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

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• 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.