Gut microbiome dysregulation in noninfectious uveitis

Abstract

Noninfectious uveitis (NIU) is a vision-threatening autoimmune disease of the eye, but its pathogenesis is still not fully understood. Recently, accumulating evidence suggests that gut microbiome dysbiosis may affect the development and progression of NIU through potential mechanisms, including translocation, molecular mimicry, and bystander activation. Understanding the mechanisms of gut microbiome-host interactions, especially the gut-eye axis regulation, can offer a theoretical foundation for developing novel therapeutic strategies. We summarized current evidence on the dysregulation of gut microbiome and metabolites in NIU, and explored potential mechanisms involved. Furthermore, possible therapeutic measures are discussed, including probiotics, prebiotics, dietary modifications, antibiotic interventions, as well as fecal microbial transplantation, aiming to exert beneficial effects on NIU progression by reshaping the gut microbial composition.

Keywords: T helper 1/17 cell; T regulatory cells; dysregulation; gut microbiome; gut-eye axis; noninfectious uveitis; treatment intervention.

Figure 1

The factors that influence the gut microbiome and possible interactions between the gut and eye in uveitis. Many factors (such as stress, diet, antibiotics, smoking, infections, genetics, and age) may alter the composition of the gut microbiome. In most cases, these factors lead to changes in the abundance of SCFAs-producing bacteria (such as Clostridium, Lachnospiraceae, Butyricicoccus), lactic acid-producing bacteria (such as Bifidobacterium, Lactobacillus), and opportunistic pathogens like Pseudomonas, thereby affecting the levels of related metabolites (including SCFAs, secondary bile acids, and tryptophan metabolites such as kynurenine). Ultimately, an imbalance in the gut microbiome may regulate host immunity and drive the development of uveitis. (Created with BioRender.com) SCFAs, short-chain fatty acids; Th, T helper cells; Treg, regulatory T cells; Mφ, macrophage; DC, Dendritic cells.

Figure 2

Major microbial metabolic hypothesized pathways to impact uveitis risk and severity. (A) The gut microbiome breaks down host dietary fibers and indigestible carbohydrates to produce SCFAs. SCFAs can maintain the integrity of the intestinal barrier in uveitis and regulate immune cells by binding to FFAR2 or inhibiting HDAC. In addition, propionate can inhibit the migration of Teff cells, especially Th1 cells, from the gut to extra-intestinal lymph nodes. (B) CA and CDCA are metabolized by the gut microbiome to produce DCA and LCA. These two secondary bile acids can bind to TGR5, activate the cAMP-PKA signaling pathway, and inhibit NF-κB-mediated DC activation, thereby reducing the expression of proinflammatory cytokines and costimulatory molecules. (C) The tryptophan metabolism pathway includes the indole pathway, kynurenine pathway, and serotonin pathway. The indole pathway occurs in the intestinal lumen via the gut microbiome. Kynurenine can be further metabolized into anthranilic acid, which is a precursor of the quorum-sensing signal molecule PQS. PQS is synthesized by Pseudomonas through the pqsABCDE gene cluster. Upon binding with MvfR, it regulates the quorum-sensing system of Pseudomonas, thereby influencing the expression of its virulence factors. (Created with BioRender.com) SCFAs, short-chain fatty acids (A, acetate; P, propionate; B, butyrate); Th, T helper cells; Treg, regulatory T cells; DC, Dendritic cells; FFAR2, Free Fatty Acid Receptor 2; HDAC, Histone Deacetylase; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; TGR5, T G-protein coupled receptor 5; IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; TPH, tryptophan hydroxylase; Kyn, kynurenine; PQS, Pseudomonas Quinolone Signal; MvfR, Multiple Virulence Factor Regulator.

Figure 3

Probiotics, prebiotics, and antibiotics administration as a potentially beneficial strategy against uveitis. Probiotics. Preclinical studies through the EAU model have shown that probiotics used before or during immune induction can significantly reduce clinical scores. Clinical studies have found that combining conventional treatment (topical steroids) or prebiotics with probiotics can also significantly reduce disease severity and improve vision. Prebiotics. A significant positive correlation between secondary bile acid levels and Clostridium scindens was found in EAU mice. Clinical studies have highlighted changes in gut microbiome composition, with relative increases in Clostridium XIVa, Roboutsia, and Eggerthella, following supplementation with a butyrate-rich diet. Antibiotics. Preclinical studies have shown that long-term (oral administration of ANMV from maternal pregnancy to offspring after weaning) administration of ANMV in R161H mice significantly affected the gut microbiome composition (increased Proteobacteria, Tenericutes, and decreased Bacteroidetes, Firmicutes). Short-term administration of ANMV or ANMV+gentamicin (from one week before induction to the end of the experiment) also significantly affected the gut microbiome in B10.RIII induced EAU mice. (Created with BioRender.com) IRT-5 (Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Bifidobacterium bifidum, Streptococcus thermophilus); fructo-oligosaccharide (FOS); Escherichia coli Nissle 1917 (EcN); a broad-spectrum antibiotic cocktail of ampicillin, metronidazole, neomycin and vancomycin (AMNV); Experimental autoimmune uveitis (EAU).