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Functional Gastroenterology Bolus: The Grey Areas in Gl Health and Disease.

Common thought processes about the pathophysiology of septicemia, appendicitis, and diverticulitis tend toward black and white concepts. Either the patient has one of these acute conditions - or they don't. I would like to explain my observations on the continua at work in these three conditions and how thinking outside the box can allow holistically oriented health practitioners to recognize the grey areas in diagnosis. This article will focus on septic shock.

Naturopathic medicine's philosophy is, in large part, based on the concept of unity of disease causation. The theory is that most diseases are due to accumulation of "morbid matter." Under conditions of healthy functioning, these toxins are removed by the emunctories--exhalation, perspiration, defecation and urination. When toxic metabolites accumulate in levels beyond the capacity of the emunctories, inflammation goes to a higher level, eventually triggering "vicarious elimination." This form of detoxification involves suppuration and other exudates, skin lesions, fistulae, respiratory congestion and discharge, diarrhea, vomiting, urinary casts, etc. Standing on the shoulders of the giants of naturopathic philosophy, I agree that this accumulation of "morbid matter" is, in fact, the cause of many diseases. We used to invoke the edict "death begins in the colon." Seen with a broader scope, we might also say that dysfunction and autoimmunity begin in the digestive tract as a whole.

According to Medscape:
The pathophysiology of septic shock is not precisely understood but is
considered to involve a complex interaction between the pathogen and
the host's immune system. The normal physiologic response to localized
infection includes activation of host defense mechanisms that result in
the influx of activated neutrophils and monocytes, release of
inflammatory mediators, local vasodilation, increased endothelial
permeability (in part though the zonulin pathway), and activation of
coagulation pathway. (1)

The present focus in research on the effects of the Gl microbiota is bringing us to a better physiological explanation of the unity of disease theory. Lipopolysaccharide (LPS) derived mostly from the outer cell wall of gram negative bacteria, leads to activation of macrophages, neutrophils, and platelets, and triggers the endothelia to release various cytokines (especially tumor necrosis factor and interleukin-1) and other mediators. LPS is also referred to as endotoxin. Peptidoglycans are similar pro-inflammatory substances derived from the outer cell wall of gram positive bacteria. These mediators, along with lipotechoic acid and superantigen, induce Th17 and therefore are significant in the pathophysiology of Crohn's disease, systemic lupus erythematosus, and rheumatoid arthritis. (2)

There are 1 million copies of LPS in each gram-negative microbe and these are released from both living and dead bacteria. (3) Release may also be triggered by antibiotic therapy. Adults have approximately one gram of total gut LPS. (4, 5) When absorbed into the portal vein, LPS is a burden on the liver; and when excessive, LPS serum levels rise and have far reaching effects. Clearly, intestinal bacteria do not need to cross into the bloodstream to trigger systemic inflammation and even life-threatening pathology.

As I wrote in a previous Townsend article on the gut-brain axis (June 2017), not all bacterial LPS is the same. For example, Enterobacter-derived LPS may be 1000 times more potent than LPS derived from other gram-negative bacteria. (6) Obesity increases the amount of LPS, which may be two to three times higher in the obese population compared to lean individuals.

Many mechanisms are in place to metabolize and remove LPS. In the neonate, LPS is bound and inactivated by a bacterial pattern recognition receptor CD14 found in human breast milk. CD14 is also found in bovine colostrum. Lactoferrin in breast milk also binds to LPS. (3) After weaning, LPS binds to Toll-like receptor 4 (TLR-4) on intestinal epithelial cells; and secretory IgA in enterocytes inactivates LPS. Lowering this endotoxin reduces the NF-KB pathway and its cascade of proinflammatory cytokines interferon, interleukins, and TNF alpha. (7) Mucins (from goblet cells) and antimicrobial peptides such as defensins (from Paneth cells) act on gram negative bacteria and therefore reduce exposure of intestinal epithelia to LPS. Defensins also alter the structure of developing bacterial cell walls to weaken the gram-negative microbes.

Intestinal alkaline phosphatase is another first-line mechanism for removal of LPS. Hepatic alkaline phosphatase helps reduce LPS arriving via the portal vein. When LPS from gut bacteria is absorbed into the bloodstream at higher levels, the alkaline phosphatase mechanism may not be adequate and serum levels of LPS rise. The ensuing inflammatory cascade has physical, emotional, and cognitive effects. (8)

Recent case reports illustrate that altering Gl flora by the use of fecal microbiota transplantation can resolve sepsis and the multiple organ dysfunction associated with sepsis. (9-11) A prospective placebo-controlled trial of elderly patients with intestinal bacterial overgrowth found that use of probiotic food (yogurt) decreased serum LPS and pro-inflammatory cytokines.12 Another prospective placebo-controlled trial studied the effects of yogurt consumption in premenopausal women. Results included reduced biomarkers of chronic inflammation and reduced evidence of endotoxin exposure compared with a soy-based control food. (13)

The feeding of omega-3 fish oils is a common intervention in nutritional immune support. A multicenter, prospective, randomized, double-blinded, controlled trial showed that the ingestion of omega 3 fish oils and gamma linoleic acid (EPA/GLA) may be beneficial in the treatment of patients in the early stages of sepsis--before organ dysfunction has begun. These oils slowed the progression of sepsis-related organ dysfunction. (14)

Does one need to have life-threatening septic shock in order to have disease-causing LPS levels? The gray area may be those increased levels due to shifts in the gastrointestinal microbiota that induce a spectrum of immune responses. Small intestine bacterial overgrowth--increased levels of commensal flora in a highly absorptive mucosal region--is associated with over 40 major illnesses and provides a major burden of LPS, peptidoglycans, and cytokines. If the mechanisms of secretory IgA, toll-like receptors, intestinal and hepatic alkaline phosphatase, defensins and mucins fail to inactivate and remove these inflammatory triggers, vicarious elimination will ensue. All manner of acute and chronic inflammatory diseases may begin in this way.



(2.) Li H, et al. Commercial peptidoglycan preparations are contaminated with superantigen-like activity that stimulates IL-17 production. J Leukocyte Biology. 2008; (89): 409-418.

(3.) Guerville M, Boudry G. Gastrointestinal and hepatic mechanisms limiting entry and dissemination of lipopolysaccharide into the systemic circulation. Am J Physiol Gastrointest Liver Physiol. 2016;311(1):G1-G15.

(4.) Erridge C, et al. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr. 2007;86(5): 1286-92.

(5.) Bested AC, et al. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part I--autointoxication revisited. Gut Pathog. 2013;5(1):5.

(6.) Mayer E. The Gut-Brain Connection. New York : Harper-Collins, 2014.

(7.) Boullier S, et al. Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits. J Immunol. 2009;183(9):5879-85.

(8.) Grigoleit JS, et al. Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PLoS One. 2011;6(12):e28330.

(9.) Li Q, et al. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit Care. 2015,19:37.

(10.) Wei Y, et al. Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis. Crit Care. 2016; 20: 332.

(11.) Li Q, et al. Therapeutic modulation and reestablishment of the intestinal microbiota with fecal microbiota transplantation resolves sepsis and diarrhea in a patient. Am J Gastroenterol. 2014; 109(11):1832-4.

(12.) Schiffrin EJ, et al. Probiotic yogurt in the elderly with intestinal bacterial overgrowth: endotoxaemia and innate immune functions. Br J Nutr. 2009;101(7):961-6.

(13.) Pei R, et al. Low-fat yogurt consumption reduces biomarkers of chronic inflammation and inhibits markers of endotoxin exposure in healthy premenopausal women: a randomised controlled trial. Br J Nutr. 2017;118(12):1043-1051.

(14.) Pontes-Arruda A, et al. Enteral nutrition with eicosapentaenoic acid, y-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT study. Crit Care. 2011;15(3):R144.

by Steven Sandberg-Lewis, ND, DHANP
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Author:Sandberg-Lewis, Steven
Publication:Townsend Letter
Article Type:Report
Date:Apr 1, 2018
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