Modulating Systemic Inflammation Via The Gut

Inflammation is a normal part of the body’s response to harmful stimuli such as tissue damage, infection or exposure to toxins. Inflammation is mediated by the immune system, and serves three immediate needs for self-preservation: to contain and repair damaged or infected tissues; to attract immune cells to local sites through inflammatory mediators, such as cytokines; and to orchestrate a healing response. Inflammation is not in itself pathological. Without it, we could not survive. It limits, for example, the persistence of pathogens. But the cardinal signs of inflammation—redness, heat, pain and swelling—especially if chronic, are often indicative of underlying disease.

The Gut as Source of Inflammation

Hippocrates of Kos famously said all disease begins in the gut. As our understanding of the human microbiome expands, and inter-relations between that system and other body systems become increasingly evident, the words of the “Father of Modern Medicine" ring even truer today than they did when they were spoken more than 2,000 years ago.

Inflammation originating in the gut may play an underlying role in many systemic inflammatory conditions, and dysbiosis of the gut microbiota is emerging as an important mediator of immune and inflammatory status throughout the body.

Gut microbiota are well known to help maintain tight junctions between gut epithelial cells. It should therefore come as no surprise that dysbiosis and associated increases in intestinal permeability are now recognized features of rheumatoid arthritis, Alzheimer's disease, asthma, autism spectrum disorders and other systemic ills—both inflammatory and otherwise.

Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function. Disruption of epithelial barrier integrity is likely one of the major etiological factors associated with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotizing enterocolitis, irritable bowel syndrome and inflammatory bowel disease.[1]

Modulating Systemic Inflammation Via the Gut

Many of the effective therapies for managing inflammation naturally (e.g., curcumin, omega-3 fatty acids, probiotics) are now being seen through the lens of their activity on the gut. Consider two examples:

Curcumin: Poor bioavailability of curcumin has spurred formulation wars in which companies have sought to enhance bioavailability through a variety of means. But how does one explain the centuries-long observed relationship between oral supplementation with ordinary turmeric and its clear anti-inflammatory effects? Turmeric has been fighting inflammation a lot longer than there have been phytosomes and nanoparticles. Could curcumin be modulating systemic inflammation from within the gut, prior to absorption?

Some researchers have hypothesized that curcumin attenuates Western diet-induced chronic inflammation and associated metabolic diseases by modulating the function of intestinal epithelial cells and the intestinal barrier function. By reducing intestinal barrier dysfunction, up-regulating the expression of occludin in the intestinal mucosa, and reducing the levels of TNFα and lipopolysaccharides, curcumin could effectively modulate chronic inflammatory diseases despite poor bioavailability.[2]^,[3]^,[4]

Omega-3 Fatty Acids: Fish oil and its constituent fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well-known as modulators of inflammation. Much has been written on the anti-inflammatory and pro-resolution mechanisms of action of these fatty acids, and fish oil has been clinically effective in managing inflammatory diseases, including intestinal conditions such as ulcerative colitis. But do long-chain polyunsaturated fatty acids (PUFAs) exert any of their systemic effects by interacting with the intestinal epithelium directly?

Zonulin is a protein that modulates the permeability of tight junctions between intestinal epithelial cells. Activation of zonulin leads to increased intestinal permeability to macromolecules. One group of researchers recently investigated whether the gut microbiota and diet differ according to serum zonulin concentration in overweight pregnant women. They found that dietary quantitative intakes of omega-3 PUFAs (as well as fiber and a range of vitamins and minerals) were higher in women in the low zonulin group than those in the high zonulin group.[5]

The richness and composition of the gut microbiota was also inversely associated with zonulin. These observations led researchers to conclude that modification of the gut microbiota (e.g., with probiotics) and improvement of the diet (e.g., by increasing omega-3s) may beneficially affect intestinal permeability by down-regulating zonulin, leading to improved metabolic health overall.

While diverse clinical trials in humans continue to demonstrate efficacy of natural medicines in inflammation and in the health of the gut, further research is warranted to validate the connections between gut mucosal and microbial health and the modulation of systemic inflammation.

Learn more about how inflammation works in the body from Jeremy Appleton, ND, during the Addressing Inflammation Naturally … and Legally Workshop on Friday, Sept. 29 at 8:30 a.m. at SupplySide West in Las Vegas. The Workshop is underwritten by NEC.

Jeremy Appleton, ND, is a licensed naturopathic physician, educator, and supplement industry executive. He is the author of numerous articles on natural medicine. Dr. Appleton currently works as vice president of scientific and regulatory affairs for SFI-USA, which manufactures supplements for healthcare professionals under the Klaire Labs brand.

[1] Bron PA, Kleerebezem M, Brummer R-J, Cani PD. Can probiotics modulate human disease by impacting intestinal barrier function? Br J Nutr. Volume 117, Issue 1 January 2017, pp. 93-107

[2] Wang J, Ghosh SS, Ghosh S. Curcumin improves intestinal barrier function: modulation of intracellular signaling, and organization of tight junctions. Am J Physiol Cell Physiol. 2017 Apr 1;312(4):C438-C445. doi: 10.1152/ajpcell.00235.2016. Epub 2017 Mar 1.

[3] Monfoulet LE, Mercier S, Bayle D, et al. Curcumin modulates endothelial permeability and monocyte transendothelial migration by affecting endothelial cell dynamics. Free Radic Biol Med. 2017 Jul 22;112:109-120. doi: 10.1016/j.freeradbiomed.2017.07.019. [Epub ahead of print]

[4] Hou HT, Qiu YM, Zhao HW, et al. [Effect of curcumin on intestinal mucosal mechanical barrier in rats with non-alcoholic fatty liver disease]. Zhonghua Gan Zang Bing Za Zhi. 2017 Feb 20;25(2):134-138. doi: 10.3760/cma.j.issn.1007-3418.2017.02.011. [Article in Chinese]

[5] Mokkala K, Röytiö H, Munukka E, et al. Gut Microbiota Richness and Composition and Dietary Intake of Overweight Pregnant Women Are Related to Serum Zonulin Concentration, a Marker for Intestinal Permeability. J Nutr. 2016 Sep;146(9):1694-700. doi: 10.3945/jn.116.235358. Epub 2016 Jul 27.