Written by: Sandeep Ravindran, Ph.D. | Issue # 46 | 2016
- Rheumatoid arthritis is a chronic inflammatory disorder affecting about 1% of the US population, and current therapies have many limitations.
- Previous work found that a non-pathogenic Salmonella strain engineered to express the Escherichia coli protein, Colonization factor antigen I (CFA/I) ameliorated arthritis symptoms in a mouse model.
- In a new study, researchers genetically modified the probiotic bacteria Lactococcus lactis to express CFA/I.
- The new study showed that arthritic mice fed these bacteria experienced a dramatic reduction in arthritis symptoms, and the effect appeared to be mediated by a suppression of inflammatory responses.
- Mice fed milk fermented with L. lactis also experienced a dramatic reduction in arthritis symptoms.
- The findings suggest that milk fermented with CFA/I-expressing L. lactis could be developed as a therapy against arthritis and other autoimmune or inflammatory diseases.
Consuming dairy products, such as milk or yogurt, is known to be good for general health [1]. New research may make dairy products even more beneficial by enabling them to treat certain autoimmune diseases such as arthritis.
In a study conducted by David Pascual at the University of Florida, arthritic mice were fed genetically-modified probiotic bacteria, or a yogurt-like product created using the same bacteria. In both treatments, the mice experienced a dramatic reduction in their arthritis symptoms [2]. “We believe that a yogurt-like therapeutic may have a tremendous appeal to a segment of consumers who are less willing to use ‘pills’,” writes Pascual in an email.
The same approach could be used to develop therapeutics against other autoimmune and inflammatory diseases as well. “What really makes our approach unique is that the very same ‘tool’ can be adapted to different autoimmune diseases, like a sort of panacea,” writes Pascual.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that affects about 1% of the US population [3,4]. Physical and nutritional therapies are unable to stop the disease’s progression, and pharmacological therapies typically rely on anti-inflammatory drugs, which have harmful side-effects and often increase the risk of other infections [5,6].
To find other ways to modulate harmful autoimmune and inflammatory reactions, researchers have looked to pathogenic bacteria for inspiration. “One of the ideas we pursued is that pathogens attach to mucosal tissues in such a way as to silence the immune response, avoiding detection,” writes Pascual. To attach to the intestinal mucosa and colonize it, certain pathogenic Escherichia coli express proteins known as “colonization factor antigens.” In previous work, the researchers genetically modified a non-pathogenic strain of Salmonella typhimurium to express one of the E. coli proteins, Colonization factor antigen I (CFA/I). They found that the modified bacteria could serve as an oral vaccine with anti-inflammatory properties, and could help treat autoimmune diseases [7,8]. “Our data showed that the Salmonella-CFA/I remarkably ameliorated RA symptoms in an experimental mouse model,” writes Pascual.
“Because S. typhimurium is intrinsically proinflammatory, as well as [due to] regulatory concerns about its therapeutic application, we decided to switch to a food-grade organism,” writes Pascual. “The logical choice was lactic acid bacteria and specifically, Lactococcus,” he writes. Lactococcus lactis is commonly used in fermented dairy products and has been approved for human use [9,10].
The researchers engineered Lactococcus to express CFA/I and tested their therapeutic properties in a mouse model of arthritis. “Following two doses, our recombinant Lactococcus expressing CFA/I showed a stunning capability to ameliorate RA in mice,” writes Pascual. “In contrast, untreated mice or mice given Lactococcus (without CFA/I) only were still susceptible to RA,” he writes. The therapeutic effect appeared to be mediated by the suppression of pro-inflammatory signaling molecules.
The researchers then fermented milk using the CFA/I-expressing bacteria, creating “a dairy product whose texture and olfactory features are indistinguishable from yogurt,” writes Pascual. When the mice were fed this yogurt-like preparation, their arthritic symptoms reduced dramatically.
The researchers are currently testing their approach in a mouse model of type I diabetes, as well as in large animal models of human disease. “Once we can demonstrate efficacy in these larger animals, we can pursue testing in humans,” writes Pascual. “While the final application in humans may not be exactly around the corner, we are ecstatic at the flexibility of our system,” he writes.
References
1. Tunick MH, Van Hekken DL. Dairy products and Health: recent insights. J Agric Food Chem. 2015 Nov 4;63(43):9381–8.
2. Maddaloni M, Kochetkova I, Jun S, Callis G, Thornburg T, Pascual DW. Milk-based nutraceutical for treating autoimmune arthritis via the stimulation of IL-10- and TGF-β-producing CD39+ regulatory T cells. Fang D, editor. PLoS ONE. Public Library of Science; 2015;10(1):e0117825.
3. Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, et al. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. BMJ Publishing Group Ltd and European League Against Rheumatism; 2014 Jul;73(7):1316–22.
4. Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid arthritis. Best Pract Res Clin Rheumatol. Elsevier; 2010 Dec;24(6):733–45.
5. Rosenblum H, Amital H. Anti-TNF therapy: safety aspects of taking the risk. Autoimmun Rev. 2011 Jul;10(9):563–8.
6. Keyser FD. Choice of biologic therapy for patients with rheumatoid arthritis: the infection perspective. Curr Rheumatol Rev. 2011 Feb;7(1):77–87.
7. Pascual DW, Ochoa-Repáraz J, Rynda A, Yang X. Tolerance in the absence of autoantigen. Endocr Metab Immune Disord Drug Targets. 2007 Sep;7(3):203–10.
8. Wu S, Pascual DW, VanCott JL, McGhee JR, Maneval DR, Levine MM, et al. Immune responses to novel Escherichia coli and Salmonella typhimurium vectors that express colonization factor antigen I (CFA/I) of enterotoxigenic E. coli in the absence of the CFA/I positive regulator cfaR. Infect Immun. American Society for Microbiology (ASM); 1995 Dec;63(12):4933–8.
9. Wells J. Mucosal vaccination and therapy with genetically modified lactic acid bacteria. Annu Rev Food Sci Technol. Annual Reviews; 2011;2(1):423–45.
10. Steidler L, Rottiers P, Coulie B. Actobiotics as a novel method for cytokine delivery. Ann N Y Acad Sci. Blackwell Publishing Inc; 2009 Dec;1182(1):135–45.