¹.

The major observatory criteria for RA are inflammation in symmetric joints (proximal interphalangeal and metacarpophalangeal joints), morning stiffness, fatigue, swelling, and redness near joints; which if left untreated, proceeds to extra-articular sites and increases mortality and morbidity.

Untreated RA leads to the development of various complications like rheumatoid nodules, lung disease, atherosclerosis, hematologic complexity, bone erosion, and restricted motion due to joint damage ². RA affects 0.5 to 1% of adults worldwide, with most patients being above 50 years of age ³. Numerous factors such as genetic factors like HLA-DRB1 and environmental factors like diet, smoking, alcohol, and obesity contribute to the pathogenesis of RA causing chronic inflammation ⁴. Synovial vascular injury, immune system activation, and neoangiogenesis induce autoimmunity. This assists in the proliferation of synoviocytes and fibroblasts, activation of residential macrophages, and infiltration of lymphocytes and neutrophils in the synovial membrane. Etiological factors lead to the modification of auto-antigens which causes activation of CD4+ T-cells and B-cells, stimulating the increased release of pro-inflammatory cytokines accompanied by the production of autoantibodies against them. Further osteoclast activity is increased in the synovial membrane due to activation of TNF-alpha, IL-6, RANK-L, and various cartilage degrading enzymes like metalloproteases which are produced by attracted neutrophil granulocytes pain, swelling, and bone erosion are manifested through this cellular event ^{5, 6}.

Pharmacological medications used to treat rheumatoid arthritis are traditional, synthetic, biological DMARDs, corticosteroids, NSAIDs, and COX-2 inhibitors that show a range of side effects on the lungs, heart and liver and changes in lipid profile ². Nutritional interventions along with medications, physiotherapy, and regular exercise have been applied in the management of Rheumatoid arthritis. Out of several factors involved in the onset and progression of Rheumatoid arthritis, one such inciting factor is gut dysbiosis. This causes disturbance in the gut microbiome, eliciting an immune response and triggering chronic inflammation. Thus, modulation of immune homeostasis by gut microbiota is a possible alternative in treating autoimmune diseases ⁷.

GUT Microbiome and Immune System: The word microbiome refers to a collection of all microorganisms present within a biotic community. The majority of constituent microorganisms which include commensal and symbiotic microbes are bacteria ⁸. In the human gut, approximately 1000 types of bacteria are present. In the human body, gut microbiota produces metabolites to communicate with the immune system and modulates immune responses. The interaction between gut microbiota and the immune system of humans plays a crucial function in the development of a range of disorders ⁹. RA affects approximately 1% of the human population and is characterized by persistent synovial inflammation, ultimately leading to bone damage ¹⁰. Many studies have shown evidence that oral and gut microbiome plays an important role in the pathogenesis of RA ¹¹. Disbalance in oral and gut microbiome concentration induces immune response as shown in Table 1. Analysis of dental, fecal, and salivary samples of RA patients by Zhang et al. shows dysbiosis of the gut and oral microbiome ¹⁰. Breban et al. performed a study on fecal microbiota which showed evidence of increased R. gnavus leading to dysbiosis in spondylarthritis and rheumatoid arthritis patients ¹².

One of the main connections between RA and gut microbiota is considered to be T-cells. Regulatory T cells which are a CD4+ T cell subtype and Th17 cells are in equilibrium in healthy individuals but an elevated level of Th17 cells and a decrease in T reg cells is observed in RA patients. An increase in Prevotellacopri and a decrease in Bacteroides in RA patients have shown that P. copri may be pathogenic ¹⁰. Studies have highlighted that the immune response generated from P. copri could stimulate Th1 cells. Under normal conditions, gut microbiota like Faecalibacterium prausnitzii, Roseburia intestinalis, and Anaerostipes butyraticus break down complex carbohydrates into SCFA ¹³.

SCFAs consisting of butyrate, acetate, and propionate play a crucial role in inflammatory signaling, protecting against pathogen infiltration and maintaining intestinal barrier integrity as demonstrated in Fig. 1. SCFAs act on colonocytes via sodium-dependent monocarboxylate transporter-1 (SLC5A8) and increase the function of Treg cells by inhibiting the expression of the HDAC gene. Studies have shown the involvement of HDACs in auto aggressive phenotype of fibroblast-like synoviocytes (FLSs) which is one of the main cell types involved in damage to RA joint tissue. SCFAs activate many G-Protein coupled receptors like GPR109a, GPR43, and GPR41 which regulate cellular turnover and maintain intestinal epithelium physiology. SCFAs like butyrate stimulate DCs and Macrophages by binding with GPR109a leading to pro-inflammatory responses. Studies have shown that butyrate led to increased production of IL-10 and regulation of pro-inflammatory cytokines like TNF-α, IL-12, and IL-6 ¹³. Butyrate also increases the production of TGFβ in intestinal epithelial cells which leads to the accumulation of Treg cells and regulation of inflammatory mechanism. TGF-β inhibits T effector proliferation and suppresses the differentiation of T effector into Th1 and Th17 cells. PPAR γ stimulated by SCFAs is necessary for maintaining a hypoxic environment in the gut that allows the growth of only obligate anaerobes ¹⁴. An increase in the quantity of facultative anaerobes leads to gut dysbiosis that causes disruption of barrier function. Dysbiosis causes elevated inflammatory response leading to inflammation in the mucosal line and disrupts barrier function leading to a leaky gut ¹⁵.

TABLE 1: ALTERATION IN THE CONCENTRATION OF ORAL AND GUT MICROBIOME DURING RA

FIG. 1: ROLE OF GUT HOMEOSTASIS DISTURBANCE IN INDUCING RHEUMATOID ARTHRITIS RELATED. PPAR-γ= Peroxisome proliferator-activated receptor gamma, T-reg cells= T regulatory cells, Th cells= T-helper cells, TNF-α= Tumor necrosis factor-alpha, TGF-β= transforming growth factor.

Probiotics: The word probiotics is derived from the Greek words “pro” and “bios” meaning “for life” and was first used by Lilly and Stillwell in 1965 to represent substances secreted by bacteria that aid in the growth of other microorganisms ¹⁶. Probiotics play an essential role in maintaining health by boosting the immune system. Among the various definitions provided, FDA and WHO defines probiotics as “live microorganisms which confer health benefits to the host when administered in adequate amounts” ¹⁷. In recent years, the use of probiotics has increased drastically. Many probiotic products are present in the market that uplift the immune system, express anti-inflammatory reactions, reduce digestive discomfort, and can also be used in the treatment of many gut-related diseases like IBD, IBS, and gastroenteritis ¹⁸.

The last decade has seen extensive research about probiotics in inflammatory responses. Many preclinical and clinical studies conducted so far shown in Table 2 & 3, have given evidence of probiotics modulating the innate and adaptive immune system. Alleviated joint inflammation in mice and reduced mucosal inflammation have been observed in the administration of probiotics ^{19, 20}. Clinical studies to study the effectiveness of probiotics in treating infections were mainly carried out using strains belonging to the genera Lactobacillus and Bifidobacterium ²¹. Lactobacillus which comprises a variety of species such as L. acidophilus, L. rhamnosus, L. bulgaricus, L. reuteri, L. casei, L. johnsonii, L. Plantarum, L. crispatus, L. delbruckii, L. gallinarum, L. gasseri, L. paracasei can bind to intestinal cells and are acid-tolerant in the stomach's acidity ²².

Probiotic Lactobacillus strains have shown enhancement in intestinal barrier integrity followed by maintenance of immune tolerance and decreased movement of bacteria across the intestinal mucosa ²³. Bifidobacterium species include B. animalis, B. adolescentis, B. bifidum, B. breve, B. infantis, B. lactis, and B. longum which inhibit inflammatory responses in intestinal epithelial cells. Apart from these other bacterial strains used as probiotics include Bacillus subtilis, Streptococcus thermophilus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Lactococcus lactis, Pediococcus pentosaceus, as well as the yeasts like Saccharomyces boulardii and Saccharomyces cerevisiae ²². Probiotic strains have been tested to study clinical effects on Helicobacter pylori infection, inflammatory bowel disease, antibiotic-associated diarrhea (AAD) in children, and many other gastrointestinal infections. Strains like Lactobacillus GG have shown a positive effect on urinary tract infections and even in AAD in children. Also, strains like Lactobacillus gasseri OLL 2716 (LG21) and Lactobacillus acidophilus (johnsonii) La1 showed reduced gastric inflammation ²¹.

Inflammation is one of the defense mechanisms of the body that can be triggered by both internal and external aspects. In GIT, an assemblage of lymphoid tissues forms gut-associated lymphoid tissue (GALT) and acts as a checkpoint for inflammatory responses. On the ingress of bacteria, NLRs, and TLRs cooperate to give an inflammatory response. During inflammation caused by either allergy or autoimmune diseases, the bacterial flora of the gut plays a significant role in its mitigation ²⁴. Probiotics alter the gut microbiome by maintaining an equilibrium of beneficial and harmful bacteria. They mediate intestinal immunity by enhancing the level of good bacteria and lowering the levels of bad bacteria that cause allergies and diseases ⁹.

Probiotics can withstand physiological stress conditions like stomach acid, low pH, and the presence of bile salts. Properties exhibited by probiotic strains include resistance to pancreatic enzymes and bile acids, the ability to adhere to the intestinal mucosa and epithelia, child development, immune regulation, creation of antimicrobial-like substrates, fitness, and health ²⁵. Many experiments performed on mice model has shown that joint inflammation may occur due to local and systemic immunity activated by gut microbiota. Probiotics impact systemic immune responses and ensure homeostasis of healthy microbiota leading to increased application of probiotics in autoimmune diseases as adjuvant therapy. The studies performed in EAE mice after probiotic administration showed immunoregulatory effects. Probiotic strains like Lactobacillus spp., Pediococcus acidolactici, Bifidobacterium bifidum, Bifidobacterium animalis, and Bacteroides fragilis showed decreased Th1/Th17 levels and elevation of Treg cells along with the promotion of IL-10 and TGF β secretion ²⁶.

Selection of Probiotics: The selection of probiotic strains depends on various criteria of which safety and efficacy play the most essential role. Basic strain identification and its characterization is crucial as many non-living cells may also showcase properties of probiotics after which investigating with established assays in experimental animals in a controlled manner should be carried out. The selection of probiotics also depends on their ability to cross natural barriers of GIT like acidic environments and degradation by digestive enzymes. Their in-vivo function needs to be predicted but their in-vitro studies are usually utilized. Scientific parameters like strain’s replication capability, stabilization, and integration into the final product must be checked. Its stability till the expiration date and inside the host must also be determined. The viability and activity of probiotics during their movement in GIT and storage should also be determined. Their ability to obstruct pathogens and antibiotic resistance are also determining factors. Lactobacillus and Bifidobacterium are the most commonly used probiotic strains because of their beneficial effects in the human gastrointestinal tract, such as reduction of serum cholesterol, alleviation of lactose intolerance, anti-infection, antimicrobial, antioxidant, anti-allergic, antimutagenic, anticarcinogenic properties, blood lipid reduction, and immune system stimulation. L. casei as well as L. acidophilus both show their viability in acidic conditions and L. rhamnosus CRL1505 hauls down viral-linked lung damage by modulating immune-coagulative responses and removing respiratory viruses. Bifidobacteria are generally used because of their wide range of mechanisms for bile salt tolerance. Some of its examples are B. adolescentis, B. animalis subsp. animalis, B. animalis subsp. lactis, B. bifidum, B. longum, B. breve and B. infantis. The threshold limit of tolerance varies from strain to strain according to the research ⁹.

Some other criteria include protein and carbohydrate utilization patterns, phenotype and genotype testing for stability, development of compounds with antibacterial properties and immunity-inducing ability, suppression of spoilage-type infection or organisms, and so on. A probiotic strain should neither be pathogenic nor trigger an allergic response to the host and have the ability to proliferate and colonize in GIT. Some of the techniques used for strain identification are: Screening by In-vitro testing, Molecular techniques for identification, and Strain-specific identification techniques ^{9, 27, 28}.

Mechanism of Action of Probiotics:

FIG. 2: DIFFERENT MECHANISMS OF ACTION THROUGH WHICH PROBIOTICS ACT

1. Probiotic bacteria bind to immune cells and increase T-reg cell activity, reducing pro-inflammatory response. They increase the release of secretory IgA antibodies mediated by upregulation of TGF-β and increased plasma cell activation.
2. They also release antimicrobial peptides which help inhibit pathogen growth.
3. Maintain gut wall integrity by inducing the release of tight junction proteins and increasing mucus secretion which prevents entry of pathogens inside the lumen.
4. By inhibiting various intracellular pathways directly, reduce immune cell production.

The beneficial outcome of probiotics on inflammatory markers and immunity has led to extensive study of the mechanism of probiotics. Many animal models like the Collagen-Induced Arthritis Animal Model (CIA) and Adjuvant-Induced Arthritis Animal Model (AIA) have been experimented on to study the effect of probiotics on rheumatoid arthritis. Studies showed that treatment with probiotics like Bifidobacterium adolescentis improved the balance between pro and anti-inflammatory markers and abate gut dysbiosis ²⁹.

The combination of lactobacillus and Bifidobacterium species elevates the level of tolerogenic dendritic cells and encourages naive T cells to develop into T reg cells and also control the imbalance between Th1/Th2 inflammatory response. An animal model for rheumatoid arthritis, collagen-induced arthritis (CIA) is used to demonstrate that L. casei has a positive effect by reducing immunological responses of the Th1 type ^{30, 31}. Probiotics shows strain-specific mechanism and their action is based on their capability to reduce the production of pro-inflammatory cytokines, including IL-12, TNF-α, and IFN-γ ³². Intestinal flora plays a major role in enhancing immunity, treating metabolic disorders, and maintaining the integrity of the mucosal barrier ²⁶. Imbalance in intestinal flora leads to a change in gut homeostasis causing gut dysbiosis i.e., perturbations in gut microbiota that may trigger autoimmune disease and chronic inflammation ³². Probiotics show a certain regulatory effect on intestinal microecology and assist in the restoration of balance in gut microbes.  Modulation in the immune response can be achieved by either proliferation, inhibition of pathogenic bacteria, or elevating the immune response of commensal bacteria. The method of inhibiting the growth could either be the production of an antimicrobial agent like bacteriocin or through competitive inhibition of binding to gut mucosal receptors. Butyrate is a biologically active molecule essential in regulating gut barrier function and immune response. The production of such secondary metabolites elevates by increasing the quantity of good commensal bacteria like Faecalibacterium, Eubacterium, Roseburia, and Akkermansia ³¹.

Gut-associated lymphoid tissue (GALT) consists of 70% of the host’s immune cells and is a crucial protective immune system in GIT. Antigens and pathogens that enter GIT through follicular epithelial cells and microfold cells present on the Peyer’s patches get recognized by the pattern recognition receptor (PRR). Pattern recognition receptors such as toll-like receptors (TLR) and nucleotide-binding oligomerization domains (NODs) are expressed in epithelial cells, endothelial cells, dendritic cells, and macrophages. Microorganisms like pathogens, commensal bacteria, and probiotics express microbe-associated molecular patterns (MAMPs) which interact with pattern recognition receptors (PRR) present in intestinal mucosa and give action on the host immune system ³³.

The recognition of microbial-associated molecular pattern (MAMPs) plays an important role in innate immunity; a major contributor to acute inflammation caused by microbial infection or tissue damage ³⁴. On invasion by the pathogen in the body, the lipopolysaccharides present in pathogens form a complex with TLR-4 receptor which is anchored to the cell surface by surface molecule CD14. This further stimulates the migration of transcription factor-nuclear factor kappa B (NFκB) in the nucleus which increases the production of inflammatory cytokines like IL-6 & IL-8 and develops acute inflammation ^{33, 35}. As shown in Fig. 2 different mechanisms through which Probiotics work: 1. Reinforcement of intestinal epithelial barrier, 2. Blocking pathogen adhesion to the intestinal mucosa, 3. By secretion of anti-microbial substances, 4. Secretory IgA antibody and 5. Immune response modulation.

Reinforcement of Intestinal Epithelial Barrier: The epithelial barrier is the semi-permeable membrane regulating the entry of certain nutrients and restricting the entry of pathogens. Epithelial integrity is influenced by tight junctions, mucus production, and antimicrobial peptides. Being the first line of defense, the epithelial barrier protects against harmful compounds, and its disruption can cause entry of toxins and antigens in the lumen and induce an inflammatory response. Lactobacilli enhance the quality of tight junctions by regulating the production of tight junction proteins E-cadherin and β-catenin.

E. coli nissle 1917 prevents the destruction of barrier by enteropathogenic bacteria E. coli and restores epithelial integrity by changes in tight junction protein expression (zonula occludens (ZO-2), occludins, and claudins) and PKC which helps in the enhancement of tight junction complex. VSL3 and L. casei also help in maintaining barrier function by similar actions. Peptides p40 & p75 secreted by L. rhamnosus help reduce inflammation by inhibiting epithelial cell apoptosis. They prevent cytokine-induced damage by activating anti-apoptotic PK-B in a phosphatidyl inositol-3-kinase-dependent pathway and by inhibiting pro-apoptotic p-38/mitogen-activated protein kinase (MAPK). Mucin is a major macromolecular glycoprotein constituent of mucus secretions from goblet cells. During pathological conditions, their function is disrupted. Lactobacillus plantarum (strain 299v) increases the expression of mucin (MUC2 and MUC3) in cells and prevents direct contact of the pathogen to cell surface and their entry. VSL3 and L. acidophilus also induce mucin gene expression in HT29 cells ^{17, 36}.

Blocking Adhesion of Pathogen To Intestinal Mucosa: Interaction of pathogen proteins with mucosal receptors leads to infection. Therefore, probiotics and host cells are necessary for averting interaction. Due to their ability of adhesion, probiotics compete with pathogens for attachment to receptors and prevent them from doing it ³⁶. Lactic acid bacteria have surface proteins like adhesin protein, or lipoteichoic acids and saccharide moieties which promote attachment of bacteria to the mucous layer. After which they increase the synthesis of mucus by cells. The mucus forms a thick layer over cells and prevents the adhesion of pathogens. This shows the link between a surface protein of probiotic bacteria and the competitive exclusion of pathogens. Without adhesion, colonization cannot take place and inflammation is prevented. L. plantarum induces expression of MUC2 & MUC3 mucins and also prevents attachment of enteropathogenic E. coli ¹⁷. Adhesion of L. reuteri and L. fermentum to mucus is mediated by MapA (mucus adhesion-promoting protein) ³⁷.

Antimicrobial Peptides: Probiotics produce metabolites (histamine, butyrate, inosine, GABA) that show anti-inflammatory effects. SCFAs produced by commensal bacteria as well as probiotics play a significant role in maintaining gut homeostasis. They bind to FFAR2, FFAR3, OR GPR109a receptors of intestinal cells and reduce cytokine production by neutrophils and inhibit the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. They induce tolerogenic DC cells, which stimulate naïve T cells to differentiate into T-reg cells. Butyrate inhibits histone deacetylase and increasesthe accumulation of T-reg cells. Indole derivatives produced by probiotics reduce TNF-α production and increase anti-inflammatory cytokine production by interacting with AhR (Aryl Hydrocarbon Receptor) present on immune cells ³⁸. Histamine released by L. reuteri 6475 acts on H2 receptors of IECs (Intestinal epithelial cells) and macrophages to reduce pro-inflammatory cytokines ³⁶.

Other antimicrobial substances synthesized by probiotics are LMW molecules like organic acids and bacteriocins. Organic acids such as acetic acid and lactic acid enter the bacterial cell in undissociated form and dissociate inside the cytoplasm. This causes a lowering of intracellular pH and accumulation of ionized organic acids inside the cell leading to the death of the pathogen. Antibacterial substances like bacteriocin are synthesized by Gram-positive bacteria (usually Lactic Acid Bacteria, including lactacin B from L. acidophilus, plantaricin from L. plantarum, and nisin from Lactococcus lactis) ¹⁷. “Small molecules microbe originated (SMOM) homeostasis” in the host is attributed to the proficiency of bacteriocin in maintaining homeostasis.

They structurally and functionally resemble molecules synthesized by the host cells. They assist in killing pathogens by pore formation or inhibiting cell wall synthesis ³⁹.

Secretory IgA Antibodies: Plasma cells present in the epithelial lining of the gut produce IgA antibodies which exist as dimers, linked by the J chain produced from plasma cells, and form a complex with secretory component assembled by polymeric-Ig receptor (pIgR). sIgA antibodies regulate adaptive immune response by interacting with immunoglobulin receptors, getting secreted in the intestinal lumen, and exhibiting an anti-inflammatory response.

The secretory component ensures firm adherence of IgA to the mucosal surface while the antibody gives action by preventing pathogen adhesion as well as invasion, neutralizing toxins, antigens, and virus replication, and maintaining gut homeostasis. IgA antibody complexes with antigens and when taken up by dendritic cells, it down-regulates T-cell production and expression of pro-inflammatory cytokines ^{40, 41}. A study suggested that oral administration of L. gasseri SBT 2055 for 5 weeks activated the TLR2 pathway which increases expression of TGF-β in dendritic cells and promotes B-cell differentiation into IgA-producing plasma cells ⁴².

Immune Response Modulations: The humoral and innate immunity responses are mediated by probiotics through the pathway of bacterial-epithelial-immune cells crosstalk ³⁶. TLRs present on Intestinal epithelial cells recognize MAMPs of bacteria and activate MAPK and NF-kB pathways. These pathways are important for the transcription and release of TNF-α in case of inflammation. When any environmental factor affects the host, mitogen-activated protein kinases: ERK1, ERK2, JNK, and p38 undergo phosphorylation which increases transcription of the gene coding for pro-inflammatory cytokine, TNF-α. Being bound to inhibitor molecule IkB, NF-kB is present in an inactive form in the cytoplasm.

When external factor affects homeostasis, IkB gets phosphorylated by the IkB kinase complex (IKK) and undergoes degradation via ubiquitation. Thus NF-kB which is a heterodimer molecule with 2 sub-units=p50 & p65 is released free. It translocates to the nucleus and activates TNF-α production. Probiotics reduce inflammation by down regulating these pro-inflammatory cytokine-producing pathways. It will inhibit the phosphorylation of MAPK proteins and IkB, in turn preventing translocation of AP-1 and NF-kB to the nucleus respectively. So, the production of TNF-α will be hampered. L.casei Shirota inhibits phosphorylation of ERK1, ERK2 & IkB, acting on both cell-signaling pathways. VSL3 reduces TNF-α by inhibiting the NF-kB pathway ^{43, 44}.

TABLE 2: PRE-CLINICAL STUDIES OF PROBIOTICS

TABLE 3: CLINICAL STUDIES OF PROBIOTICS

CONCLUSION: The last few decades have observed an emergence in research and studies demonstrating the vital play of nutrients in the management of diseases and disorders while safeguarding health.

The microbiota present in the human body regulates immunity as well as other functions of the body. This has led to an extensive study on probiotics and their positive intervention in mediating inflammatory pathways. Clinical and preclinical studies have observed a reduction in inflammation through the consumption of probiotics. When used as an adjuvant therapy along with prescribed drugs and meal, probiotics has shown drastic positive changes in diseases. Species like Lactobacillus have shown satisfying results in the management of rheumatoid arthritis. However, there is still room for development in the field of probiotics and its effects as nothing is ascertained due to a lack of intricate study.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: The authors have no conflicts of interest.

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    Shah JM, Sutar BV, Pradhan VS, Patel PP and Goswami PD: Probiotics: anavant-gardestep in the therapy of rheumatoid arthritis. Int J Pharm Sci & Res 2024; 15(3): 699-09. doi: 10.13040/IJPSR.0975-8232.15(3).699-09.

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