Systemic Disease and the LPS Connection

Lipopolysaccharide Review

In Part 1 of this series, we discussed Lipopolysaccharide (LPS), an endotoxin found on the membrane of gram-negative bacteria. LPS binds to TLR4 which is a receptor that is at play with autoimmune diseases. Once LPS crosses the epithelial barrier, it stimulates NF-KB and resulting cytokines are released, stimulating systemic inflammation.

Part 1 was full of physiology and a deeper dive into what you learned in school, but how will that help you daily in your practice? By identifying specific diseases associated with LPS-induced systemic inflammation, we can pull clinical pearls from this knowledge to broaden our differential diagnosis, therefore elevating treatment for “those” patients that just can’t seem to get well.

Chronic Fatigue Syndrome

What comes to mind for a differential diagnosis when a patient presents with chronic fatigue? Thyroid, anemia, sleep apnea, depression? What may not be on your differential diagnosis is inflammation due to elevated levels of systemic LPS, dysbiosis of the gut microbiota, or decreased diversity of gut microbes. A-model-representing-curcumin-molecular-targets-in-TLR4-MAPK-NF-kB-pathway-TLR4.png (841×628) ( Gastrointestinal (GI) disturbances are among symptoms commonly reported by individuals diagnosed with chronic fatigue syndrome (CFS), as well as elevated levels of LPS (1). A study by Giloteaux et al. concludes, “Our results indicate dysbiosis of the gut microbiota in this disease (CFS) and further suggest an increased incidence of microbial translocation, which may play a role in inflammatory symptoms in CFS” (1).

The gut microbiome is an important factor to consider when trying to support a patient with CFS. Research by Maes et al. shows that persons with CFS have elevations in IgA and IgM against LPS, and that normalization of antibodies was predictive of symptomatic improvement (2). The results support the view that “a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS” (2).

These studies make it clear that adding inflammation as a result of dysbiosis to your differential diagnosis for fatigue patients may identify another piece of the puzzle, and move them in the right direction toward whole-body healing.

Rheumatoid Arthritis

What comes to mind when a patient presents with swollen, painful, and stiff joints? Rheumatoid arthritis is definitely included in your differential diagnosis. But are you thinking outside the box by asking yourself if it could be caused by LPS? Wherever the blood carries this endotoxin, an inflammatory condition can take hold, resulting in localized inflammation. “Injection of LPS in mouse studies caused reactivation of collagen-induced arthritis via increased production of anti-CII IgG and IgG2a antibodies as well as enhanced secretion of cytokines( IL-12, IFN-γ, IL-1β, and TNF-α). Thus, LPS may play a role in the exacerbation of autoimmune rheumatoid arthritis” (3).

Oral Health and Periodontitis

Does a patient who presents with early signs/symptoms of dementia, atherosclerosis, cardiovascular disease, or diabetes trigger a referral to the dentist? A review of literature done by Hashioka et al. showed that periodontal gram-negative bacteria like Porphyromonas gingivalis (P. gingivalis) and its component LPS are found in the periodontal pocket (4). These har mful bacteria form biofilms and enter the pocket epithelium where they gain access to systemic circulation and release pro-inflammatory cytokines. “Periodontitis thus causes or hastens other chronic systemic inflammatory diseases, including atherosclerosis, cardiovascular diseases, diabetes, and rheumatoid arthritis” (4).

Once in the bloodstream, LPS breaks down the blood-brain barrier (BBB), resulting in neuroinflammation. In one of the studies reviewed by Hashioka et al. mice were infected orally with P. gingivalis and showed subsequent transmission of P. gingivalis DNA to brain tissue (4). This was a startling discovery because P. gingivalis-derived LPS has been detected in the brains of Alzheimer’s disease patients.

Not only can periodontal pathogens enter the brain through the bloodstream, but also the cranial nerves. “The olfactory and trigeminal nerves are known to be used by periodontal bacteria to bypass the BBB” (4). As clinicians, this is relevant because when you think of a patient presenting with symptoms of systemic inflammation, you may not think of doing a cranial n erve exam. If the pathogens are using the cranial nerves to access the brain, you may have positive testing on a cranial nerve exam. Adding this exam to your routine may reveal significant information about why your patient is experiencing symptoms that seem unrelated. Ultimately, these symptoms may have the same root cause—systemic LPS from gram-negative periodontal pathogens.

Regardless of whether the periodontal bacteria reach the brain by the bloodstream or the cranial nerves, they will have the same damaging effect. Further review of the literature from Hashioka et al. showed, “Periodontal pathogens that reach the brain could result in inflammatory activation of microglia … even a single intraperitoneal injection of P. gingivalis LPS (5 mg/kg) into 8-week old mice has been shown to impair spatial learning and memory with neuroinflammation ... and activation of the TLR4/nuclear factorkappa B (NF-κ B) signaling pathway” (4).

Wrapping it up and a Clinical Challenge

As practitioners and clinicians, we have tried treatments that do not work or work for a while and stop working. It is frustrating when the patient cannot get back to the life desired because of poor health. Let’s challenge ourselves to continue to ask the hard question of why the person sitting in front of us cannot get well.

What steps can you take today?

  • Take a more thorough history
  • Ask questions outside of your normal intake
  • Connect more deeply with the patients so he/she feels comfortable opening up
  • Evaluate GI and oral health • Add a cranial nerve assessment to your exam

We need to take the time in our practice to educate ourselves on the devastating health consequences of LPS. I ask you to consider a different approach to patient history, treatment plan, and ongoing care for the patient. You can use the information from the research above to help the next patient you see in your office. Do they have gut issues in addition to arthritis, joint inflammation, and chronic fatigue? LPS may be the culprit or, at the least, it will open the door to a more complex diagnosis than what meets the eye.

Now that we are getting to the root cause of some of the illnesses that come through your office door, in Part 3, we will discuss how to support healing with botanicals.

Common Symptoms Related to the Microbiome

Oral Health Intake 

  • Oral hygiene routine
  • Frequency of dental evaluations
  • Ongoing periodontal disease
  • History of root canals
  • Halitosis (bad breath)
  • Dental implants
  • Plaque overproduction
  • Bleeding gums while brushing or flossing

GI Intake

  • Gas/bloating
  • Regular bowel movements
  • Acid reflux or frequent belching
  • Nausea
  • Irritable Bowel Syndrome
  • Irritable Bowel Disease (Crohn’s, ulcerative colitis)
  • Undigested food in stool

Symptoms of Cranial Nerve Disorders

  • Intermittent attacks of excruciating facial pain
  • Vertigo (dizziness)
  • Hearing loss
  • Weakness
  • Paralysis
  • Facial twitch
  • Senses, such as seeing, hearing, smell and taste.


  1. Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016 Jun 23;4(1):30. doi: 10.1186/s40168-016-0171-4. PMID: 27338587; PMCID: PMC4918027.
  2. Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. 2007 Apr;99(1-3):237-40. doi: 10.1016/j.jad.2006.08.021. Epub 2006 Sep 27. PMID: 17007934.
  3. Yoshino, S. and Ohsawa, M. The role of lipopolysaccharide injected systemically in the reactivation of collageninduced arthritis in mice. British Journal of Pharmacology, (2000) 129, 1309–1314; doi:10.1038/sj.bjp.0703166.
  4. Hashioka, Sadayuki et al. “The Possible Causal Link of Periodontitis to Neuropsychiatric Disorders: More Than Psychosocial Mechanisms.” International Journal of Molecular Sciences, vol. 20,15 3723. 30 Jul. 2019, doi:10.3390/ijms20153723.