Dysbiosis is defined as an altered diversity, composition, and structure of the intestinal microbiota, which can be caused by a spectrum of chronic inflammation and is collectively identified as IBD. [25, 26] The understanding and control of the gut microbiota is the key to overcoming IBD. However, despite the critical role of anti-TNF-α therapy in the treatment of UC, limited knowledge exists regarding the longitudinal changes in the gut microbiome following anti-TNF-α therapy. While the restoration of gut diversity has been previously noted with anti-TNF therapy, [12] a comprehensive understanding of the distinctions in the gut microbiome linked to the clinical responses during anti-TNF-α therapy is still lacking. We conducted a longitudinal analysis of changes in the gut microbiome in patients with UC before and after ADA treatment, followed by a description of these changes in relation to clinical response in the present study.
In patients with UC, notable variations in the microbial community structure were observed when compared to those in the HC, as evidenced by distinct features in Shannon’s diversity and beta diversity. However, alpha diversity comparisons based on disease severity or extent did not reveal significant differences. Nonetheless, the composition of gut microbes varies according to the severity or extent of the disease. Three ASVs assigned to Lactobacillus, Streptococcus sp., and class Bacilli were consistently identified as the predominant ASVs in patients with UC when comparing both HC and patients with UC based on the extent of the disease and disease severity. In particular, Bacilli (ASV2551) and Streptococcus (ASV3437, ASV3508, and ASV3519) were consistently present in patients with severe disease and extensive colitis. Previous studies related to UC also reported the enrichment of Lactobacillus and Streptococcus in patients with UC, [27, 28] while several species within Lactobacillus and Streptococcus are categorized as lactic acid bacteria. [29] Specific highly virulent strains of Streptococcus species have been considered potential risk factors for systemic inflammatory diseases, including UC. [30, 31] Additionally, certain Lactobacillus species are proposed to be linked with extensive disease involvement and heightened disease activity. [32] Although no clear evidence supports the association of a specific type of gut bacteria with UC development, these findings suggest that as the disease progresses, the gut environment may change to favor the colonization and expression of certain bacteria. Thus, the changing gut environment should be considered with the progression of the disease through further research.
In our study, despite patients with UC achieving clinical remission at 8 or 56 weeks after ADA treatment, their overall microbial diversity did not recover to the levels observed in the HC group. When comparing the gut microbiota composition of patients who reached clinical remission at 56 weeks with HC using LEfSe analysis, a notable difference in the abundance of various bacterial species was observed between the two groups. However, dissimilarity significantly decreased in patients who achieved clinical remission compared to before treatment, and notably, at 8 weeks of treatment, remitters showed significantly lower dissimilarity compared to non-remitters. The dissimilarity is a measure used to quantify how distinct one microbial community is from another in terms of composition, structure, or function. These findings suggest that clinical remission with anti-TNF-α therapy does not result in the transformation of the gut microbiota composition to resemble that of HC; instead, patients seem to establish their distinct gut microbial community.
The genus-level analysis showed a significant decrease in Burkholderia-Caballeronia-Paraburkholderia and Staphylococcus and significant increase in Bifidobacterium and Dorea from baseline to week 56 in patients with UC who showed clinical remission. A previous study reported that a higher proportion of the Burkholderiales order could be a biomarker of clinical response to anti-TNF treatment. [33] This suggests that, although very little is known about this aspect, Burkholderia-Caballeronia-Paraburkholderia may be associated with anti-TNF treatment response in patients with UC. Further research is warranted on these taxa in patients with UC treated with anti-TNF agents. A low relative abundance of Bifidobacterium and Dorea in patients with active UC was consistent with the findings of previous studies, [34, 35] and a high relative abundance of Staphylococcus in patients with UC was observed in a previous study that revealed S. aureus infection in the gut during IBD. [36] Bifidobacterium is the well-known butyrate-producing bacteria in the human gut and showed lower abundance in patients with active UC than in the remitters. [37, 38] Although a simple increase or decrease in specific bacteria may not fully reflect the overall gut microbiome status of patients with UC, our study provided a specific list of gut microbes for patients who achieved clinical remission through ADA treatment and suggested the evidence of the correlation between ADA treatment and gut microbes. We considered that the changes in the gut microbiome composition observed in patients who achieved remission through ADA treatment could be applied for exploring therapeutic targets for the treatment of UC.
In the present study, we identified a notable difference in the abundance of each gut microbe at the ASV level between baseline samples showing clinical remission and those showing no remission. ASVs belonging to Sporosarcina, Bacteroides spp., Enterobacter, and Prevotella bivia DSM 20514 were higher in baseline samples of week-8 remitters. ASVs assigned to taxa, including Bifidobacterium, Blautia, Enterococcus, and Lachnospiraceae, were less common in baseline samples of remitters. In addition, the log ratio of positive to negative ASVs was higher in remitters than in non-remitters based on the ROC curve analysis of baseline samples for predicting the response to ADA treatment. This result shows the importance of analyzing ASV levels to identify key microbes associated with an active member of the UC gut. The ratio of positive to negative ASVs could be a key factor for evaluating the effectiveness of ADA treatment in patients with UC.
Our study has several limitations. First, the smaller number of samples at 56 weeks could introduce bias into the longitudinal analysis. Additionally, the majority of samples collected at 56 weeks were from patients who demonstrated treatment efficacy at that time point. Second, this study may not account for all potential confounding factors that could influence the gut microbiome, such as dietary habits or lifestyle factors. Third, while this study contributes to understanding the microbial community dynamics influenced by anti-TNF treatment, the specific mechanisms and causal relationships between microbial changes and treatment outcomes were not elucidated. Lastly, the duration of the study, up to 56 weeks post-treatment, might not capture the long-term effects or changes that could occur beyond this timeframe. Considering these limitations, future research with larger and more diverse cohorts, longer follow-up durations, and consideration of potential confounding factors would provide a more comprehensive understanding of the effects of ADA therapy on the gut microbiome in patients with UC.