Bacteroides fragilis

Bacteroides fragilis, a member of the Bacteroidetes phylum, is a significant component of the human gut microbiota, playing a crucial role in maintaining gut homeostasis. 

These gram-negative, anaerobic bacteria are prevalent in the colon and are involved in various metabolic processes, including the fermentation of complex polysaccharides. 

Bacteroides fragilis is generally a commensal organism, but it can become pathogenic if the mucosal barrier is disrupted by factors such as inflammation, trauma, or surgery. This disruption can lead to abscess formation, bacteremia, and other serious infections, often involving polymicrobial communities. 

Effective management of Bacteroides fragilis infections requires prompt evaluation, appropriate antibiotic therapy, and coordinated care by an interprofessional team. 

While Bacteroides fragilis is resistant to penicillin due to beta-lactamase production, antibiotics like metronidazole, Piperacillin/tazobactam, and meropenem are typically effective. 

However, emerging resistance to metronidazole highlights the need for continuous monitoring and potentially the use of newer antibiotics such as eravacycline and tazobactam/ceftolozane. 

Understanding the dual nature of Bacteroides fragilis—as both a beneficial gut inhabitant and a potential pathogen—is essential for optimizing patient outcomes and advancing treatments.

Overview of Bacteroides spp. [1., 7., 8., 12., 17., 19., 21., 22.] 

Bacteroides spp., members of the Bacteroidetes phylum, are significant components of the human gut microbiota, crucial for maintaining gut homeostasis. 

This phylum, constituting about 30% of the human gut microbiota, includes several genera such as Bacteroides, Prevotella, and Porphyromonas. 

The proportion of Bacteroidetes varies based on population, geography, age, and diet.

Characteristics and Taxonomy

Bacteroides spp. are gram-negative, non-spore forming, anaerobic, rod-shaped bacteria. Approximately 24 species have been identified, with Bacteroides fragilis and Bacteroides thetaiotaomicron being the most studied. 

These bacteria thrive in anaerobic conditions, utilizing complex polysaccharides for energy through fermentation. 

They possess unique genetic and metabolic features that enable efficient degradation of dietary fibers and carbohydrates, producing short-chain fatty acids (SCFAs) and other metabolites that impact host physiology.

The Bacteroides genus uses a Type VI secretion system (T4SS) to maintain competitive advantage in the gut. [3.] 

The T4SS in Bacteroides helps maintain competition and balance in the human gut by releasing toxins that target other bacteria, enabling these bacteria to outcompete others and stabilize the gut ecosystem, often through the transfer of these systems via mobile genetic elements among neighboring strains. [3.] 

Role in the Human Microbiome [7., 8., 17., 22.] 

Bacteroides spp. are key members of the human gut microbiome, significantly contributing to the microbial community in the colon. 

Their presence and abundance are influenced by diet, host genetics, and environmental exposures. 

Bacteroides spp. interact with other commensal bacteria and host cells, participating in complex microbial networks that regulate immune responses, nutrient metabolism, and intestinal barrier function.

Bacteroidetes, primarily found in the distal gut, possess a similar function of harvesting energy from diet through the fermentation of indigestible polysaccharides, producing short-chain fatty acids (SCFAs). [18.]

Metabolic Contributions

In adults, Bacteroides and other Bacteroidetes produce SCFAs such as acetate, propionate, and butyrate from the fermentation of undigested dietary polysaccharides. SCFAs play crucial roles in gut health, glucose homeostasis, and lipid metabolism. 

Bacteroides and Prevotella are major contributors to SCFA production, especially propionate. These bacteria adapt flexibly to the gut's nutritional environment, using a wide range of dietary polysaccharides and proteins.

Despite their diversity, Bacteroidetes share a high capacity for polysaccharide utilization, aided by numerous carbohydrate-active enzymes (CAZYmes). Their metabolic flexibility allows them to switch between different substrates based on availability and competition within the gut ecosystem. [7.] 

Diet and Bacteroidetes:

Diet significantly influences Bacteroidetes levels. 

Diets rich in animal products increase Bacteroides levels, whereas plant-based diets promote a more diverse microbial community. [7., 25.] 

Overnutrition decreases Bacteroidetes, affecting energy harvest efficiency. Conversely, undernutrition and fasting can either increase or deplete Bacteroidetes levels, depending on the conditions. [7.] 

Bacteroidetes and Metabolic Diseases:

Studies show varied associations between Bacteroidetes and type 2 diabetes. The relative abundance of Bacteroidetes can affect glucose metabolism differently in individuals, influenced by diet and other factors. 

Gnotobiotic animal studies show specific Bacteroidetes species can have different effects on host metabolism. Daily dosing with Bacteroides cultures improved glucose tolerance and insulin sensitivity in mice, suggesting microbial metabolites as potential metabolic effectors.

However, high Bacteroides have also been associated with impaired glucose tolerance. Bacteroides species' levels correlate with glucose responses post-meal, emphasizing the importance of dietary context. [7.] 

In one study, continuous blood glucose monitoring in 800 participants showed that the relative abundance of Bacteroidetes in stool was associated with a poor postprandial glucose response. [7.] 

However, within the phylum, many Bacteroides species correlated positively with a healthy postprandial glucose response when participants consumed diets optimized to their individual microbiota, dietary habits, and other factors. [7.] 

Overall, the effects of Bacteroidetes on glucose metabolism can vary significantly depending on dietary context and on the relative levels of Bacteroides subspecies. [7.] However, overall a healthy amount of Bacteroides seems to be beneficial for human metabolic health. [7., 9.]

Health Implications

Modulating Bacteroides metabolism through dietary interventions holds potential for restoring gut microbiota balance and promoting metabolic health. 

Imbalances in the composition of the gut microbiota, including alterations in Bacteroides spp. abundance, have been associated with numerous disease states. 

Bacteroidetes have been associated with metabolic disease, although the association between Bacteroidetes and metabolic diseases like obesity and type 2 diabetes is complex and context-dependent. [7.] 

Bacteroides has shown potential in preventing and treating non-alcoholic fatty liver disease (NAFLD) by modulating gut health.  [24.]

By reducing liver inflammation, mitigating hepatic steatosis, and enhancing intestinal barrier function, they contribute to metabolic regulation, improve insulin resistance, and balance cytokines. 

While the mechanisms are not fully understood, Bacteroides’ ability to influence lipid metabolism and gut barrier integrity positions them as promising candidates for NAFLD therapy, although more clinical research is needed to confirm their efficacy.

Bacteroides fragilis in Health and Disease

Bacteroides fragilis, a commensal bacterium in the human gut, has been implicated in various diseases affecting the gastrointestinal tract. Its role in disease is highly correlated with specific toxin-producing strains. [20.]

The Bacteroides fragilis Toxin, Produced by Enterotoxigenic Bacteroides fragilis (ETBF) [20.] 

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. [20.] 

‍

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

NTBF strains have been shown to serve as symbionts, protecting the host from colonic inflammation. [20.]

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. [20.] 

Studies suggest NTBF or its polysaccharide capsules (PSA) can protect against experimental colitis. [20.]

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. [20.] 

In adults, ETBF is more commonly associated with diarrhea in older individuals. [20.]

Studies have also identified ETBF as a potential cause of traveler’s diarrhea and possibly linked it to inflammatory bowel disease and colorectal cancer. [20.]

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

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), 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.

B. fragilis in Colorectal Cancer (CRC) 

Clinical studies have shown higher rates of B. fragilis in CRC patients compared to controls. ETBF has been detected more frequently in tumor tissues and has been associated with low-grade dysplasia, tubular adenomas, and serrated polyps, indicating its potential role in CRC development. [2.] 

B. fragilis Infections [5.] 

B. fragilis infections, where a compromised gut lining allows for entry of the B. fragilis organism into the bloodstream, are associated with significant morbidity and mortality. Gut lining damage in this setting is typically attributed to inflammation, trauma or surgery. [5.] 

The crude mortality rate for B. fragilis bacteremia is between 10.9%-30.7%. [5.] 

When the mucosal barrier is breached, B. fragilis can cause abscesses, bacteremia, and other serious infections. It is frequently involved in polymicrobial infections. 

These B. fragilis infections can result in intra-abdominal infections, surgical site infections, bloodstream infections, and abscesses. It has also been associated with periprosthetic joint infections, necrotizing pancreatitis, and septic thrombophlebitis. [5.] 

B. fragilis is resistant to penicillin due to beta-lactamase production. Effective treatments include metronidazole, piperacillin/tazobactam, and meropenem.

Eravacycline and tazobactam/ceftolozane have also shown promise in treating mixed aerobic/anaerobic infections involving B. fragilis.

B. fragilis in Leaky Gut and Psychiatric Disorders

B. fragilis is associated with gut health and gut dysfunction and pathology; it is known to exert positive immune-modulating effects on the gut and the enteric nervous system.  

However, B. fragilis has also been linked to leaky gut syndrome and pro-inflammatory states in the gut and nervous system.  [11.] 

ETBF

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. [11.]

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. [11.] 

NTBF

Conversely, non-toxigenic Bacteroides fragilis (NTBF) produces polysaccharide A (PSA), which promotes the expansion of regulatory T cells (Tregs) expressing the transcription factor Foxp3. 

These Tregs produce anti-inflammatory cytokines like IL-10 and TGF-β, crucial for controlling inflammatory cell proliferation. PSA from B. fragilis induces IL-10 production, providing protection against neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). [11.] 

PSA-induced IL-10-producing regulatory cells, such as Tregs and regulatory B cells, have shown protective effects against CNS inflammation in models of MS and viral encephalitis.

The potential therapeutic applications of B. fragilis and its products are significant. Purified PSA from B. fragilis has shown promising results in experimental models by inducing IL-10-producing regulatory cells and controlling CNS inflammatory diseases. 

Probiotic interventions, including PSA-producing B. fragilis, have been explored for their neuroprotective effects in various models of neuroinflammation and CNS diseases. [11.] 

Overall, B. fragilis plays a significant role in maintaining immune homeostasis by promoting anti-inflammatory responses and balancing pro-inflammatory Th17 cells with anti-inflammatory Tregs. [11.] 

However, the neurotoxic properties of fragilysin produced by ETBF can exacerbate neuroinflammatory conditions, linking gut health to CNS diseases. [11.] 

Symptoms of B. fragilis Overgrowth

A healthy balance of microbes in the digestive tract includes NTBF, the nonpathogenic variant of B. fragilis, which is associated with reduced inflammation in the gut and enteric nervous system. [11.] 

Healthy levels of this organism would be more likely to cause a reduction or resolution of troubling digestive symptoms.  

In contrast, increasing numbers of B. fragilis, particularly enterotoxigenic B. fragilis (ETBF), are associated with troubling digestive symptoms which may include: [16.]

• Abdominal Pain: significant discomfort in the abdomen, reported in 88% of ETBF-infected individuals.

• Tenesmus: a frequent sensation of needing to pass stools, reported by 66% of patients.

• Nonfebrile Inflammatory Diarrhea: diarrhea without fever, observed in both children and adults.

• Nocturnal Diarrhea: diarrhea occurring at night, reported by 79% of patients. [16.] 

• Fecal Leukocytes: presence of white blood cells in stool, indicating inflammation.

• Lactoferrin in Stool: a marker of intestinal inflammation.

• Increased Proinflammatory Cytokines: elevated levels of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) in stool samples.

• Persistent Intestinal Inflammation: evidence of ongoing inflammation for at least three weeks despite antibiotic therapy.

• Fecal Occult Blood: presence of blood in stool, though identified infrequently (8% of patients).

These symptoms collectively indicate that ETBF infection leads to significant gastrointestinal distress and inflammation.

Laboratory Testing for Bacteroides fragilis

Test Type, Sample Collection and Preparation

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

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

It is important to consult with the laboratory company used for test interpretation.  Bacteroides levels are typically assessed by species.  

One lab company provides the following reference range for Bacteroides fragilis levels: 1.6e9 - 2.5e11org/g [14.]

Clinical Implications of High Bacteroides fragilis

High levels of Bacteroides in the gut microbiome are generally associated with a healthy state and favorable metabolic outcomes. 

A high relative abundance of Bacteroides compared to other phyla like Firmicutes is considered essential for maintaining gut health, biodiversity, and homeostasis of metabolism, immune function, and colonization resistance. [19.]

High levels of Bacteroidetes species like commensal non-toxigenic Bacteroides fragilis (NTBF) and B. thetaiotaomicron are considered beneficial, fermenting polysaccharides to produce short-chain fatty acids that serve as an energy source for the host. 

They also contribute to bile acid metabolism and provide colonization resistance against pathogens like Clostridioides difficile.  [19.]

However, 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 [5.] 

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. This is frequently seen 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 [6.]

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.

FAQ: Understanding Bacteroides fragilis

Bacteroides fragilis is a species of bacteria that plays a significant role in the human gut microbiome and is also known for its potential to cause infections. This FAQ section addresses common questions about Bacteroides fragilis, its significance, and its impact on health.

What is Bacteroides fragilis?

Bacteroides fragilis is a type of Gram-negative, anaerobic bacterium that belongs to the Bacteroides genus. It is commonly found in the human gastrointestinal tract, where it plays a crucial role in digestion and maintaining gut health. 

Despite its beneficial roles, it can also be an opportunistic pathogen.

What is the Role of Bacteroides fragilis in the Gut Microbiome?

In the gut microbiome, Bacteroides fragilis helps in the breakdown and fermentation of complex carbohydrates. It produces short-chain fatty acids and other metabolites that support gut health, regulate the immune system, and contribute to overall metabolic functions.

How is Bacteroides fragilis Detected?

Bacteroides fragilis can be detected using microbiological and molecular techniques such as stool or tissue culture, 16S rRNA gene sequencing, and metagenomic analysis. 

These methods allow for the identification and quantification of Bacteroides fragilis in the gut microbiome or clinical samples.

What Are the Benefits of Bacteroides fragilis?

The benefits of Bacteroides fragilis include aiding in the digestion of complex carbohydrates, producing beneficial short-chain fatty acids, supporting the gut barrier function, and helping to maintain a balanced gut microbiome. It also plays a role in modulating the immune system.

Can Bacteroides fragilis Be Harmful?

While Bacteroides fragilis is generally beneficial in the gut, it can become harmful if it translocates to sterile areas of the body or if there is an imbalance in the gut microbiome. 

It can cause infections such as intra-abdominal abscesses, bacteremia, and sepsis, particularly in immunocompromised individuals.

How is a Bacteroides fragilis Infection Treated?

Treatment of Bacteroides fragilis infections typically involves antibiotics.

 Due to its potential resistance to some antibiotics, treatment often requires the use of broad-spectrum antibiotics. 

Surgical intervention may also be necessary to drain abscesses or address other complications.

What are the Symptoms of a Bacteroides fragilis Infection?

Symptoms of a Bacteroides fragilis infection can vary depending on the site of infection but may include:

• Abdominal pain and tenderness

• Fever and chills

• Pus or abscess formation

• Signs of sepsis such as rapid heart rate and confusion in severe cases

• Various digestive symptoms may also be seen including diarrhea, tenesmus, and blood in stool

How Can I Support a Healthy Balance of Bacteroides fragilis in the Gut?

Supporting a healthy balance of Bacteroides fragilis in the gut involves:

• Eating a balanced diet rich in dietary fiber, particularly from fruits, vegetables, and whole grains

• Consuming fermented foods such as yogurt, kefir, and sauerkraut

• Avoiding excessive use of antibiotics, which can disrupt the gut microbiome

• Maintaining a healthy lifestyle with regular exercise and stress management

When Should I Consult a Healthcare Provider About Bacteroides fragilis?

You should consult a healthcare provider if you experience symptoms of an infection or have persistent digestive issues such as abdominal pain, bloating, diarrhea, or constipation. 

A healthcare provider can evaluate your symptoms, potentially recommend microbiome testing, and suggest appropriate treatments or dietary changes to improve gut health.

Order Bacteroides fragilis Testing

Click here to compare testing options and order Bacteriodes fragilis testing.