Zinkernagel et al.
13 noted a significant change in the relative abundance of Firmicutes and Bacteroidetes at the phylum level among AMD patients, with a relative increase in Firmicutes and a decrease in Bacteroidetes. This observation is consistent with previous studies indicating that a high ratio of Firmicutes to Bacteroidetes is often associated with obesity, which is itself a risk factor for AMD.
41 This is consistent with our research. Here, we observed that the
Eubacterium oxidoreducens group,
Faecalibacterium, and Ruminococcaceae
UCG-011 are risk factors for AMD. It is worth noting that all of them are Firmicutes. In a study using a mouse model, it was demonstrated that high-fat diets can worsen choroidal neovascularization by increasing the prevalence of Firmicutes bacteria. These observations were linked to an increase in intestinal permeability and chronic inflammation, with elevated levels of interleukin (IL)-6 and IL-1b, tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor A (VEGF-A) cytokines. These cytokines have been previously associated with the progression of neovascular AMD.
37 From the phylum standpoint, the effect of Firmicutes increases the risk of the onset of AMD perhaps both directly and indirectly, because, with the increase of Firmicutes, there is often a decrease in Bacteroides. The generation of volatile fatty acids from the fermentation of carbohydrates, which is then reabsorbed through the intestinal mucosa and serves as a key source of energy for the host, is known to be significantly influenced by the Bacteroides genera.
42 Moreover, Bacteroides has the capacity to produce polysaccharide A (PSA), which, through interactions with ligand receptors, may be implicated in the control of the immune response to pathogens. In fact, research has demonstrated that PSA produced from Bacteroides species can guard against autoimmune encephalitis in an experimental setting.
43 A more detailed analysis of the microbiota in patients with AMD revealed significant increases in the relative abundances of two specific bacterial taxa:
Ruminococcus torques, a Gram-positive bacterium known for its ability to degrade mucin, and
Oscillibacter, which has been previously linked to high-fat diets.
44 These findings suggest that these particular bacteria may play a role in the development or progression of AMD. This is consistent with our analysis results, which indeed suggest that they are risk factors for AMD. Recent studies have suggested that specific bacterial taxa, including
Oscillibacter,
Anaerotruncus, and
Eubacterium ventriosum spp., may contribute to the pathogenesis of age-related diseases such as AMD. Increased populations of
Oscillibacter have been associated with heightened gut permeability, potentially due to a reduction in the mRNA expression of tight junctions such as zonula occludens 1 (ZO-1).
45 Likewise, elevated levels of
Anaerotruncus species have been linked to aging and age-associated inflammation in a mouse model, with corresponding increases in proinflammatory chemokines.
46 In humans, high levels of
Eubacterium ventriosum spp. have been associated with elevated levels of proinflammatory cytokines such as IL-6 and IL-8.
47 These findings provide important insights into the mechanisms underlying the development and progression of AMD. Overall, our predictions are consistent with the data previously obtained in the laboratory, and the relevant mechanisms have also been reported. It is logical that the
Eubacterium oxidoreducens group,
Faecalibacterium, and
Ruminococcaceae UCG-011, as risk factors for AMD, have shown increased abundance in AMD compared to control groups. However, the research by Zinkernagel et al.
13 about
Anaerotruncus is not consistent with the results of our study. They pointed out this bacterium increased when triggered by inflammation. However, in the overall context of the disease, we believe that it has a protective effect against AMD. This may be because there are not many SNPs acting as instrumental factors, and they only account for causation in a limited way. However, this cannot completely negate the possibility of
Anaerotruncus being protective. Inflammation is a double-edged sword in the onset of diseases. The abnormal proliferation of
Anaerotruncus may be due to the overall growth suppression of other phyla by Firmicutes, creating favorable conditions for the proliferation of
Anaerotruncus. In summary, we have raised an intriguing question, and further laboratory validation is necessary. Let us focus on another protective role on AMD that we observed. The hallmark of neovascular or wet AMD, one of the advanced stages of AMD, is the presence of CNV.
48 Li et al.
49 found that, compared to normal mice, the abundance of
Candidatus Soleaferrea was significantly downregulated. In CNV mice, the proportion of
Candidatus Saccharimonas increased and the proportion of
Candidatus Soleaferrea decreased. This suggests that, perhaps in normal mice,
Candidatus Soleaferrea may play a protective role by resisting the metabolic pathway changes and inflammation induced by
Candidatus Saccharimonas. Hence, although the precise mechanisms remain unclear, there is a possibility that
Candidatus Saccharimonas is linked to inflammation and the resulting immune response of the host.
50