The Systemic Antimicrobiota IgG Repertoire Can Identify Gut Bacteria That Translocate Across Gut Barrier Surfaces

Alterations in gut microbiota are associated with inflammatory disease, although evidence suggests that bacterial translocation and engagement of systemic immunity may be a more important functional indicator although the specifics of this are hard to assess. The purpose of this study was to identify microbes associated with gut translocation and increased systemic IgG responses in humans.

The study included male C57BL/6J-CD45a(Ly5a) mice aged 3 to 7 weeks infected with T. gondii and Y. pseudotuberculosis. Healthy human volunteers (N = 12) had serum and autologous stool collected. A second group of participants, both healthy (N = 9) and with inflammatory bowel disease (IBD) (N = 29), had serum sampling matched to a surrogate fecal community (SFC).

Antimicrobiota systemic IgG (IgG-seq) and mucosal IgA were profiled using magnetic bead-based separation and 16S ribosomal RNA sequencing of Ig-bound and unbound fecal bacteria. Ig-scores were calculated by comparing relative abundance of bound microbial taxa in serum and stool. A modified IgG-seq procedure was developed using human serum samples and an SFC, which demonstrated concordance with autologous stool. IgG reactivity toward translocating bacteria in mice was experimentally induced using T. gondii and Y. pseudotuberculosis. SFC-IgG-seq was applied to a cohort of patients with IBD using mesenteric adipose tissue sampling as a marker of gut translocation. Microbial transcriptional activity and growth rates were correlated with systemic IgG.

Translocating microbes demonstrated higher Ig-scores in mice infected with T. gondii and Y. pseudotuberculosis. Antimicrobial IgG targeted translocating microbiota, whereas antimicrobial IgA did not. IgG-targeted bacteria had heightened markers of T cell activation in the blood. SFC-IgG-seq when applied to those with IBD had a significant increase in IgG-score when gut translocation was present. Specific taxa were preferentially targeted by IgG in serum samples from IBD compared with healthy controls (eg, Collinsella, Bifidobacterium, Lachnospiraceae, and Ruminococcaceae.).

Microbial proliferative activity and taxa whose transcriptional rate correlated with dysbiosis overlapped with taxa identified by IgG-seq.

IgG specific to translocated microbiota can be reliably identified in humans and appear to be a marker of systemic immune response and link to inflammatory disease.

The authors use a unique study design to identify microbiota that translocate the gut and elicit systemic IgG antibody responses. They were further able to validate a means to quantify IgG against microbiota using blood specimens on a surrogate human fecal community, hence not requiring paired stool sample or culture. This study offers a novel means to measure the functional impact of increased gut translocation and dysbiosis, further improving our understanding of the link with inflammatory disease and immune dysregulation.