Malevolent Design - A Newly-Discovered Gut Bacterium That Suppresses Immunity!

Drs. Thaddeus Stappenbeck, M.D., Ph.D., (left) and Qiuhe Lu, Ph.D., in the lab.

Cleveland Clinic Discovers Bacterium Causing Gut Immunodeficiency

The human gut, like that of other mammals, birds and vertebrates in particular and the gut of many insects and worms, in fact any organism with a moth and an anus, is an ideal environment for a whole host of other organisms, most of which will have co-evolved with humans and have been with us since our ancestors were small insectivores, skulking in the dark of the night to avoid dinosaurs and predatory proto-birds.

They for a complex and dynamic ecosystem of competing and cooperating bacteria, viruses, fungi and protozoa which exists in a more or less stable balance of arms races, predation and symbiosis.

Tell me all about the human gut microbiome and the dynamics of the arms races amongst them and with their human host? The human gut microbiome is a complex and diverse ecosystem of microorganisms, primarily bacteria, that inhabit the gastrointestinal tract. These microbes play crucial roles in various physiological processes, including digestion, immune system function, and even mental health. The interactions within this microbial community, as well as between the microbes and their human host, are dynamic and often involve evolutionary "arms races," characterized by both cooperation and competition.

Composition and Function of the Gut Microbiome

The gut microbiome consists of trillions of microbes, including bacteria, archaea, fungi, and viruses, although bacteria (especially from the Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria phyla) dominate. These microbes:

• Aid in digestion: They help break down complex carbohydrates, fibers, and other food components that the human body cannot digest on its own, producing short-chain fatty acids (SCFAs) like butyrate, propionate, and acetate, which are essential for gut health.
• Modulate immune responses: The gut microbiota interacts with the immune system, training it to distinguish between harmful and harmless entities. It influences the development of immune tolerance, preventing excessive inflammation and autoimmunity.
• Synthesize vitamins and metabolites: Certain gut bacteria synthesize vitamins like B12, K, and folate, as well as key metabolites that influence various aspects of human physiology.

The Evolutionary Arms Race Among Microbes

The microbes within the gut are not in perfect harmony; they engage in a constant evolutionary arms race with each other as they compete for space and nutrients. This intra-microbial competition involves several mechanisms:

1. Production of antimicrobials: Some bacteria produce bacteriocins or other antimicrobial peptides to inhibit or kill rival species. For example, Lactobacillus species can produce lactic acid and other compounds that lower the gut’s pH, making it less hospitable for certain pathogens.
2. Resource competition: Microbes in the gut compete for limited nutrients, such as fiber and sugars. They have evolved sophisticated systems to rapidly acquire and metabolize these nutrients. Some species can metabolize resources more efficiently, outcompeting others for energy sources.
3. Horizontal gene transfer (HGT): Bacteria can exchange genetic material through horizontal gene transfer, acquiring new abilities such as antibiotic resistance or enhanced metabolic capabilities. This enables them to rapidly adapt to environmental pressures, including competition with other microbes.
4. Bacteriophages: Viruses that infect bacteria, known as bacteriophages, are part of the gut microbiome’s ecosystem. These phages can exert selective pressure on bacterial populations by infecting and lysing susceptible strains, altering the competitive balance.

The Host-Microbe Arms Race

In addition to the competition among gut microbes, there is an ongoing evolutionary "arms race" between the human host and its microbial inhabitants. While many gut microbes are beneficial, some are opportunistic and can become harmful if not properly controlled. The host employs several strategies to regulate its microbiome, while microbes evolve to resist these controls.

1. Immune surveillance: The human immune system constantly monitors the microbiome, recognizing microbial patterns via receptors like Toll-like receptors (TLRs) on immune cells. The immune system can mount responses to limit overgrowth of certain microbes or to eliminate pathogens. Conversely, microbes have evolved ways to evade or modulate immune responses. Some gut bacteria produce molecules that dampen immune reactions to avoid being attacked.
2. Mucosal barriers: The gut lining produces mucus that serves as a physical barrier, preventing bacteria from coming into direct contact with epithelial cells. However, certain bacteria have developed mechanisms to penetrate or degrade this mucus layer to access nutrients closer to the gut lining.
3. Host diet as a selective pressure: The food humans eat shapes the composition of the gut microbiome. For example, a diet rich in fiber promotes the growth of certain bacteria that specialize in breaking down complex carbohydrates, while a high-fat or high-protein diet favors different microbial communities. Microbes have adapted to these dietary changes, evolving metabolic flexibility.
4. Microbial mimicry and immune modulation: Some microbes have developed mechanisms to mimic host molecules or modulate the immune system to avoid detection or suppression. For example, certain gut bacteria produce molecules that resemble host molecules, reducing the likelihood of an immune attack.

Symbiosis and Mutual Benefits

While there is competition and conflict within the gut microbiome and between microbes and the host, there is also significant cooperation. Many gut microbes form mutually beneficial (symbiotic) relationships with their host. For instance:

• Gut homeostasis: Commensal bacteria, which are harmless or beneficial to the host, help to maintain gut homeostasis by occupying niches that might otherwise be colonized by pathogens. This phenomenon is called "colonization resistance," where the established microbial community prevents harmful bacteria from gaining a foothold.
• Nutrient exchange: Certain microbes break down dietary components into metabolites that are beneficial for both the host and other microbial species. For instance, SCFAs produced by the fermentation of fiber by gut bacteria are used as an energy source by both the microbes and human colonocytes (cells lining the gut).

Dysbiosis and Disease

When the balance between the gut microbiome and the human host is disturbed, it can lead to dysbiosis, a state of microbial imbalance associated with a range of diseases, including:

• Inflammatory bowel disease (IBD): Dysbiosis can trigger chronic inflammation in conditions like Crohn’s disease and ulcerative colitis, where the immune system becomes overly responsive to the gut microbiota.
• Metabolic disorders: An imbalance in the gut microbiome has been linked to obesity, type 2 diabetes, and metabolic syndrome, where gut microbes influence energy harvest and fat storage.
• Autoimmune diseases: Dysregulated microbial populations can contribute to autoimmune diseases by affecting immune system function and promoting inflammation.

Conclusion

The gut microbiome is a dynamic, evolving ecosystem, shaped by interactions between microbial species and the human host. It’s a fine balance between cooperation and conflict, with evolutionary arms races playing out at multiple levels. These intricate interactions can profoundly affect human health, with both beneficial and harmful outcomes depending on the balance achieved between the microbes and their host. Understanding these dynamics is critical for developing new therapeutic strategies to manipulate the microbiome in ways that promote health and prevent disease.

While we have evolved to be dependent on many of them, some of them have the potential to become seriously pathogenic, so there is an inevitable evolutionary arms race between them and us. (see the AI panel to the right for more detail).

Now a team of researchers at Cleveland Clinic has identified a new bacterium that appears to suppress our immune system - the result of an evolutionary arms race in which we mobilized our immune system to attack the bacterium because it was pathogenic and the bacterium responded by evolving a way to suppress out immune system.

Cleveland Clinic Researchers Discover New Bacterium that Causes Gut Immunodeficiency

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Findings lay the groundwork for potential new treatments for variety of inflammatory and infectious diseases including inflammatory bowel disease, Crohn’s and ulcerative colitis

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Cleveland Clinic researchers have discovered a new bacterium that weakens the immune system in the gut, potentially contributing to certain inflammatory and infectious gut diseases.

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.

Identifying this bacterium is the first step to developing new treatments for a variety of inflammatory and infectious gut diseases. These conditions, including inflammatory bowel disease, Crohn’s and ulcerative colitis, are associated with decreased levels of secretory immunoglobulin A (SIgA), an antibody that protects mucosal surfaces.

The study, published in Science, was led by Thaddeus Stappenbeck, M.D., Ph.D., chair of Cleveland Clinic’s Department of Inflammation and Immunity, and Qiuhe Lu, Ph.D., research associate and the paper’s first author.

Our research represents a critical role of a specific component of the gut microbiome in human health and disease. By identifying this specific bacterium, we have not only enhanced our understanding of gut diseases but also opened a promising new avenue for treatment. Pinpointing the culprit behind the breakdown of the gut’s protective adaptive immune barrier is a significant step toward developing much-needed therapies for conditions like inflammatory bowel disease, Crohn’s and ulcerative colitis.

Dr. Thaddeus S. Stappenbeck, senior author
Department of Inflammation and Immunity
Lerner Research Institute
Cleveland Clinic, Cleveland, OH, USA.

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.

In this new study, researchers found that T. immunophila’s presence in the gut increases susceptibility to pathogens and delays repair of the gut’s protective barrier. T. immunophila’s name is an homage to a pioneer in immunology. SIgA was discovered by Dr. Thomas Tomasi, who published his findings in a foundational paper in Science in 1963.

Drs. Stappenbeck and Lu's rigorous and elegant study provides a key insight and an exciting potential mechanism for why some people have low or absent levels of SIgA in their gut, yet retain normal levels of SIgA in their bloodstream.

This discovery is quite important, as SIgA in the intestine functions as a critical component of the barrier for the trillions of microbes that live in our intestines. This study provides a new avenue to develop therapeutics to manipulate SIgA in the gut and improve health.

Dr. Michael Silverman, M.D., Ph.D.,
Division of Infectious Diseases
Children’s Hospital of Philadelphia.

Dr. Silverman, whose expertise includes immune system development, provided input on the research findings.

We know that there are a substantial number of patients that have this defect in are at risk for infection and inflammation in the intestine. We surmised that a gut microbe that can degrade SIgA was the culprit. We believe that important therapeutic targets for a variety of inflammatory and infectious diseases in humans can be found through our work.

Dr. Qiuhe Lu, first author
Department of Inflammation and Immunity
Lerner Research Institute
Cleveland Clinic, Cleveland, OH, USA.

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.

Screening and functional study of immunoglobulin-degrading bacteria in the intestine.
Screening of WT mice with low levels of fecal SIgA identified a previously unreported bacterium that degrades immunoglobulins. This bacterium, proposed as Tomasiella immunophila, secretes outer membrane vesicles (OMVs) containing IgA-degrading enzymes. Mice colonized with T. immunophila showed reduced IgA levels and enhanced susceptibility to Salmonella infection post vaccination. [Figure created with BioRender.com]

Abstract
Harnessing the microbiome to benefit human health requires an initial step in determining the identity and function of causative microorganisms that affect specific host physiological functions. We show a functional screen of the bacterial microbiota from mice with low intestinal immunoglobulin A (IgA) levels; we identified a Gram-negative bacterium, proposed as Tomasiella immunophila, that induces and degrades IgA in the mouse intestine. Mice harboring T. immunophila are susceptible to infections and show poor mucosal repair. T. immunophila is auxotrophic for the bacterial cell wall amino sugar N-acetylmuramic acid. It delivers immunoglobulin-degrading proteases into outer membrane vesicles that preferentially degrade rodent antibodies with kappa but not lambda light chains. This work indicates a role for symbionts in immunodeficiency, which might be applicable to human disease.

Qiuhe Lu et al. ,
A host-adapted auxotrophic gut symbiont induces mucosal immunodeficiency. Science 385, eadk2536 (2024). DOI:10.1126/science.adk2536

© 2024 American Association for the Advancement of Science.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

Which creationists is going to be brave enough to spring forth and defend their putative designer by explaining how it shouldn't be held responsible for this harmful new pathogen because gaining an advantage in an arms race against the human immune system is a 'devolutionary' change caused by 'genetic entropy, and in any case something else must have designed bacteria because, although the biblical god is the only entity capable of designing and creating living organisms, something else designs and creates the nasty things, including the bacterial flagella that are 'irreducibly complex and so 'prove' a creator god must exist.

In other words, which creationists is going to be brave enough to commit blasphemy to defend the creationist cult?

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