Rosa Rubicondior: Malevolent Designer News - How C. difficile is Designed to Kill Off Competition in Our Gut

Tuesday, 25 March 2025

Malevolent Designer News

How C. Difficile Is Designed To Kill Off Competition In Our Gut

C. diff uses toxic compound to fuel growth advantage VUMC News

Like all organisms, and particularly pathogenic parasites that colonise our intestines, Clostridioides difficile (C. diff) must compete with other organisms for nutrients. This competition inevitably fuels evolutionary arms races.

For devotees of creationism’s ‘intelligent designer’, C. diff might appear to be a cunning response to medical science's successful use of antibiotics against bacterial pathogens. This is because C. diff is equipped with multiple antibiotic-resistance genes, allowing it to thrive in hospital environments. It often infects patients who are already vulnerable due to other health conditions or compromised immunity, making it a significant medical challenge.

Furthermore, if one follows William A. Dembski's reasoning, the ‘complex specified information’ in C. diff’s genome, which grants it a competitive edge, must logically be attributed to an intelligent designer. Michael J. Behe’s attempt to absolve his version of an intelligent designer by blaming ‘sin’, ‘genetic entropy’, or alleged ‘devolution’ fails here. A mutation that clearly provides an adaptive advantage cannot logically be termed a ‘devolution’ from a supposedly more ‘perfect’ ancestral state.

If creationism’s intelligent designer intended to kick people when they were down, it could hardly have done better than designing C. diff.

How C. diff competes for resource in our gut by waging chemical warfare against the other gut biota is the subject of a paper in the journal Cell Host & Microbe by researchers at Vanderbilt University Medical Center (VUMC). Their findings are described in VUMC News:

Tell me all about Clostridium difficile including its evolutionary origins and pathology in humans.

Clostridium difficile(now officially known as Clostridioides difficile) is a Gram-positive, anaerobic, spore-forming bacterium responsible for a range of gastrointestinal diseases collectively known as Clostridioides difficile infection (CDI). It's particularly notable as a healthcare-associated pathogen, often associated with antibiotic use.

Here's a detailed overview covering taxonomy, evolutionary origins, pathology, epidemiology, and treatment:

Taxonomy and classification

Kingdom: Bacteria
Phylum:Bacillota (formerly Firmicutes)
Class:Clostridia
Order:Eubacteriales
Family:Peptostreptococcaceae
Genus:Clostridioides
Species:Clostridioides difficile (formerly known as Clostridium difficile)
The reclassification from Clostridium to Clostridioides reflects genomic analyses showing distinct evolutionary divergence.
Evolutionary origins

Clostridioides difficile diverged from other members of the Clostridium genus millions of years ago, adapting uniquely to colonise and survive in the mammalian gastrointestinal tract.
Genomic studies suggest it has undergone significant horizontal gene transfer, acquiring antibiotic resistance genes and virulence factors, enabling rapid adaptation to clinical environments.
The evolutionary success of C. difficile has been significantly influenced by human activities, particularly widespread antibiotic use, which disrupts normal gut microbiota and creates an ecological niche favouring its growth and pathogenicity.

Microbiology and transmission

It is an obligate anaerobe, thriving without oxygen.
Forms resilient spores that can survive harsh environmental conditions, resisting heat, disinfectants, and drying.
Transmission is mainly faecal-oral, commonly via contaminated surfaces, healthcare workers’ hands, or medical equipment.
Often colonises the human gut asymptomatically, especially in infants, though it can turn pathogenic under conditions of microbiota imbalance (dysbiosis).

Pathogenesis in humans

C. difficile pathogenesis is primarily driven by its two major toxins:

Toxin A (TcdA): an enterotoxin disrupting intestinal cell integrity, causing fluid secretion, inflammation, and diarrhoea.
Toxin B (TcdB): a potent cytotoxin causing significant cellular damage and inflammation.
A third toxin, the binary toxin CDT, found in some strains (e.g., epidemic ribotype 027), may enhance virulence but is less consistently expressed.

Disease progression:

Antibiotic treatment disrupts normal gut microbiota.
Spores of C. difficile germinate into vegetative forms, multiply, and colonise the gut.
Toxins damage colonic epithelium, trigger inflammatory responses, and lead to disease manifestation.

Clinical manifestations

In humans, the clinical spectrum ranges from mild diarrhoea to severe and life-threatening colitis:

Mild to moderate CDI:Watery diarrhoea, abdominal cramping, fever, loss of appetite, nausea.
Severe CDI:Profuse diarrhoea, dehydration, severe abdominal pain, pseudomembranous colitis (characteristic formation of pseudomembranes on the colon mucosa), toxic megacolon, bowel perforation, and sepsis, potentially fatal if untreated.
Risk factors include antibiotic exposure, advanced age, prolonged hospital stays, immunocompromise, proton-pump inhibitor usage, and inflammatory bowel disease.
Epidemiology and public health impact

CDI is primarily hospital -or healthcare-associated, although community-acquired infections have been increasingly documented.
Epidemic strains (e.g., ribotype 027, also known as NAP1 or BI) emerged in the early 2000s, demonstrating increased virulence, toxin production, antibiotic resistance, and morbidity/mortality rates.
Global incidence has been rising, influenced by antibiotic prescription practices and ageing populations, prompting greater vigilance in infection control.

Diagnosis

Clinical suspicion (recent antibiotics use, hospitalisation, symptoms) prompts laboratory testing.
Laboratory tests typically include:

Stool toxin assays(enzyme immunoassays, ELISA, PCR for toxin genes)
Glutamate dehydrogenase (GDH) antigen testfor rapid screening
Culture: Used less frequently due to longer turnaround time, but necessary for strain typing and antibiotic susceptibility.

Treatment and management

Initial management:

Discontinue or alter antibiotics that predispose to CDI.
Restore fluids and electrolytes.

Medical therapies:

Oral vancomycin or fidaxomicin:Recommended first-line treatments for severe or recurrent CDI.
Metronidazole:Less preferred now due to reduced efficacy, recommended only if vancomycin or fidaxomicin unavailable.

Recurrent CDI management:

Faecal Microbiota Transplantation (FMT):Restores normal microbiota and has shown high efficacy (>85%) in preventing recurrence.

Monoclonal antibodies (Bezlotoxumab):Target toxin B, reducing recurrence risk.
Infection control measures:

Strict hand hygiene (soap and water preferred over alcohol rub due to spore resistance).
Environmental cleaning with sporicidal disinfectants (e.g., chlorine-based agents).

Prevention and ongoing research

Improved antibiotic stewardship to reduce CDI risk.
Ongoing vaccine development aimed at toxin neutralisation.
Research continues into probiotic formulations and other microbiota-directed therapies for prevention and treatment.

Summary

Clostridioides difficile is a rapidly evolving bacterium whose success is closely tied to human interventions, especially antibiotic use.
Pathogenicity stems from toxin production causing severe inflammation and colonic injury.
CDI remains a significant public health concern globally, demanding continued attention to prevention, effective treatment protocols, and infection control measures.
Understanding its evolutionary dynamics, microbiology, and host interactions is critical in managing and mitigating its clinical impact.

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Information Continually updated

C. diff uses toxic compound to fuel growth advantage
The findings of a new research study increase understanding of the molecular drivers of C. diff infection and point to novel therapeutic strategies aimed at a pathogen that causes about half a million infections in the U.S. each year.
The pathogen C. diff — the most common cause of health care-associated infectious diarrhea — can use a compound that kills the human gut’s resident microbes to survive and grow, giving it a competitive advantage in the infected gut.

A team led by investigators at Vanderbilt University Medical Center has discovered how C. diff (Clostridioides difficile) converts the poisonous compound 4-thiouracil, which could come from foods like broccoli, into a usable nutrient. Their findings, published March 25 in the journal Cell Host & Microbe, increase understanding of the molecular drivers of C. diff infection and point to novel therapeutic strategies.

C. diff causes about half a million infections in the U.S. each year, according to the Centers for Disease Control and Prevention. Factors that increase risk of C. diff infection include antibiotic use, age over 65, and recent stays in hospitals and other health care facilities.

Like other pathogens, C. diff must acquire nutrients to survive and grow.

We’re interested in trying to understand the nutrients that C. diff needs during infection, and how what you eat influences what C. diff eats in your gut.

Matthew Munneke, first author
Department of Pathology, Microbiology, and Immunology
Vanderbilt Institute for Infection, Immunology, and Inflammation
Vanderbilt University Medical Center, Nashville, TN.

The group focused on nucleotides — the building blocks of DNA and RNA — which are a class of nutrients that hasn’t been well studied for C. diff .

The researchers found that C. diff must acquire a certain type of nucleotides (pyrimidines) to cause infection, and they discovered an enzyme they named TudS (thiouracil desulfurase) that C. diff uses to salvage the pyrimidine nucleotide uracil from a related compound: 4-thiouracil.

They showed that 4-thiouracil gets incorporated into RNA and is toxic to resident gut microbes that do not have the TudS enzyme. In C. diff , however, TudS modifies and detoxifies 4-thiouracil, making it available as a nutrient. The researchers demonstrated that TudS contributes to C. diff “fitness” in mice fed 4-thiouracil and in a novel MiniBioreactor model that contains a community of bacteria isolated from human feces with added 4-thiouracil.

We think that 4-thiouracil metabolism is beneficial to C. diff because it acts as a nutrient to fuel the bacteria, and it also may inhibit neighboring bacteria, which would give C. diff a further competitive advantage within the gut environment.

Matthew Munneke

The TudS enzyme may represent a novel therapeutic target for treating C. diff infections. It is not present in many resident gut microbes (or in human cells), so an antimicrobial targeting it to kill C. diff might help preserve the healthy gut microbiota, he noted.

The researchers also showed that adding C. diff TudS to a probiotic strain of E. coli blunted C. diff ’s fitness advantage in an in vitro model.

It might be possible to use a probiotic with this enzyme to diminish C. diff ’s ability to thrive in the gut and push it out.

Matthew Munneke
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Although the researchers showed that 4-thiouracil is present in the human gut, the source of this compound is unclear. Livestock that consume a diet rich in cruciferous vegetable family members (such as kale and other leafy greens, broccoli and cauliflower) have elevated levels of 4-thiouracil, and it is present in broccoli, both suggestive that a dietary source may contribute to the presence of 4-thiouracil in the human gut.

More research is needed to understand the source of 4-thiouracil, but if it comes from the diet, that could inform dietary interventions for C. diff infection.

Matthew Munneke

It’s not time to give up eating cruciferous vegetables though. In the healthy gut, some resident microbes contain a TudS-related enzyme and can likely convert 4-thiouracil into nutrients. These microbes may be missing in the C. diff -infected gut, Munneke said.

Other VUMC authors of the Cell Host & Microbe paper are Catherine Shelton, PhD, Darian Carroll, PhD, Nicole Kirchoff, PhD, Martin Douglass, PhD, M. Wade Calcutt, PhD, Katherine Gibson-Corley, DVM, PhD, Maribeth Nicholson, MD, MPH, and Mariana Byndloss, DVM, PhD. Collaborators at the University of Florida and Baylor College of Medicine contributed to the studies.

Highlights

Pyrimidine nucleotide synthesis is critical for Clostridioides difficile infection
A thiouracil desulfurase (TudS) enables C. difficile to utilize 4-thiouracil (4-TU)
TudS prevents 4-TU toxicity and incorporation into RNA by converting it to uracil
4-TU is present in the human gut and confers a fitness advantage to C. difficile

Summary
Nucleotides are essential building blocks for major cellular macromolecules and are critical for life. Consequently, bacterial pathogens must acquire or synthesize nucleotides during infection. Clostridioides difficile is the most common hospital-acquired gastrointestinal infection, and nutrient acquisition is critical for pathogenesis. However, the impact of nucleotide metabolism on C. difficile infection remains unclear. Here, we discover that 4-thiouracil (4-TU), a pyrimidine analog present in the human gut, is toxic to commensal bacteria. 4-TU hijacks the uracil salvage pathway for incorporation into RNA through the uracil phosphoribosyltransferase activity encoded by PyrR and Upp. C. difficile can salvage 4-TU as a pyrimidine source through the enzymatic action of a thiouracil desulfurase (TudS), thereby contributing to C. difficile fitness in mice fed 4-TU or MiniBioreactor models of infection containing exogenous 4-TU. Collectively, these results reveal a molecular mechanism for C. difficile to utilize a poisonous pyrimidine analog in the vertebrate gut to outcompete commensal microbes.
Graphical abstract

Munneke, Matthew J.; Yuan, Yifeng; Preisner, Eva C.; Shelton, Catherine D.; Carroll, Darian T.; Kirchoff, Nicole S.; Dickson, Ken P.; Cantu, Jose O.; Douglass, Martin V.; Calcutt, M. Wade; Gibson-Corley, Katherine N.; Nicholson, Maribeth R.; Byndloss, Mariana X.; Britton, Robert A.; de Crécy-Lagard, Valérie; Skaar, Eric P.
A thiouracil desulfurase protects Clostridioides difficile RNA from 4-thiouracil incorporation, providing a competitive advantage in the gut Cell Host & Microbe (2025) DOI:10.1016/j.chom.2025.03.001.

© 2025 Elsevier.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

Of course, as anyone with even a basic grasp of evolutionary biology knows, all aspects of parasitic organisms and their ability to survive and thrive in hostile environments can be readily explained by the Theory of Evolution, which remains unrivalled in its ability to account for the observable evidence.

In contrast, intelligent-design creationists struggle to explain why an allegedly omniscient and omnibenevolent designer would deliberately create parasitic organisms. They must also explain why such a designer would equip these organisms with adaptations specifically to out-compete beneficial microbes in our microbiome, solely enabling parasites to replicate more effectively and cause greater suffering.

To date, I have yet to encounter any persuasive explanation for parasites or parasite-host arms races that could reasonably be attributed to the purposeful actions of a supremely intelligent and benevolent designer.

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