Severity of Experimental Autoimmune Uveitis Is Reduced by Pretreatment with Live Probiotic Escherichia coli Nissle 1917

Abstract

Non-infectious uveitis is considered an autoimmune disease responsible for a significant burden of blindness in developed countries and recent studies have linked its pathogenesis to dysregulation of the gut microbiota. We tested the immunomodulatory properties of two probiotics, Escherichia coli Nissle 1917 (EcN) and E. coli O83:K24:H31 (EcO), in a model of experimental autoimmune uveitis (EAU). To determine the importance of bacterial viability and treatment timing, mice were orally treated with live or autoclaved bacteria in both preventive and therapeutic schedules. Disease severity was assessed by ophthalmoscopy and histology, immune phenotypes in mesenteric and cervical lymph nodes were analyzed by flow cytometry and the gut immune environment was analyzed by RT-PCR and/or gut tissue culture. EcN, but not EcO, protected against EAU but only as a live organism and only when administered before or at the time of disease induction. Successful prevention of EAU was accompanied by a decrease in IRBP-specific T cell response in the lymph nodes draining the site of immunization as early as 7 days after the immunization and eye-draining cervical lymph nodes when the eye inflammation became apparent. Furthermore, EcN promoted an anti-inflammatory response in Peyer’s patches, increased gut antimicrobial peptide expression and decreased production of inducible nitric oxide synthase in macrophages. In summary, we show here that EcN controls inflammation in EAU and suggest that probiotics may have a role in regulating the gut–eye axis.

A Role for Folate in Microbiome-Linked Control of Autoimmunity

“…The use of folate- and SCFA-producing microbes has the potential to form the basis for a novel approach to prophylactic control of AD. While emerging data suggests oral probiotics [ 158 , 181 ] or alternatively FMT [ 182 ] might help eliminate dysbiosis, knock-on effects on colonic folate synthesis/bioavailability and its implications for immune cell functioning remain to be explored. As dysbiosis has been found to occur in a range of AD, including uveitis [ 36 , 183 , 184 ], targeted administration of certain beneficial folate-producing bacteria or even direct oral folate treatment in AD merits clinical evaluation as a low-risk effective adjunctive treatment option.…”

“…thermophilus CRL 415 , have been shown to prevent intestinal inflammation in experimental models and proposed for the treatment of dysbiosis [ 157 ]. Probiotics have been proven to prevent EAU in mice, and delivery of folate-producing probiotics offers a safe and tolerable supplement in the treatment of AD [ 158 ].…”

Microbiome in Immune-Mediated Uveitis

“…Supplementation with IRT-5 probiotics (Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Bifidobacterium bifidum, and Streptococcus thermophilus) following removal of the microbiota with antibiotics reduced the severity of induced EAU in mice [57]. Likewise, treatment with the live probiotic Escherichia coli Nissle 1917 (EcN) prior to the induction of EAU in mice also protected against the development of uveitis and produced reinforcement of the integrity of the intestinal mucosa towards an anti-inflammatory state [56]. Supplementation with IRT-5 probiotics (Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Bifidobacterium bifidum, and Streptococcus thermophilus) following removal of the microbiota with antibiotics reduced the severity of induced EAU in mice [57].…”

“…Supplementation with IRT-5 probiotics (Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Bifidobacterium bifidum, and Streptococcus thermophilus) following removal of the microbiota with antibiotics reduced the severity of induced EAU in mice [57]. Likewise, treatment with the live probiotic Escherichia coli Nissle 1917 (EcN) prior to the induction of EAU in mice also protected against the development of uveitis and produced reinforcement of the integrity of the intestinal mucosa towards an anti-inflammatory state [56].…”

“…The above-mentioned studies have provided compelling evidence for the involvement of the microbiome in the pathogenesis and progression of NIU and have demonstrated the potentially beneficial effects of several treatment approaches that have an effect, directly or indirectly, on the microbiome, such as supplementation of probiotics or prebiotics, FMT, DMARDs and biological drugs. Probiotics and prebiotics, through direct modulation of the microbiome, have demonstrated an enhancement of the anti-inflammatory response of the intestinal immune system in animal models by increasing gut antimicrobial peptide expression [56] and decreasing the production of pro-inflammatory cytokines in the retinas [44] and cervical lymph nodes [57]. In addition, supplementation of prebiotics, mainly SCFAs, modifies the balance of T cells, switching from pathogenic Th17 to Treg [44] and decreasing induction of effector T cells [42].…”