Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a leading cause of severe vision loss in the aged population. The etiology of AMD is multifactorial including nutritional factors, genetic variants mainly in the complement pathway, environmental risk factors and alterations in the intestinal microbiome. However, it remains unexplored whether there is an interdependency of these factors leading to the development of AMD. To investigate this issue, a shotgun metagenomics analysis of 57 neovascular AMD and 58 healthy controls as well as of 16 complement C3-deficient mice and 16 wildtypes was performed. Whereas the class Negativicutes was more abundant in patients, the genus Oscillibacter and species Bacteroides had a significantly higher prevalence in persons without AMD. Similar taxonomic features were identified that distinguished wildtype mice from C3-deficient mice. Moreover, several purine signaling pathways were associated with both, neovascular AMD and C3 deficiency. While SNPs within the complement factor B gene were more abundant in controls, SNPs within the high temperature requirement A serine peptidase 1 and complement factor H (CFH) genes were associated with neovascular AMD. Using a classification model, Negativicutes was identified as a potential biomarker for AMD and furthermore, it positively correlated with CFH. This study suggests an association between the intestinal microbiome and the complement system in neovascular AMD.

Associations of ARMS2 and CFH Gene Polymorphisms with Neovascular Age-Related Macular Degeneration

“…17 In Western populations, the associations of ARMS2 and CFH were documented in American, Dutch, Italian, Spanish, and Swiss populations. 14,[18][19][20][21][22][23] In Asian, similar associations were reported in Chinese, Japanese, and Indian populations. 15,[24][25][26][27] However, very limited evidence is available from Asian Malay population, which is also one of the biggest ethnic groups in Asia.…”

The Role of the Microbiome in Age-Related Macular Degeneration: A Review of the Literature

“…Furthermore, interdependency of the functional or taxonomic profile of the commensal microbiota and the expression of the complement factor CFH gene or the deregulation of the host complement system may be a potential mechanism that could be linked with AMD [25,26]. Purine signaling pathway genes have been found to be correlated with an unstable immune system response, as seen in autoimmune diseases [27].…”

“…The genes facilitating the aforementioned pathway were found to have augmented expression in patients suffering from AMD compared to controls. Moreover, Zysset-Burri et al [26] examined the association between the intestinal microbiome and the complement system in neovascular AMD and found that single nucleotide polymorphisms in the CFH gene associated with AMD were positively correlated with Negativicutes, a proposed biomarker for AMD. A cause-and-effect relationship remains unclear; however, the intestinal microbiome may potentiate an aberrant complement activation via purine signaling pathways that aid to the development of AMD.…”

“…A cause-and-effect relationship remains unclear; however, the intestinal microbiome may potentiate an aberrant complement activation via purine signaling pathways that aid to the development of AMD. Specifically, the intestinal microbiome of C3-deficient mice was reported to be enriched in genes of the 5-aminoimidazole ribonucleotide biosynthesis pathways, which may also be involved in the pathogenesis of AMD, pointing out that this pathway may be a key point in the interconnection between the intestinal microbiome, the complement system, and AMD [26]. In addition, the complement system is a key part of the innate system, operating through TLR signaling.…”

Retinitis Pigmentosa is Associated With Shifts in The Gut Microbiome

“…Moreover, the retina re ects some of the pathological alterations of many neurodegenerative diseases, and may provide information of brain pathology severity 31,32 . In this context, a few recent studies have linked gut microbiome changes with some retinal degenerative diseases 33,34 , including age-related macular degeneration (AMD) [35][36][37][38][39] , glaucoma [40][41][42][43] and diabetic retinopathy 44 , even though the published results vary depending on the type and stage of the disease and between studies. On the other hand, in a previous study we have demonstrated that invasive infection from gastrointestinal microbiome can induce activation of retinal microglia 45 , the primary resident immune cell of the retina.…”