Bacteroides fragilis BFT

Bacteroides fragilis, a gram-negative, anaerobic bacterium in the human gut microbiota, plays a crucial role in maintaining gut homeostasis through the fermentation of complex polysaccharides, producing essential short-chain fatty acids. 

However, specific strains known as enterotoxigenic Bacteroides fragilis (ETBF) produce Bacteroides fragilis toxin (BFT), a zinc-dependent metalloprotease also called fragilysin. 

BFT disrupts the intestinal barrier by degrading E-cadherin, leading to increased intestinal permeability and triggering inflammation via the Wnt/β-catenin and NF-κB pathways. 

This disruption is linked to various pathologies, including inflammatory bowel disease, colorectal cancer, leaky gut syndrome, and psychiatric disorders. 

While non-toxigenic B. fragilis strains are beneficial, promoting immune regulation and gut health, the pathogenic ETBF strains highlight the dual nature of this bacterium, underscoring the need for targeted therapies to manage gut microbiota balance and prevent related diseases.

What is Bacteroides fragilis? [1., 3., 5., 6., 11., 16., 17., 19., 20.] 

Bacteroides fragilis, a member of the Bacteroidetes phylum, is a key component of the human gut microbiota, essential for maintaining gut homeostasis. 

These gram-negative, non-spore forming, anaerobic, rod-shaped bacteria thrive in the anaerobic environment of the colon, where they play a significant role in the fermentation of complex polysaccharides, producing short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate. 

These metabolites are crucial for gut health, glucose homeostasis, and lipid metabolism. 

While Bacteroides fragilis is generally a commensal organism, disruptions in the mucosal barrier due to inflammation, trauma, or surgery can lead to infections, making it a significant clinical pathogen. 

Its ability to adapt to different dietary environments and its interactions with other gut microbes and host cells highlight its complex role in immune regulation, nutrient metabolism, and intestinal barrier function. 

Understanding the dual nature of Bacteroides fragilis—as both a beneficial gut inhabitant and a potential pathogen—is vital for developing targeted therapies to restore gut microbiota balance and treat related diseases.

The Bacteroides fragilis Toxin, Produced by Enterotoxigenic Bacteroides fragilis (ETBF) [18.] 

Bacteroides fragilis is the only strain of Bacteroides spp. associated with diarrheal disease, specifically due to toxin-producing strains termed enterotoxigenic Bacteroides fragilis (ETBF). 

ETBF is known to cause abdominal pain, tenesmus, and inflammatory diarrhea. 

Recent murine studies have shown that ETBF infection can enhance the development of colonic tumors in mice with a predisposition to colorectal cancer. [18.] 

The "Good" B. fragilis: Nonenterotoxigenic B. fragilis (NTBF)

NTBF strains have been shown to serve as symbionts, protecting the host from colonic inflammation. [18.]

NTBF strains facilitate metabolism of various polysaccharides found in the colon and express a complex polysaccharide capsule system.

NTBF has been demonstrated to correct immune system defects in germ-free mice, promoting beneficial mucosal and systemic immune responses. [18.] 

Studies suggest NTBF or its polysaccharide capsules (PSA) can protect against experimental colitis. [18.] 

The "Bad" B. fragilis: Enterotoxigenic B. fragilis (ETBF)

ETBF strains differ from NTBF by acquiring a genetic “pathogenicity island” with a gene encoding the Bacteroides fragilis toxin (BFT), a 20-kDa metalloprotease.

BFT increases colon permeability and activates proinflammatory signaling, leading to diarrhea.

ETBF has been linked to lamb and human diarrheal disease, with studies showing a higher prevalence in young children and some adults. [18.] 

In adults, ETBF is more commonly associated with diarrhea in older individuals. [18.] 

Studies have also identified ETBF as a potential cause of traveler’s diarrhea and possibly linked it to inflammatory bowel disease and colorectal cancer. [18.] 

Murine models have shown ETBF can induce colitis and colonic tumors, with tumor formation being IL-17 dependent.

What is the Bacteroides fragilis Toxin (Bacteroides fragilis BFT)? 

ETBF secretes a key virulence factor, B. fragilis toxin (BFT), a zinc-dependent metalloprotease. BFT is also known as fragilysin. [9.] BFT increases epithelial permeability by degrading E-cadherin, leading to enhanced signaling through the Wnt/β-catenin and NF-κB pathways. 

This disruption promotes inflammation and has been strongly associated with pathologies including colorectal cancer (CRC), inflammatory bowel disease, leaky gut and psychiatric disorders. [2., 7., 10.]

BTF and Colorectal Cancer

Studies show ETBF colonization is significantly higher in CRC patients, and animal models demonstrate its role in tumorigenesis. [7.] 

BFT induces the release of inflammatory mediators, activating pathways like Stat3 and IL-17, contributing to CRC development. 

Conversely, NTBF promotes mucosal immunity and inhibits colitis and CRC through its immunogenic components. Understanding the dual nature of B. fragilis, especially the carcinogenic effects of BFT, is crucial for developing targeted therapies against CRC.

B. fragilis in Inflammatory Bowel Disease [2.] 

Bacteroides fragilis (B. fragilis) is a Gram-negative anaerobe that constitutes about 25% of the gut's anaerobic bacteria. It generally exists in a commensal relationship with the host, contributing to nutrition and immunity. 

However, certain strains, specifically enterotoxigenic Bacteroides fragilis (ETBF), produce B. fragilis toxin (BFT), also known as fragilysin, which can disrupt the intestinal epithelial cell (IEC) barrier by cleaving E-cadherin. 

This disruption leads to inflammation and has been linked to both ulcerative colitis and Crohn’s disease. [2.] 

ETBF can induce colitis, worsen dextran sodium sulfate (DSS)-induced colitis, and can also promote colon tumorigenesis through various signaling pathways, including NF-κB, STAT3, and MAPK.

BFT in Leaky Gut and Psychiatric Conditions

Enterotoxigenic Bacteroides fragilis (ETBF) produces a toxin called fragilysin, a zinc metalloproteinase that affects intestinal barrier integrity, promoting a "leaky gut" by cleaving E-cadherin and increasing intestinal permeability. [10.] 

When the gut barrier is compromised, microbial products like fragilysin can disseminate systemically, activating the pro-inflammatory IL-23 inflammatory pathway, promoting Th17 responses, and potentially leading to sepsis and neuroinflammatory processes. 

The endotoxin properties of fragilysin can result in neuroinflammatory responses associated with CNS diseases such as Alzheimer’s disease. [10.] 

Laboratory Testing for Bacteroides fragilis BFT

Test Type, Sample Collection and Preparation

Bacteroides fragilis toxin levels are typically assessed in stool samples.  Stool samples may be collected from the comfort of home.  

A stool sample is assessed, often via PCR, for the presence of the enterotoxigenic b. fragilis (ETBF) strains, which are known to produce the B. fragilis toxin fragilysin.

Testing may require avoidance of certain medications and/or supplements including probiotics prior to sample collection.  It is important to consult with the ordering provider for full test preparation instructions. 

Interpretation of Test Results

Optimal Levels of Bacteroides fragilis Toxin

The presence of the enterotoxigenic b. Fragilis strain implies the presence of the B. fragilis toxin fragilysin.  Optimal levels of this bacterial strain, and of the bacterial toxin, are undetectable.

Clinical Implications of High Bacteroides fragilis Toxin

Elevated levels of the pathogenic enterotoxigenic B. fragilis (ETBF), especially in the setting of troubling digestive symptoms and/or pathologies including cancer, inflammatory bowel disease, or systemic symptoms of infection, signal a need for treatment.

Treatments for B. fragilis

Common Antibiotic Therapies [3.] 

Bacteroides fragilis can cause serious infections if it breaches the mucosal barrier due to inflammation, trauma, or surgery. Proper specimen collection and prompt lab processing are crucial to avoid contamination. 

When the mucosal barrier is disrupted, it can lead to abscess formation and bacteremia, with Bacteroides fragilis producing toxins that contribute to its virulence and inhibition of clot formation, aiding its spread.

Bacteroides fragilis is part of the normal colon flora but can cause significant morbidity when the mucosal lining is breached, frequently involved in infections post-surgery or trauma, and in patients with malignancies. 

The bacterium is resistant to penicillin due to beta-lactamase production, with effective antibiotics including metronidazole, Piperacillin/tazobactam, and meropenem. 

However, resistance to metronidazole is emerging, with mechanisms involving nim genes, while newer antibiotics like eravacycline and tazobactam/ceftolozane show promise in treating complex infections.

The overall mortality rate for Bacteroides fragilis bacteremia is high, particularly in patients with comorbid conditions like malignancy, and complications can include sepsis and abscess formation in various tissues. 

In conclusion, while Bacteroides fragilis is normally harmless in the colon, it can cause serious infections if it spreads to other tissues. Prompt evaluation, appropriate antibiotic use, and interprofessional management are crucial to improving patient outcomes.

Natural Ways to Optimize Microbiome Health [4.] 

A healthy diet and lifestyle are foundational for microbiome health.  

Diet and Nutrition

• Consume Diverse Foods: increase the variety of fruits, vegetables, whole grains, nuts, seeds, and legumes to promote microbial diversity.

• High-Fiber Diet: focus on fiber-rich foods to support the growth of beneficial bacteria.

• Fermented Foods: include yogurt, kefir, sauerkraut, kimchi, and other fermented foods to introduce probiotics.

• Polyphenol-Rich Foods: consume foods high in polyphenols such as berries, green tea, dark chocolate, and red wine to stimulate beneficial bacteria growth.

• Prebiotics: incorporate prebiotic-rich foods like garlic, onions, asparagus, and bananas to nourish beneficial bacteria.

Lifestyle

• Regular Exercise: engage in consistent physical activity to enhance gut microbiota diversity and composition.

• Stress Management: practice stress-reducing activities such as yoga, meditation, and mindfulness to prevent microbiota dysbiosis.

Medications and Supplements

• Probiotics: consider probiotic supplements to increase beneficial bacteria in the gut.

• Avoid Unnecessary Antibiotics: use antibiotics only when necessary to avoid disrupting the gut microbiome.

Environmental Factors

• Limit Artificial Sweeteners: avoid artificial sweeteners that can negatively affect gut microbiota.

• Healthy Sleep Patterns: maintain regular sleep patterns to support a balanced gut microbiome.

Hygiene Practices

• Avoid Over-Sanitization: limit the use of antibacterial soaps and sanitizers to maintain a healthy microbiota balance.

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