When undergoing a course of antibiotics, whether for Small Intestinal Bacterial Overgrowth (SIBO) or another infection, it is crucial to consider the role of probiotics and Saccharomyces boulardii in maintaining gut health. Antibiotics, while effective at killing harmful bacteria, do not discriminate between the good and bad bacteria in the gut, often leading to disruptions in the gut microbiome. This disruption can cause a range of side effects, including diarrhea, gut inflammation, and even pave the way for opportunistic infections like Clostridium difficile (C. difficile). Incorporating probiotics and Saccharomyces boulardii during and after antibiotic treatment can help mitigate these risks and support overall gut health.

Rifaximin is the preferred antibiotic to use against SIBO. Due to its minimal systemic absorption, Rifaximin is uniquely positioned to primarily act within the gastrointestinal tract. This characteristic makes it less likely to disrupt the overall gut microbiome and more effective in treating SIBO in the lower small intestines compared to more systemically absorbed antibiotics. As a result, the risk of developing C. difficile infection while taking Rifaximin alone is considered relatively low.

Reasons Why C. difficile Infection Risk is Lower with Rifaximin

Minimal Systemic Absorption 

Many antibiotics cause broad-spectrum depletion of the gut microbiome, predisposing it to C. difficile overgrowth. Rifaximin is poorly absorbed from the gastrointestinal tract, meaning it primarily remains within the gut to exert its effects. This localized action reduces the disruption of beneficial gut bacteria that occurs with systemically absorbed antibiotics.

Selective Antimicrobial Activity

Rifaximin is less disruptive to the gut microbiome than many other antibiotics. By selectively targeting pathogenic bacteria within the gut, Rifaximin spares much of the normal flora. Therefore, Rifaximin maintains the integrity of the gut environment that helps prevent C. difficile colonization and overgrowth.

Reduced Risk of Resistance

Rifaximin has a lower propensity for inducing antibiotic resistance compared to other antibiotics. It is effective against many Gram-positive and Gram-negative bacteria, but its mechanism of action and low systemic absorption minimize the development of resistant strains that could contribute to secondary infections like C. difficile.

Increased Risk with Neomycin

When Rifaximin is paired with Neomycin, the risk of C. difficile infection can potentially increase. Neomycin is commonly paired with Rifaximin in cases of methane positive SIBO due to its significantly improved treatment outcomes (up to 30% greater than Rifaximin alone). Neomycin is a broad-spectrum antibiotic that can significantly disrupt the gut microbiota, reducing the population of beneficial bacteria that typically help keep C. difficile in check. This disruption creates an environment where C. difficile can flourish, increasing the risk of infection.

Key Points:

• Rifaximin Alone: The risk of C. difficile infection is low due to its localized effect in the gut and minimal systemic absorption. Rifaximin is less likely to disrupt the gut’s beneficial bacteria, which helps prevent C. difficile overgrowth.
• Rifaximin + Neomycin: The combination increases the risk of C. difficile infection. Neomycin, being more disruptive to the gut microbiome, can create conditions conducive to C. difficile proliferation. While combining these antibiotics is often effective for treating methane-dominant SIBO, the increased risk of C. difficile infection must be carefully considered.

Probiotic Support in SIBO

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. During antibiotic treatment, probiotics can help replenish the beneficial bacteria that antibiotics often deplete. This is especially important in maintaining a balanced gut microbiome, which is essential for healthy digestion, immune function, and overall well-being. Probiotics like Lactobacillus and Bifidobacterium species have been shown to reduce antibiotic-associated diarrhea, a common side effect of antibiotic therapy.

However, the use of probiotics in the context of SIBO is more complex. SIBO is characterized by an overgrowth of bacteria in the small intestine, so introducing more bacteria via probiotics might seem counterintuitive. Yet, certain strains of probiotics have been found to be beneficial in managing SIBO symptoms. These strains work by:

• Outcompeting harmful bacteria
• Producing antimicrobial substances
• Enhancing gut motility

Additionally, probiotics can help restore the balance of gut flora after the bacterial overgrowth has been reduced by antibiotics, potentially reducing the risk of SIBO recurrence.

Timing of probiotics when taking antibiotics is important. Traditional probiotics must be taken 2-hours away from antibiotics to prevent the antibiotic from killing the beneficial probiotics and the probiotics from reducing the antibiotics efficacy. Taking a probiotic at bedtime (2-hrs away from the evening antibiotic dose) is preferred.

Saccharomyces boulardii for SIBO

Saccharomyces boulardii, a beneficial yeast, plays a particularly important role when taking antibiotics. Unlike bacterial probiotics, S. boulardii is not affected by antibiotics, allowing it to remain active in the gut even during treatment. It has been shown to protect against antibiotic-associated diarrhea and C. difficile infections in multiple ways:

• Inhibiting the growth of pathogenic bacteria
• Enhancing the immune response
• Promoting the production of short-chain fatty acids that nourish the gut lining.

For individuals with SIBO, S. boulardii can be especially valuable as it helps to restore gut health without contributing to bacterial overgrowth.

Saccharomyces boulardii is not a bacteria, therefore it is safe to take at the same time as antibiotics. Rifaximin is typically taken three times daily, so taking S. boulardii with the morning and evening dose is common.

Summary

In summary, while the use of probiotics in SIBO treatment requires careful consideration, the combination of probiotics and S. boulardii with antibiotic therapy is generally beneficial for:

• Supporting gut health
• Reducing side effects
• Preventing the recurrence of infections.

Their ability to restore balance to the gut microbiome and provide protective effects against antibiotic-associated disruptions makes them a valuable addition to any antibiotic regimen, including for those dealing with SIBO.

For more about how Dr. Bradley Bush addresses SIBO, check out these blogs: Two Step SIBO Treatment, Herbal Protocols, and Ranking SIBO Antibiotics. Become a Neurovanna healthcare provider for more tips on addressing SIBO.

 

Disclaimer: The information on this site is for educational purposes only. Individual results may vary. Patients should consult with their healthcare providers before taking any interventions.

References

Jian J, Nie MT, Xiang B, Qian H, Yin C, Zhang X, Zhang M, Zhu X, Xie WF. Rifaximin Ameliorates Non-alcoholic Steatohepatitis in Mice Through Regulating gut Microbiome-Related Bile Acids. Front Pharmacol. 2022 Apr 4;13:841132. doi: 10.3389/fphar.2022.841132. PMID: 35450049; PMCID: PMC9017645.

Torre A, Córdova-Gallardo J, Frati Munari AC. Rifaximin Alfa and Liver Diseases: More Than a Treatment for Encephalopathy, a Disease Modifier. Ther Clin Risk Manag. 2023 Oct 24;19:839-851. doi: 10.2147/TCRM.S425292. PMID: 37899985; PMCID: PMC10612522

One of the primary treatments for small intestinal bacterial overgrowth (SIBO) is the use of antibiotics, which aim to reduce the bacterial load in the small intestine. Below, we explore the most common antibiotic treatments for SIBO, their published efficacy rates, and potential side effects in order of efficacy.

Rifaximin

Efficacy: Approximately 70-80%

Details: Rifaximin is the most commonly prescribed antibiotic for SIBO due to its broad-spectrum activity and minimal systemic absorption. It is particularly effective against hydrogen-producing bacteria.

Research has consistently shown that Rifaximin improves symptoms in a majority of patients with SIBO, making it the first-line treatment in many cases.

Common Side Effects:

• Nausea
• Abdominal pain
• Headache
• Dizziness

Sources:

Pimentel, M. et al. (2006). “A 14-day course of rifaximin is effective in treating SIBO.” The American Journal of Gastroenterology.

Neomycin

Efficacy: Approximately 63% when used alone; 85% when combined with Rifaximin

Details: Neomycin is often used in combination with Rifaximin, especially in cases where methane-producing bacteria are involved, such as in constipation-predominant SIBO. The combination of these two antibiotics is particularly effective for patients who do not fully respond to Rifaximin alone. My own clinical experience shows a 30% improvement of outcomes in patients with elevated methane SIBO using combined Rifaximin (4 week treatment) along with neomycin (2 week treatment). I do not recommend using it alone.

Common Side Effects:

• Nausea
• Diarrhea
• Ototoxicity (hearing loss with prolonged use)
• Nephrotoxicity (kidney damage with prolonged use)

Sources:

Pimentel, M. et al. (2010). “Combination of rifaximin and neomycin is more effective than rifaximin alone in treating methane-positive SIBO.” The American Journal of Gastroenterology.

Metronidazole

Efficacy: Approximately 55-70%

Details: Metronidazole is another antibiotic option, particularly in patients who are intolerant to Rifaximin or in cases where Rifaximin is not effective. It is often combined with other antibiotics such as ciprofloxacin or neomycin to enhance its efficacy. In my own clinical experience, I use Metronidazole for 2 weeks along with rifaximin to improve SIBO outcomes in addition to treating large intestinal overgrowths that often lead to SIBO.

Common Side Effects:

• Metallic taste in the mouth
• Nausea
• Vomiting
• Diarrhea
• Potential neurotoxicity (with prolonged use)

Sources:

Lacy, B. E., & Rosemore, J. (2001). “Small intestinal bacterial overgrowth: diagnosis and treatment.” Gastroenterology & Hepatology.

Ciprofloxacin

Efficacy: Approximately 52-60%

Details: Ciprofloxacin is a broad-spectrum antibiotic used less frequently due to its lower efficacy compared to Rifaximin and potential for serious side effects. It is generally reserved for cases where other treatments have failed or are not suitable. Ciprofloxacin is a poor option for SIBO treatments since it is absorbed in the intestines too quickly to be beneficial in the mid-to-lower intestines. Additionally, its use can lead to SIBO. Other interventions are recommended.

Common Side Effects:

• Nausea
• Diarrhea
• Tendonitis and tendon rupture
• Central nervous system effects (e.g., confusion, dizziness)

Sources:

Di Stefano, M. et al. (2000). “Treatment of small intestine bacterial overgrowth with ciprofloxacin.” Alimentary Pharmacology & Therapeutics.

Amoxicillin-Clavulanate

Efficacy: Approximately 50-55%

Details: Amoxicillin-Clavulanate is sometimes used in treating SIBO, particularly in combination with other antibiotics. Its efficacy is generally lower than that of Rifaximin, but it may be beneficial for certain bacterial profiles or in patients who cannot tolerate other antibiotics. Amoxicillin-Clavulanate is commonly required by insurance companies before other options, such as Rifaximin, are authorized. However, Amoxicillin-Clavulanate is absorbed in the intestines too quickly to be beneficial in mid-to-lower intestines, making it a poor option for most SIBO cases.

Common Side Effects:

• Nausea
• Diarrhea
• Rash
• Allergic reactions

Sources:

Rao, S. S., & Nawaz, H. (2007). “Small intestinal bacterial overgrowth in irritable bowel syndrome: are there any predictors?” The American Journal of Gastroenterology.

Tetracycline

Efficacy: Approximately 48-60%

Details: Tetracycline is another antibiotic option, though it is less commonly used due to potential side effects and slightly lower efficacy. It is often considered for patients who are intolerant to other treatments or have specific bacterial resistance patterns. Tetracycline is absorbed in the intestines too quickly to be beneficial in the mid-to-lower intestines. Therefore, it is a poor option for most SIBO cases. In some instances, it has been known to cause SIBO.

Common Side Effects:

• Photosensitivity (increased risk of sunburn)
• Gastrointestinal upset
• Discoloration of teeth (in long-term use, especially in children)
• Risk of antibiotic resistance

Sources:

Lauritano, E.C. et al. (2005). “Small intestinal bacterial overgrowth and irritable bowel syndrome.” Digestive Diseases and Sciences.

Conclusion

Antibiotics remain a cornerstone in the conventional treatment of SIBO, with Rifaximin being the best option due to its high efficacy and favorable safety profile. However, the choice of antibiotic often depends on the patient’s insurance coverage, specific symptoms, bacterial profile, and previous responses to treatment. While antibiotics can be highly effective in treating SIBO, they also carry the risk of side effects, and their use should be carefully monitored by a healthcare professional. Combination treatments incorporating both herbals and prescriptive antibiotics offer a superior approach versus single therapies.

Our SIBO experts are available to consult with Neurovanna healthcare providers for difficult cases. Become a Neurovanna provider today.

Antibiotic	Efficacy Rate	Primary Use Case	Clinical Note
Rifaximin	70–80%	Hydrogen SIBO (First-line)	Best safety profile; stay in the gut.
Neomycin	85% (Combined)	Methane SIBO (Constipation)	Use with Rifaximin; do not use alone.
Metronidazole	55–70%	Rifaximin-intolerant / Large Intestine	Good for treating underlying root causes.
Ciprofloxacin	52–60%	Last resort only	Poor option: Absorbed too quickly; can cause SIBO.
Amoxicillin	50–55%	Insurance requirement	Poor option: Often fails to reach mid-intestine.
Tetracycline	48–60%	Specific resistance	Poor option: High risk of antibiotic resistance.

Disclaimer: The content of this article is for informational purposes only and does not constitute medical advice. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this article.

Small intestinal bacterial overgrowth (SIBO) is a complex condition where excessive bacteria in the small intestine disrupt digestion, cause bloating, and drive inflammation. While conventional options are available, many clinicians and patients are turning to herbals for a natural alternative.

Often recommended herbals to support GI health include oregano oil, berberine, allicin, and neem. Among these botanical interventions, oregano oil and berberine stand out as two of the most research-backed herbal interventions for SIBO. However, not all products are created equal—many supplement companies lack clinical data or standardization.

Oregano Oil: A Potent Broad-Spectrum Agent

Oregano oil, particularly its active component carvacrol, has been shown in studies to possess antibacterial, antifungal, and antiparasitic properties. One landmark 2014 study published in Global Advances in Health and Medicine compared herbal treatments for SIBO and found that a combination including oregano oil and berberine was highly effective in addressing SIBO, proven with breath test results.

Why oregano oil works:

• Disrupts bacterial cell membranes
• Broad-spectrum activity (Gram-positive and Gram-negative bacteria)
• Synergistic with other antimicrobials like berberine and garlic

Berberine: An Herbal Heavyweight

Berberine, an alkaloid found in plants like Oregon grape, barberry, and goldenseal, exerts strong antimicrobial effects by:

• Disrupting bacterial DNA
• Inhibiting quorum sensing and biofilm formation
• Modulating inflammatory cytokines

It’s been widely used not only in SIBO protocols but also in dysbiosis, candida overgrowth, and even metabolic disorders due to its blood sugar and cholesterol–lowering properties.

Dihydroberberine: A Next-Gen Upgrade

While traditional berberine HCl is clinically effective, it suffers from low bioavailability and may cause GI discomfort in sensitive individuals. For individuals with sensitive digestion, the high HCl content may limit tolerability.

Dihydroberberine (DHB) offers an alternative. As a neutral-charged, hydrogenated metabolite of berberine, DHB demonstrates up to five times greater bioavailability. This results from DHB’s ability to passively diffuse across cell membranes, bypassing the need for active transport. It also avoids first-pass hepatic metabolism, allowing smaller doses to deliver equal or superior therapeutic effects. Importantly, because DHB is not bound to hydrochloric acid, it tends to be much more tolerable for individuals with gastric sensitivity.

Clinical Tip: Dihydroberberine may be especially useful in patients with poor absorption, sensitive GI tracts, or those people with insulin resistance.

Allicin: Methane Gas Assassin

Methane-predominant SIBO (now often classified as IMO – Intestinal Methanogen Overgrowth) is notoriously harder to treat than hydrogen-dominant types. Allicin, the active antimicrobial compound in garlic, has shown impressive results in targeting methane-producing Archaea, especially Methanobrevibacter smithii.

Clinical notes:

• Use stabilized Allicin extracts, not standard garlic capsules
• Allicin works synergistically with berberine and oregano
• Effective against sulfur-metabolizing organisms in some patients
• Has good anti-fungal properties

Neem: Ancient Herb with Modern Utility

Neem (Azadirachta indica) has been used for thousands of years in Ayurvedic medicine for its bitter, antimicrobial, and anti-inflammatory properties. In the context of SIBO, neem:

• Disrupts bacterial adhesion and replication
• Inhibits fungal overgrowth
• May help reduce biofilms that protect resistant bacteria
• Can also be used daily to manage acne and support skin health

Though less studied in Western trials compared to berberine or oregano, neem is considered a gentle, broad-spectrum agent and is often included in multi-herb SIBO protocols.

Buyer Beware: Not All Supplements Are Equal

A well-designed herbal protocol for SIBO—using research-supported agents like oregano oil, berberine (or its more bioavailable form, dihydroberberine), stabilized allicin, and neem—can be remarkably effective, often with fewer side effects than conventional antibiotics. However, the success of such protocols depends heavily on the quality and integrity of the supplements used.

 

Many products on the market lack standardized extracts, fail to disclose active compound concentrations, or contain fillers and substandard plant materials. For optimal outcomes—especially in persistent or relapsing cases—choose third-party tested, clinician-formulated products, and consult a qualified healthcare provider to ensure proper dosing and therapeutic synergy.

 

Neurovanna offers its healthcare providers one-on-one consults with SIBO experts to help develop comprehensive treatment plans or better understand complex cases. Become a Neurovanna provider for expert support.

Disclaimer: The content of this article is for informational purposes only and does not constitute medical advice. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this article.

Using a combination protocol that begins with herbal treatments for small intestine bacterial overgrowth (SIBO) followed by prescription antibiotics can significantly enhance treatment outcomes, reduce side effects, and lower the likelihood of recurrence. This stepwise approach leverages the benefits of both natural and pharmaceutical therapies, creating a more comprehensive and effective treatment plan.

Step 1: Herbal Antimicrobials

Starting with herbal antimicrobials, such as oregano oil, berberine, and thyme, helps to reduce the bacterial load in the small intestine in a gentler manner. These herbs not only target the harmful bacteria responsible for SIBO but also possess antifungal and anti-inflammatory properties, which contribute to a more balanced gut environment. By addressing the overgrowth with herbs first, the overall bacterial population is lowered, making it easier for the subsequent antibiotic treatment to effectively target the remaining bacteria without overwhelming the gut microbiome.

Step 2: Prescription Antibiotics

Following up with prescription antibiotics, such as Rifaximin or a combination of Rifaximin with Neomycin and/or Metronidazole, allows for a more focused and potent elimination of the remaining bacteria. Since the bacterial load has already been reduced by the herbal treatment, a lower dose or shorter course of antibiotics may be sufficient, which can help to minimize potential side effects such as diarrhea, nausea, and gut dysbiosis. Additionally, this dual approach helps to address both hydrogen-producing and methane-producing bacteria, ensuring a more thorough eradication of the overgrowth.

The Benefits of the Combo Approach

By first reducing the bacterial population with herbs and then using antibiotics for a targeted cleanup, this combination protocol also reduces the chances of antibiotic resistance. The use of herbal treatments can decrease the need for high doses of antibiotics, which are more likely to lead to resistance. Furthermore, this approach may prevent the common recurrence of SIBO, as the gut flora is better preserved and less disrupted, allowing for a healthier environment that is less conducive to bacterial overgrowth in the future.

Overall, a combination protocol that incorporates both herbal and antibiotic treatments provides a holistic and effective strategy for managing SIBO, improving outcomes, and reducing the risk of side effects and recurrence.

Neurovanna offers complimentary one-on-one consults with SIBO experts to healthcare providers to help better understand test results and the best course of treatment. Sign up to get help with interpreting results and addressing complex cases.

Disclaimer: The content of this article is for informational purposes only and does not constitute medical advice. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this article.

When addressing small intestine bacterial overgrowth (SIBO), lipopolysaccharide (LPS) interventions should be considered. LPS is an endotoxin released from the cell walls of bacteria when they die that can lead to inflammation, endotoxemia, insulin resistance, and adrenal dysfunction. Serum-derived immunoglobulins (SDI) offer a novel approach to mitigating the harmful effects of LPS. These immunoglobulins are derived from bovine serum and are rich in antibodies that can bind to and neutralize LPS and other bacterial toxins.

How SDI Helps

Neutralization of LPS

• Binding to LPS: SDI contains antibodies that specifically bind to LPS, neutralizing their endotoxin activity and preventing them from interacting with TLR4. This reduces the immune activation and inflammation caused by LPS.
• Blocking Absorption: By binding to LPS in the gut, SDI can prevent their absorption into the bloodstream, thereby reducing systemic endotoxemia.

Supporting Gut Barrier Function

• Reduction of Inflammation: By neutralizing LPS, SDI can help reduce inflammation in the gut, promoting a healthier gut lining and preventing “leaky gut.”
• Restoration of Tight Junctions: The reduction in inflammation helps restore the integrity of tight junctions in the gut epithelium, further preventing the translocation of LPS and other toxins.

Immune Modulation

• Regulation of Immune Response: SDI can modulate the immune response, reducing the overactivation that leads to chronic inflammation. This helps in managing conditions like IBD, rheumatoid arthritis, and other inflammatory diseases.

Clinical Evidence and Applications for SDI

Several studies have demonstrated the effectiveness of SDI in reducing the harmful effects of LPS.

• Gut Health: Research shows that SDI can improve gut barrier function and reduce intestinal inflammation, making it a promising treatment for conditions like irritable bowel disease/syndrome (IBD and IBS) (Frontiers) (Revista ACTA).

• Metabolic Health: By reducing systemic inflammation, SDI has potential benefits for managing metabolic disorders such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD).

• Immune Support: SDI can help regulate the immune system, providing benefits for autoimmune and inflammatory conditions.

Comprehensive SIBO Treatment

In addition to SDI, the effective management of SIBO often involves a combination of dietary changes, antibiotics, or herbal antimicrobials, and lifestyle modifications.

Antibiotics and Herbal Treatments: Rifaximin is a commonly prescribed antibiotic for SIBO that targets the small intestine. Herbal treatments like berberine, oregano oil, and garlic extract can also be effective in reducing bacterial overgrowth.

Dietary Adjustments: Low-FODMAP diets and specific carbohydrate diets (SCD) can help reduce symptoms by limiting the fermentable substrates available to bacteria.

Probiotics and Prebiotics: These can help restore a healthy balance of gut microbiota and support gut barrier function.

Anti-inflammatory Supplements: Omega-3 fatty acids, curcumin, and other anti-inflammatory agents can help reduce systemic inflammation.

Adrenal support: During an acute stress response, calming support, such as L-theanine, ashwagandha and 5-HTP could be beneficial.  To address a chronic stress response, stimulating and re-sensitizing support such as licorice root and phosphatidylserine are helpful.

Conclusion

Addressing LPS is a critical aspect of SIBO treatment for some patients. SDI offers a promising solution by neutralizing LPS, supporting gut barrier function, and modulating the immune response. This innovative approach can help reduce the side effects associated with bacterial endotoxins and improve overall health outcomes. However, LPS is just part of a comprehensive approach to addressing and mitigating the side effects of SIBO.

Healthcare providers, are you wondering what aspects of SIBO treatment are right for your patient? Neurovanna offers complimentary one-on-one consults with SIBO experts to our customers. Sign up to get help with interpreting results and addressing complex cases.

References

Raison, C. L., et al. (2006). “Cytokines sing the blues: inflammation and the pathogenesis of depression.” Trends in Immunology.

Webb, E. et al. (1998). “Hypothalamic-pituitary-adrenal axis function and the pathophysiology of chronic fatigue syndrome.” Psychoneuroendocrinology.

Silverman, M. N., & Sternberg, E. M. (2012). “Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction.” Annals of the New York Academy of Sciences.

Pimentel, M., et al. “Small Intestinal Bacterial Overgrowth: Associations With Irritable Bowel Syndrome and Gastrointestinal Motility Disorders.” Gastroenterology.

Rezaie, A., et al. “Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus.” The American Journal of Gastroenterology.

Lauritano, E. C., et al. “Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome.” Gut.

Tana, C., et al. “Altered Profiles of Intestinal Microbiota and Organic Acids May Be the Origin of Symptoms in Irritable Bowel Syndrome.” Neurogastroenterology & Motility.

When bacteria overgrow in the small intestine—a condition known as small intestinal bacterial overgrowth (SIBO)—they can spark a powerful response throughout the body. As these bacteria multiply and die off, they release fragments of their cell walls called lipopolysaccharides (LPS). Left unchecked, these large molecules lead to rampant inflammation and a dysfunctional stress response.

Side Effects of Bacterial Cell Walls

Bacterial cell walls, particularly from gram-negative bacteria, contain components that can be harmful when the bacteria overgrow and die off in large numbers. Three components are:

• LPS: Endotoxins that trigger severe immune responses, systemic inflammation, and metabolic disturbances.

• Peptidoglycan Fragments: Stimulate immune responses and inflammation.
• Exotoxins: Damage the gut lining and other tissues resulting in ‘leaky gut’, which allows LPS and other toxins to enter the bloodstream more easily. This leads to symptoms like diarrhea and abdominal pain.

Dysbiosis can lead to the proliferation of harmful bacteria further compounding the effects.

Three Ways LPS Affects the Body

• Inflammation: LPS is recognized by the immune system as a pathogen-associated molecular pattern (PAMP). This recognition activates immune responses and the release of pro-inflammatory cytokines like TNF-alpha and IL-6, which can cause systemic inflammation.

• Endotoxemia: LPS can translocate from the gut into the bloodstream, especially when the gut barrier is compromised. This endotoxemia can contribute to chronic inflammation and is implicated in various conditions including metabolic syndrome, liver diseases, and autoimmune disorders.

• Insulin Resistance: Chronic exposure to LPS can lead to insulin resistance, which is a precursor for type 2 diabetes and metabolic syndrome.

How LPS Dysregulates the Stress Response

LPS attacks the hypothalamic-pituitary-adrenal (HPA) axis that modulates the stress response from multiple angles, eventually overwhelming it. Ultimately, the stress response may be left unable to adequately respond to threats.

LPS Triggers Pro-inflammatory Immune Activity 

Cytokine Release

LPS, as a potent endotoxin, triggers an immune response that leads to the release of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-alpha. These cytokines activate the HPA axis.

Hypothalamic Response

Cytokines signal the hypothalamus to release corticotropin-releasing hormone (CRH). In turn, CRH stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which prompts the adrenal glands to produce cortisol, the stress hormone.

LPS Increases Blood-Brain Permeability

Blood-Brain Barrier Permeability

LPS can increase the permeability of the blood-brain barrier, allowing more cytokines and other inflammatory mediators to enter the brain and directly affect the hypothalamus.

Neuroinflammation

The presence of pro-inflammatory mediators trigger neuroinflammation. Within the brain, inflammation can disrupt the normal functioning of the hypothalamus and pituitary gland, leading to abnormalities in hormone secretion, including cortisol.

LPS-Associated Inflammation Wears Down the Stress Response

Acute Phase Response

During acute inflammation, the release of cytokines can lead to increased production of cortisol as part of the body’s stress response. Cortisol helps to modulate inflammation and maintain homeostasis. During short-term exposure to LPS, the increased release of cortisol creates a negative feedback loop helping to manage inflammation and stress, by decreasing cytokines and suppressing the release of CRH and ACTH, ultimately reducing cortisol production.

Chronic Inflammation Response

Prolonged exposure to LPS and chronic inflammation can lead to persistent stimulation of the HPA axis. Over time, this can result in dysregulation of cortisol production, potentially leading to adrenal fatigue where cortisol levels become insufficient leaving the HPA axis unable to respond appropriately.

 

Clinical Implications of HPA Axis Dysregulation

• Chronic Fatigue Syndrome: Reduced cortisol production due to HPA axis dysfunction is associated with chronic fatigue syndrome, characterized by extreme tiredness not alleviated by rest.
• Depression and Anxiety: Both increased and decreased cortisol levels are linked to mood disorders. Elevated cortisol can contribute to anxiety, while insufficient cortisol can be associated with depression.
• Autoimmune Diseases: Dysregulation of the HPA axis and altered cortisol levels can exacerbate autoimmune conditions by failing to adequately regulate immune responses.

Conclusion

SIBO is a complex condition that not only disrupts gut function but also has far-reaching effects due to the release of bacterial endotoxins like LPS. Understanding the interplay between bacterial overgrowth, LPS, and systemic inflammation is crucial for effectively managing and treating SIBO. Additionally, awareness of HPA axis dysregulation and adrenal gland health further helps address side effects of LPS/SIBO to improve overall health.

Find out if SIBO is triggering your inflammation and stress with non-invasive lactulose or glucose breath tests from Neurovanna. Healthcare providers sign up for an account. If you are a patient interested in SIBO testing, contact us for help in finding a provider near you.

References

• Raison, C. L., et al. (2006). “Cytokines sing the blues: inflammation and the pathogenesis of depression.” Trends in Immunology.
• Webb, E. et al. (1998). “Hypothalamic-pituitary-adrenal axis function and the pathophysiology of chronic fatigue syndrome.” Psychoneuroendocrinology.
• Silverman, M. N., & Sternberg, E. M. (2012). “Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction.” Annals of the New York Academy of Sciences.
• Pimentel, M., et al. “Small Intestinal Bacterial Overgrowth: Associations With Irritable Bowel Syndrome and Gastrointestinal Motility Disorders.” Gastroenterology.
• Rezaie, A., et al. “Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus.” The American Journal of Gastroenterology.
• Lauritano, E. C., et al. “Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome.” Gut.
• Tana, C., et al. “Altered Profiles of Intestinal Microbiota and Organic Acids May Be the Origin of Symptoms in Irritable Bowel Syndrome.” Neurogastroenterology & Motility.