Probiotics and knee osteoarthritis, a clinical study

Osteoarthritis (OA) of the knee and hip is the most common musculoskeletal joint disease worldwide. Although a major symptom of OA is chronic joint pain, which has a significant effect on patients’ quality of life, the underlying pain mechanisms remain largely unknown.
Recently, clinical studies have suggested the existence of a neuropathic component in OA pain (1). Accumulating evidence has been indicating that painful OA patients show peripheral and central sensitization(2)(3) Quantitative sensory testing (QST) is a relevant way to assess peripheral and central sensitization in joint pain(4) . The majority of studies have administered mechanical stimuli, and the most commonly used modality has been pressure. A recent review concluded that that people with OA have lower Pressure Pain Thresholds (PPT), facilitated temporal summation and impaired conditioned (CPM) compared with healthy controls(1). Also, recent evidence have linked QST profiles to the development of chronic pain(5,6), which emphasises the importance of studying the central nervous system.
Inflammation markers have been correlated with the pain intensity (6) , and systemic inflammation can lead to sensitization of peripheral nociceptors(7). Recently it was reported that higher preoperative levels of TNF-α, MMP-13 and IL-6 in synovial fluid may indicate a smaller improvement in pain 2 years after total knee replacement (TKR) (8).
Although recent advances have been made in understanding OA pathogenesis, the etiology of OA still remains unknown. Both environmental and genetic factors are considered to be involved in the development of OA disease.
The effects of the gut microbiota on the pathogenesis and development of OA have been an active area of research in recent years. Previous studies have shown that the gut and oral microbiomes of OA patients were different from those of healthy individuals, but that these differences were partially resolved after OA treatment (8). The potential role of the intestinal microbiota in modulating the immune system aroused a great interest in using probiotic bacteria as a preventive or supplemental therapeutic intervention in diseases such as OA.
Although people often think of bacteria and other microorganisms as harmful “germs”, it is well known today, that many microorganisms help our bodies to function properly. For example, bacteria that are normally present in our intestines help digest food, destroy disease-causing microorganisms, and produce vitamins. Large numbers of microorganisms live in our bodies.
In 1907, the Russian Ilya Ilyich Mechnikov suggested that microbial ingestion improved host health and hypothesized that the consumption of lactic-acid-producing bacteria (LAB) strains, found in yogurt, might enhance longevity (9). Lactic-acid-producing bacteria (LAB) are a heterogeneous group of microorganisms that are often present in a person’s gut, introduced through the ingestion of fermented foods, as well as in the gastrointestinal and urogenital tract of animals. Some of these strains have probiotic effects(10).
The World Health Organization's (WHO) 2001 has defined probiotics as live micro-organisms that, "...when administered in adequate amounts, confer a health benefit on the host.". At the present time, Bifidobacterium and Lactobacillus genera (e.g., B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei) are widely used as probiotics, and are commercially available as dietary supplements.
A large number of disease states and intestinal disorders have been related to an imbalanced gastro-intestinal tract (GIT) microbiota. Scientific evidence supports the important roles that probiotics can play in the digestive system, having significant effects in alleviating the symptoms of several diseases (11) . When ingested, probiotics can restore the microbial balance of the gut in various ways including modulation of gut immunity and competition with other gut organisms for nutrients (12) . Thereby, oral probiotic supplementation can produce microbial transformation in the intestinal microbiota and exert several health-promoting properties, including maintenance of the gut barrier function and modulation of the host immune system(12–17)
Therefore, a great increasing interest in taking advantage of the probiotics ability to modulate both human and animal immune systems has been seen in the recent years (18,19). Many studies have assessed the possible use of probiotics in disease control in both humans and animals. In this regard, different functions have been attributed to the intestinal microbiota in light of the research conducted mainly in the last 10 years, among which (i) maintenance of the epithelial barrier, (ii) inhibition of pathogen adhesion to intestinal surfaces, (iii) modulation and proper maturation of the immune system, (iv) degradation of otherwise nondigestible carbon sources such as plant polysaccharides, and (v) production of different metabolites such as vitamins and SCFAs, are noteworthy(19).
The regulatory role of the gut microbiota in immune and inflammatory activity and the metabolic potential provide a novel avenue of research for musculoskeletal diseases with potentially novel treatment options (20). The production of reactive oxygen species (ROS) in different anatomical environments including the GIT by the epithelial lining and the commensal microbe cohort is a regulated process, leading to the formation of hydrogen peroxide which is now well recognized as an essential second messenger required for normal cellular homeostasis and physiological function(21).
Our own recent studies on animal models demonstrated that both lean mice, and models of diet-induced obesity, present a higher pressure-pain threshold also interpretable as lower pain sensitivity, following even a short term (4 weeks) oral probiotic consumption (22).
Probiotic treatment has been shown to promote bone metabolism, reduce pain and inflammatory responses of age-related musculoskeletal disorders, including OA (23). Several studies on animal models of OA, have reported that Lactobacillus significantly decreased inflammatory reactions during carrageenan-induced arthritis by down-regulating the pro-inflammatory cytokine pathway (19,23) Fiorentino et al. indicated that joint pathology and pain are dependent on spinal levels of IL-1 and suggested the presence of a bidirectional central nervous system—peripheral joints crosstalk that may contribute to the development, expansion, and exacerbation of arthritis (23). Therefore, pain should no longer be thought of as just a symptom of arthritis; pain signals originating in arthritic joints and the biochemical processing of those signals as they reach the spinal cord worsen and expand arthritis; nerve pathways carrying pain signals transfer inflammation from arthritic joints to the spine and back again, causing disease at both ends. Thus, it might be speculated that “not only does arthritis cause pain but pain causes arthritis”. Continuous control of pain and inflammation, which will increase the functionality of the arthritic affected joints is the essential pathogenic treatment with pain management in focus.
Gut-brain axis might be hypothesized as another pain reducing mechanism via regulating nerve and muscle inflammation, consequently affecting central sensitization(23).
Changing diets, by altering the gut microbiota towards dysbiosis, has been hypothesized to drive an increase in the incidence of inflammatory diseases (24). Obesity is regarded as a chronic low-grade inflammatory state, and inflammatory cytokines secreted from adipose tissue are associated with OA (25,26). Previous animal studies performed by our own group demonstrated the weight regulatory effect of probiotics in diet-induced obesity mice models, which in relation to the observed lower nociception in the same mice, can be suggestive of the indirect anti-inflammatory effect of probiotics based on their weight-regulatory characteristics (22).
Animal models have also provided solid data for linking bacterial antigenicity to the generation of inflammatory arthritis [69]. A recent study used molecular biological techniques to compare the faecal microbiota of patients with fibromyalgia and OA (27) showed significantly reduced faecal carriage of common commensal probiotics including bifidobacteria and Bacteroides fragilis in OA patients. Mucosal sites exposed to a high load of bacterial antigens and autoimmune generation - such as the periodontium (28), pulmonary parenchyma (29), and gut – were suggested as possible mucosal sites of initiation of autoimmunity in OA.
Lactobacillus casei has been reported to enhance type II collagen/glucosamine-mediated suppression of inflammatory responses in experimental osteoarthritis, suggesting it as a potent nutraceutical modulator for OA treatment by reducing pain, inflammatory responses, and articular cartilage degradation (30). A recent randomized double-blind, placebo-controlled clinical trial assessing the effect of the probiotic “Lactobacillus casei Shirota” on knee osteoarthritis, also reported a Strong linear correlation between serum hs-CRP levels (an acute-phase protein released into the blood by the liver during inflammation) and pain scores after 6 months of probiotic consumption; This study suggested that probiotic consumption could serve as a novel therapeutic option in the clinical management of knee OA, improving treatment outcome likely through reducing serum hs-CRP levels (23).
To date, it is still debated how much the inflammation per se contributes to pain in osteoarthritis. Table 1. and table 2. (at the end of this document) demonstrate a summary of studies on probiotic anti-inflammatory effects in in-vitro and in animal studies, respectively.
A variety of studies have investigated various aspects of inflammation in cases such as synovitis but still no clear associations to pain have been found (31). Many studies have attempted to modulate the effect of the inflammatory mediators on pain receptors by e.g., interacting with the arachidonic acid pathways (32).
The aim of this study is to investigate the systematic anti-inflammatory effect produced following two months of oral supplementation of Probiotic “Lactobacillus rhamnosus PB01” and evaluate how this can modulate pain and pain sensitivity in the osteoarthritic knee, assessed by quantitative sensory testing (QST). Lactobacillus rhamnosus PB01 is available and can be purchased in health stores under the tradenames “Maxiflor” and “Dicoflor”