In a recent study published in eBioMedicine, researchers explored the connection between the metabolic function of the gut microbiota (metabolome), its composition, and immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in inflammatory bowel disease (IBD) patients.
Patients with IBD are highly immunosuppressed, especially those receiving anti-tumor-necrosis factor (TNF) therapy, e.g., infliximab. They exhibit attenuated humoral immune responses to SARS-CoV-2 vaccines, indicating that a dysbiosis in the gut microbiota's functional metabolic output and composition plays a crucial role in shaping immunity.
About the study
In the present observational study, researchers explored the three-way interplay between IBD, gut microbiota, and immunosuppressive therapy. They prospectively collected serum and fecal samples from infliximab-treated IBD patients enrolled in the CLARITY-IBD study for SARS-CoV-2 vaccination.
The researchers subjected all participants to serological analyses at eight-week periods, regardless of the time of vaccination. Next, they measured antibody responses following two dose-regimen of ChAdOx1 nCoV-19 or BNT162b2 vaccine in these patients, categorized into individuals with immune responses above or below the geometric mean of the aggregate CLARITY-IBD cohort.
The team used an anti-SARS-CoV-2 spike (S) electrochemiluminescence immunoassay in which antibody concentration greater than or equal to 0.12 U/ml indicated that a patient had no history of coronavirus disease 2019 (COVID-19). Note that the geometric mean titer of antibody concentration, though higher in patients with previous infection, waned over time.
Next, the researchers extracted deoxyribonucleic acid (DNA) from crude fecal samples to perform 16S ribosomal ribonucleic acid (rRNA) gene sequencing. They performed one-dimensional proton nuclear magnetic resonance (1H-NMR) spectroscopy for fecal metabolite extraction and profiling. They also analyzed fecal samples using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) for bile acid profiling.
Post-statistical analyses of 1H NMR and UHPLC-MS data, the team also performed supervised Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) and unsupervised Principal Components Analysis (PCA). It helped them assess metabolite differences between study groups with disparately abundant gut metabolites reported with q value <0.2 after correction for false discovery rate (FDR).
The study recruited 43 IBD patients between 25 January and 15 March 2021. Of these, 30 and 12 had Crohn's disease and ulcerative colitis, respectively, whereas one was IBD-unclassified, and the remaining 26 were on concomitant thiopurine therapy. When stratified by vaccine type and prior infection status, 58.1% and 41.9% of 25 patients had SARS-CoV-2 antibody levels above and below the geometric mean, respectively. However, such differences were not statistically different when stratified by age, gender, type of IBD or vaccine, or immunomodulator used in a patient.
In addition, the gut microbiota composition of these 25 patients varied with above and below-average antibody concentrations. Accordingly, beta diversity analysis showed decreased dispersion of inter-sample Aitchison distances in a group with below-average antibody concentration.
The study results add to the growing evidence that the gut microbiota modulates vaccine-triggered immune responses. Though most participants in this study received BNT162b2 and fewer individuals received ChAdOx1 nCoV-19, all showed poorer serological response to vaccination associated with Parabacteroides.
On the contrary, the abundance of the Bilophila genus appeared to correlate with a higher serological response to SARS-CoV-2 vaccination. Since BNT162b2 triggers SARS-CoV-2-specific T cell responses with a T helper cells (TH1) profile, the researchers postulated that Bilophila served as an adjuvant of vaccines in some IBD patients. It then engaged beneficial T-cells to generate anti-SARS-CoV-2 antibodies.
Further, the researchers observed that the gut microbiota synthesized metabolite trimethylamine (TMA) enhanced the weakened vaccine-triggered immune response observed in IBD patients on infliximab therapy. Likewise, they noted a correlation of better immune response to SARS-CoV-2 vaccination with a short-chain fatty acid, isobutyrate, and bile acid, omega-muricholic acid.
In the liver, TMA metabolizes to trimethylamine N-oxide (TMAO), an immune sensitizer that enhances the efficacy of cancer immunotherapy by promoting CD8+ T cell-mediated immunity. Furthermore, the researchers observed that fecal metabolites, taurine, phenylalanine, and succinate reduced vaccine-induced serological responses.
The study data confirmed that immunocompromised individuals show varying serological responses to COVID-19 vaccines under the influence of the gut microbiota.
Given the link between the composition and the gut metabolome and impaired serological response to SARS-CoV-2 vaccination in immunosuppressed IBD patients, therapies targeted at modulating the gut microbiota or supplementing it might be effective in enhancing reduced vaccine-induced immunogenicity. In particular, trimethylamine might mitigate the anti-TNF-induced weakening of the immune response to SARS-CoV-2 vaccination.