Immunoglobulin A Coating Identifies Colitogenic Bacteria in Inflammatory Bowel Disease

Abstract

SUMMARY Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA−SEQ) and show that high IgA−coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA−SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with pre-defined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA−coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.

Moving beyond microbiome-wide associations to causal microbe identification

“…However, MWAS have produced long lists of implicated microbes without clearly elucidating their causal role, correlations have not always held up in subsequent studies, and notable differences have been observed between human and animal studies 1–3 . Although many correlations may simply reflect biomarkers of disease, causal links between the microbiome and disease susceptibility have been sporadically defined in studies that have initially identified immunomodulatory bacteria, functionally categorized the microbiota on the basis of immune recognition, or used complex bioinformatic heuristics to identify disease-modulating bacteria 6–11 . Ultimately, a generalizable pathway that refines the catalog of differentially abundant microbes identified by MWAS to include only those most likely causally related to the phenotype is lacking.…”

Human symbionts inject and neutralize antibacterial toxins to persist in the gut

“…However, the rules that determine community membership, especially at the species or strain level, are largely undefined. The gut environment is characterized by constant peristalsis and extensive niche heterogeneity, and factors previously implicated in shaping these communities (metabolites, vitamins, dietary polysaccharides, host IgA, bacteriocins) are freely diffusible (6)(7)(8). In this context, the recent identification of genes encoding type VI secretion systems (T6SSs) in the genomes of many prominent human gut symbionts was unexpected because the ability of these dynamic machines to inject toxic effectors into adjacent cells is strictly dependent on direct cell-to-cell contact (9)(10)(11)(12).…”

Intestinal IgA as a modulator of the gut microbiota

“…Our recent observations supported others' findings that intestinal IgA selectively binds harmful bacteria to eliminate them from the gut microbiota. 8 On the other hand, several reports demonstrated that IgA binding could facilitate gut colonization by bound bacteria, rather than suppressing their growth. 17,18 These results do not necessarily contradict our findings, because the IgA repertoire is so huge that it must contain a broad range of clones with different functions.…”

“…Intestinal IgA is important for control of commensal microbiota in the gut, [5][6][7][8] but it remains unknown how IgA recognizes and shapes this microbial community. To answer these questions, we generated IgA-producing hybridomas derived from lamina propria mononuclear cells of small intestine from unimmunized wild-type mice.…”

“…One promising agent capable of shaping the gut microbiota community is intestinal IgA. [4][5][6][7][8] Recently, we isolated a high-affinity poly-reactive IgA (clone W27) from mouse intestinal lamina propria cells, and identified it as a useful gut commensal modulator. 4 In standard mouse models of colitis and IgA disorders, oral treatment of W27 prevented pathological colon phenotypes by improving the composition of gut microbiota.…”