Causation Cleveland Clinic researchers discover new bacterium (Tomasiella immunophila) that causes gut immunodeficiency (Sep 2024) A host-adapted auxotrophic gut symbiont induces mucosal immunodeficiency

Michael Harrop

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https://www.eurekalert.org/news-releases/1058963
https://www.science.org/doi/10.1126/science.adk2536

The team identified the bacterium, Tomasiella immunophila (T. immunophila), which plays a key role in breaking down a crucial immune component of the gut’s multi-faceted protective immune barrier.

In the gut, SIgA binds continuously to microbes, preventing them from reaching and damaging the body’s tissue. In previous research, the team discovered that intestinal bacteria could reduce SIgA levels, which can lead to increased risk of infection and excess inflammation.

Editor’s summary​

The era of the microbiome has been opened by next-generation sequencing, and this tool has offered hints of multiple therapeutic targets for human diseases. However, it remains a challenge to pinpoint the cause of a clinical problem to any one species or consortium of microorganism.

Using a screen to identify immunoglobulin A–degrading bacteria, Lu et al. have identified a previously unknown genus and species called Tomasiella immunophila (see the Perspective by Slack). This organism specifically stimulates self-recognizing kappa–light chain immunoglobulin secretion. Outer membrane vesicles from the organism containing a rich array of proteases degraded these host proteins.

Thus, T. immunophila appears to be able to stimulate a supply of host origin nutrients for its own consumption while potentially immunocompromising the host sufficiently to cause disease while also selecting for resistant immunoglobulin subclasses. —Caroline Ash

Structured Abstract​

INTRODUCTION​

Secretory immunoglobulin A (SIgA) is a crucial component of mucosal barriers. Decreased SIgA levels are associated with increased vulnerability to infections and excessive inflammation in response to mucosal damage. The production of intestinal SIgA depends on the microbiome and specific microorganisms can drive the magnitude of the overall immune response. Conversely, mice have been observed with spontaneous reduction in intestinal SIgA levels; this phenotype has been proposed to be mediated by IgA degradation directed by gut symbiotic bacteria. However, the specific bacteria contributing to low levels of intestinal SIgA in mice remain unknown.

RATIONALE​

We developed an in vitro functional biochemical assay to screen gut bacteria from mice with low levels of SIgA. Our goal was to identify bacterial symbionts contributing to IgA degradation and to understand their relationship with the host and other components of the microbiome.

RESULTS​

We conducted a functional screen of the bacterial microbiota in wild-type (WT) mice with spontaneous low levels of intestinal SIgA. This screening led to the discovery and identification of a previously unidentified Gram-negative bacterium belonging to the Muribaculaceae family. The proposed name is Tomasiella immunophila, and it exhibits strong proteolytic activity against IgA. We found that T. immunophila was auxotrophic for N-acetylmuramic acid (MurNAc), a critical component of bacterial cell walls, which was essential for its optimal growth in vitro. T. immunophila alone did not colonize WT conventionally raised or germ-free mice. However, fecal slurries from IgA-high mice facilitated T. immunophila colonization in WT mice, suggesting that helper strains are crucial for its successful colonization in the mouse intestine. As a result, mice colonized with T. immunophila exhibited reduced levels of SIgA in the intestine and increased susceptibility to mucosal pathogens such as Salmonella Typhimurium and Candida albicans. Furthermore, these mice also showed delayed mucosal barrier repair in response to dextran sulfate sodium-induced intestinal injury. Additionally, mucosal exposure to T. immunophila in mice induced the production of intestinal SIgA specific to this bacterium. T. immunophila secreted multiple types of immunoglobulin-degrading proteases associated with its outer membrane vesicles and these proteases were observed to specifically degrade all isotypes and subclasses of mouse antibodies; the enzymatic activity did not extend to unrelated proteins. The degradation of immunoglobulins by T. immunophila was particularly selective for rodents. Recombinant antibodies that contain the mouse kappa chain were cleaved by T. immunophila regardless of the species of the heavy chain. Notably, T. immunophila preferentially degraded antibodies harboring kappa light chains while sparing those with lambda light chains.

CONCLUSION​

This study provides evidence regarding the critical role played by the degradative capabilities of the gut microbiome in specific aspects of the mucosal immune and intestinal barrier system. Our research highlights how certain bacterial species, here T. immunophila, are particularly pivotal in this regard. The nutrient requirements of T. immunophila for MurNAc underscores its prominent role within the gut ecosystem, highlighting the intricate and complex nature of polymicrobial interactions. The challenges associated with isolating auxotrophic microorganisms further underscore the complexity of studying these organisms. Furthermore, the host species specificity of IgA degradation suggests a coevolutionary relationship between the gut microbiome and the host. These findings emphasize the important role of symbiotic bacteria such as T. immunophila in mucosal immunodeficiency, providing potential insights into related human diseases. Our study also highlights the importance of employing functional rather than descriptive techniques to identify microorganisms associated with host phenotypes or diseases.
 
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