Microbiome, probiotics and rheumatoid arthritis
- The microbiome interacts with the immune system through the production of short-chain fatty acids. Butyrate has a favourable effect on immune tolerance, while acetate mainly stimulates the inflammatory immune response in a proinflammatory cytokine environment.
- In rheumatoid arthritis, a shift of the microbiome towards acetate producers is observed.
- Probiotics can be used to increase the colonisation of butyrate-producing bacteria.
What is the microbiome?
The intestinal microbial flora has co-evolved with the human species and has entered into a symbiotic relationship. The diversity and composition of the microbiome is determined, among other things, by genetic and dietary factors of the host. In recent years, it has become increasingly clear that the habitual intestinal bacteria interact indirectly with the host via their metabolites – short chain fatty acids (SCFAs) – whereby in a balanced microbiome intestinal epithelial cells are stimulated to maintain the balanced innate and acquired immune response in the gastrointestinal tract. In this process, the colon produces the majority of SCFAs, the most important and most studied of which are butyrate, propionate and acetate.
Butyrates are known to inhibit the proinflammatory NFκB signalling pathway, stimulate regulatory T lymphocytes as well as T effector cells (immune homeostasis) and are required by epithelial cells for proliferation and repair mechanisms to maintain the integrity of the intestinal epithelial layer. SCFAs can also influence cellular transcription and function of proteins via histone modifying enzymes (histone deacetylases, HDACs) (Fig.).
Acetate has a similar effect to butyrate, with the important difference that in a proinflammatory inflammatory milieu, mainly T effector cells (proinflammation) are stimulated, but not regulatory T cells (immune tolerance). Patients with autoimmune and autoinflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and psoriatic arthritis (PsA) show dysbiosis and reduced diversity of the intestinal microbiome.
Genetic predisposition plays a role in RA, although in recent years it has become apparent that environmental influences such as smoking, infections and the microbiome are also decisively involved in the pathogenesis.
Smoking leads to increased citrullination of proteins via peptidyl arginine deiminase (PAD), which could explain the appearance of anticitrullinated peptide antibodies (ACPA) up to 10 years before the development of the disease. In addition, smoking is associated with periodontitis, which is co-caused by Porphyromonas gingivalis. RA patients have a high incidence of periodontal disease and oral P. gingivalis colonisation. Epidemiological studies have shown a high incidence of P. gingivalis antibodies in RA patients, although despite numerous hypotheses of an infectious trigger, no direct bacterial evidence has been found. P. gingivalis is the only known commensal that expresses the PAD enzyme and thus citrullinates human proteins.
In the gastrointestinal tract, a reduction of the Bacteroidetes population and an increased occurrence of Prevotella copri (75 % compared to 25 % in the normal population) seem to be of particular importance. Furthermore, a reduction of Faecalibacterium, one of the most common physiological intestinal germs and a butyrate producer, as well as a shift of the microbiome towards acetate producers were found. The reduced diversity of the microbiome seems to be mainly determined by disease duration and the presence of autoantibodies. In a study by Zhang et al. with newly diagnosed and previously untreated RA patients, part of the healthy control group consisted of close relatives of RA patients. However, these had a microbial composition that was significantly closer to the remaining healthy controls than to the related RA patients, so that it must be assumed here that genetic, dietary and environmental influences seem to play a lesser role in the change of the microbiome. This study also showed that in therapy-naïve patients, the initiation of immune modulation and thus the reduction of disease activity led to a recompensation of the microbial flora.
Probiotics for Rheumathoid arthritis
In RA, some studies have tried to demonstrate a reduction in arthritis activity by oral probiotics. Lactobacillus casei was used for this purpose. One study showed a significant reduction in tumour necrosis factor (TNF) in serum, but no change in clinical parameters could be demonstrated. In a study by Zamai et al. with Lactobacillus rhamnosus, L. reuteri and L. casei, a significant reduction in IL-12 and TNF as well as C-reactive protein and clinical parameters was achieved. It must be mentioned, however, that the statistically significant reduction in disease activity after probiotic therapy nevertheless meant an average disease activity (DAS28 decreased from 4.0 to 3.7).
One of the biggest problems with the use of probiotics in the past was that the mostly facultative anaerobic probiotic strains were not able to colonise the lower GI tract. The most promising anaerobic bacteria that could be used here are: Akkermansia muciniphila, Bacteroides fragilis, Bacteroides thetaiotaomicron, Faecalibacterium prausnitzii and Prevotella histicola. A. muciniphila produces large amounts of SCFA and modulates the immune system; B. fragilis also appears to positively influence the immune system in the context of the disease; B. thetaiotaomicron influences the composition of the rest of the microbiome by reducing pathogenic bacteria such as Listeria monocytogenes, which in turn leads to an increase in beneficial gut bacteria; F. prausnitzii is considered one of the largest producers of butyrate (see above for effects); P. histicola promotes T-cell differentiation towards regulatory T-cells and promotes the proliferation of physiological intestinal germs such as Prevotella and Sutterella.
The extent to which the use of probiotics and rheumathoid arthritis in the future remains the subject of ongoing research. In any case, the future of probiotic therapy should lie in individual microbiome analysis and customised composition of probiotic strains to enable targeted optimisation of the microbiome.
1 Ley RE et al., Science 2008; 320(5883):1647–51
2 Zhou L et al., Inflamm Bowel Dis 2018; Doi: 10.1093/ibd/izy182
3 Scher JU et al., Nat Rev Rheumatol. 2011; 7(10):569–578
4 Chen J et al., Genome Med 2016; 1–14. DOI: 10.1186/s13073-016-0299-7
5 Zhang X et al., Nat Med 2015; 21(8):1–13
6 Alipour B et al., Int J Rheum Dis 2014; 17(5):519–27
7 Zamani B et al., In J Rheum Dis 2016; 19(9):869–79
Autor: Dr. Andreas Haidmayer, Klinische Abteilung für Rheumatologie und Immunologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz
Source (in German only): https://www.medmedia.at/univ-innere-medizin/das-mikrobiom-probiotika-und-rheumatoide-arthritis/