Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn’s disease and CFS 2024 Vogl+

Full title: Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn’s disease and chronic fatigue syndrome

Abstract

Background
Elevated systemic antibody responses against gut microbiota flagellins are observed in both Crohn’s disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting potential serological biomarkers for diagnosis. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) “stimulator” and (2) “silent” flagellins, which bind TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 (involving a C-terminal domain); (3) “evader” flagellins of pathogens, which entirely circumvent TLR5 activation via mutations in the N-terminal TLR5 binding motif.

Results
Here, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling “stimulator” and “silent” flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS.

Conclusions
These findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance.

Open access, https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-024-01858-1

 

Very similar looking previous publications from the same group
Systemic antibody responses against gut microbiota flagellins implicate shared & divergent immune reactivity in Crohn's Disease & CFS, 2024, Bourgonje

Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients, 2022, Vogl et al

 

Graphical Abstract


There is a 2-minute video abstract on the journal site.

 

Great to see this.
Apologies for my standard reply - wouldn't this turn up in a:

• GWAS [DecodeME - common genetic variants]; &/or
• whole genome sequence studies/rare variant genetic studies (e.g. families with more than 1 member affected & at least 1 severe);

i.e. if it were a common cause of ME/CFS?

 

Difficult paper to read. I assume these are the main results?

Anti-fagellin antibody responses against any type of fagellin were increased in patients with CD and ME/CFS compared to matched healthy controls (Wilcoxon tests, P=4.6× 10−10 and P=8.9× 10−10 for CD vs. HC-NL and ME/CFS vs. HC-UK, respectively) (Fig. 2a– b).

 

The p-value is really small for ME/CFS given that only 40 patients from the UK biobank were used.

The authors also wrote:

 

Borrelia is noted as one of the flagellin-culprits. Didn't see what percent.