The Microbiome and Autoimmunity

pablo

 

Scientists have long suspected a link between inflammatory bowel disease, psoriasis, and arthritis, since the same patients are often afflicted with more than one of these conditions.  As new technologies have enabled detection of invisible gut inflammation, it has become clear that in people with arthritis or psoriasis, gut inflammation is not the exception, but the rule.

The precise causes of this gut inflammation are not fully understood, but the latest evidence points to a significant role of the microbiome—the vast community of bacteria that resides in our gut.  One of the early discoveries in this area was made by a French gastroenterologist named Dr.Harry Sokol, who found that patients with Crohn’s disease (a form of inflammatory bowel disease) had lower levels of one particular bacterial species, F. prausnitzii.[i]  In the years since, the critical role of this species has emerged: it is a peacekeeper that helps to regulate the immune system, by boosting anti-inflammatory immune cells. It also helps to preserve the integrity of the gut barrier, thereby segregating harmful bacteria and toxins from the circulation and immune system.

In the years since Dr. Sokol’s discovery, there has been a massive global effort to understand the impact of the microbiome on inflammatory disease.  Further pieces of the puzzle have begun to fall into place, with the discovery that other related bacterial species fulfill the same peacekeeping function as F. prausnitzii, preserving the gut barrier and calming the immune system.

In 2015 and 2016, several groups of researchers made the groundbreaking discovery that particular species of gut bacteria that regulate the immune system are often depleted in those with psoriasis, psoriatic arthritis, juvenile arthritis, and ankylosing spondylitis.[ii]  These conditions, along with rheumatoid arthritis, are also associated with an increased prevalence of undesirable gut bacteria, such as E.coli.[iii]  In short, the balance of the microbiome is disrupted in those with psoriasis or arthritis, with a reduction in anti-inflammatory species and an increase in species that can spark an immune response.

Fortunately, the latest research also provides a road map for restoring the balance of the microbiome, through diet and carefully chosen probiotics, as my new book explains.

 

 

References

 

 

[i] Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermúdez-Humarán, L. G., Gratadoux, J. J., … & Grangette, C. (2008). Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proceedings of the National Academy of Sciences, 105(43), 16731-16736.

[ii] Scher, J. U., Ubeda, C., Artacho, A., Attur, M., Isaac, S., Reddy, S. M., … & Manasson, J. (2015). Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis & rheumatology, 67(1), 128-139.

Di Paola, M., Cavalieri, D., Albanese, D., Sordo, M., Pindo, M., Donati, C., … & Lionetti, P. (2016). Alteration of Fecal Microbiota Profiles in Juvenile Idiopathic Arthritis. Associations with HLA-B27 Allele and Disease Status. Frontiers in Microbiology, 7.

Eppinga, H., Weiland, C. J. S., Thio, H. B., van der Woude, C. J., Nijsten, T. E., Peppelenbosch, M. P., & Konstantinov, S. R. (2016). Similar depletion of protective Faecalibacterium prausnitzii in psoriasis and inflammatory bowel disease, but not in Hidradenitis suppurativa. Journal of Crohn’s and Colitis, 10(9), 1067-1075.

Stoll, M. L., Kumar, R., Morrow, C. D., Lefkowitz, E. J., Cui, X., Genin, A., … & Elson, C. O. (2014). Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. Arthritis research & therapy, 16(6), 486.

[iii] Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., … & Chai, C. (2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent inflammation. Science Translational Medicine, 9(376), eaaf9655;

Eppinga, H., Weiland, C. J. S., Thio, H. B., van der Woude, C. J., Nijsten, T. E., Peppelenbosch, M. P., & Konstantinov, S. R. (2016). Similar depletion of protective Faecalibacterium prausnitzii in psoriasis and inflammatory bowel disease, but not in Hidradenitis suppurativa. Journal of Crohn’s and Colitis, 10(9), 1067-1075;

Scher, J. U., Sczesnak, A., Longman, R. S., Segata, N., Ubeda, C., Bielski, C., … Littman, D. R. (2013). Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife, 2, e01202.

Maeda, Y., Kurakawa, T., Umemoto, E., Motooka, D., Ito, Y., Gotoh, K., … & Sakaguchi, N. (2016). Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis & Rheumatology, 68(11), 2646-2661.

Chen, J., Wright, K., Davis, J. M., Jeraldo, P., Marietta, E. V., Murray, J., … & Taneja, V. (2016). An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome medicine, 8(1), 43.

Advertisements

Mediterranean vs. Paleo

mediterranean diet anti-inflammatory

The Autoimmune Mediterranean diet and the Autoimmune Paleo diet share some basic similarities: both eliminate inflammatory refined vegetable oils and the grains and legumes that can damage the gut barrier.  Both emphasize nutrient density and whole, unprocessed foods.   But there are also some key differences.  The most important difference, and the reason why the Mediterranean diet is likely more effective for those with inflammatory disease, comes down to fat.

Followers of the paleo diet often obtain a large proportion of fat from sources such as coconut oil, ghee, palm oil, lard, beef tallow, and red meat.  This results in a very high intake of saturated fat (and a specific form of omega-6 fat called arachidonic acid).  While some of the authors who originally popularized the paleo diet have cautioned against excessive saturated fat (namely Loren Cordain, Robb Wolf, and Sarah Ballantyne), many other advocates for the paleo diet maintain that saturated fat is perfectly healthy as a main source of fat in the diet.

 

The Problem with Saturated Fat

 

Saturated fat was vilified for many years as a contributor to heart disease.  This link has now been seriously questioned, with several high-profile studies in the past ten years finding no impact of saturated fat on the risk of dying from heart disease.  But saturated fat is definitely a problem for those with inflammatory diseases, as several groundbreaking studies have now revealed.

In one study published in the journal Metabolism in 2016, [i] a randomized crossover trial found that even a short-term diet high in saturated fat resulted in higher levels of inflammatory mediators, including IL-6 and IL-1β, both of which are implicated in psoriasis and arthritis.

In a similar study published in the Journal of Nutritional Biochemistry, researchers found that when healthy adults reduced their normal consumption of a particular saturated fat for 3 weeks, their immune cells produced significantly lower levels of inflammatory mediators such as IL-1β and TNF. When the volunteers then increased their consumption of palmitic acid, TNF in the bloodstream increased.[ii]

The findings from these human studies are consistent with what has recently been discovered at a molecular level: saturated fats can activate key receptors (called TLR-4 and NLRP3) and thereby trigger the release of inflammatory cytokines.[iii] In this way, saturated fats stimulate inflammation in a range of different cell types, including various immune cells,[iv] skeletal muscle,[v] the cells lining coronary arteries,[vi] the placenta,[vii] and brain cells.[viii]

At a practical level, this research means that those with inflammatory diseases should definitely try to minimize saturated fat.

As discussed in further detail in the book, some sources of saturated fat are worse than others.  The long-chain saturated fats (found in large amounts in palm oil for example) appear to be the most problematic.  But even the medium-chain fats found in coconut oil can contribute to inflammation by facilitating the transport of bacterial fragments across the intestinal wall. These bacterial fragments (known as endotoxin or lipopolysaccharide) can then trigger a widespread inflammatory response.

In a well-designed randomized study involving 20 healthy adults and published in 2016, researchers found that fish oil decreased the level of endotoxin in the bloodstream after a meal, whereas coconut oil significantly increased it. Olive oil and grapeseed oil had little effect.[ix]

In theory, there are two possible explanations for the ability of coconut oil to increase endotoxin: it may either be compromising the intestinal barrier or participating in the transport of endotoxin across the barrier.[x] Animal and laboratory studies support the second theory, with findings that the transport of endotoxin across the intestine was 60 percent higher in the presence of coconut oil, even without any observable harm to the integrity of the gut barrier.[xi] Researchers now believe that the fatty acids in coconut oil help to form “lipid rafts” that transport endotoxin across the gut barrier.[xii]

 

Taken together, the new research on saturated fats gives us good reason not to add additional saturated fats to our diet in the form of ghee, palm oil, animal-based cooking fats, or even coconut oil.

Fats in the Mediterranean Diet

While saturated fat can make inflammation worse, the fat sources that are emphasized in the Mediterranean diet have powerful anti-inflammatory effects. This is not just theory. We know from clinical studies that the Mediterranean diet reduces the severity of psoriasis and arthritis, and the more fish and olive oil are consumed, the more effective the Mediterranean diet is.  You can read more about these studies in The Keystone Approach.

References

[i] Dumas, J. A., Bunn, J. Y., Nickerson, J., Crain, K. I., Ebenstein, D. B., Tarleton, E. K., … & Kien, C. L. (2016). Dietary saturated fat and monounsaturated fat have reversible effects on brain function and the secretion of pro-inflammatory cytokines in young women. Metabolism, 65(10), 1582-1588.

[ii] Kien, C. L., Bunn, J. Y., Fukagawa, N. K., Anathy, V., Matthews, D. E., Crain, K. I., … & Poynter, M. E. (2015). Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-sensitive genes. The Journal of nutritional biochemistry, 26(12), 1599-1606.

[iii] Rocha, D. M., Caldas, A. P., Oliveira, L. L., Bressan, J., & Hermsdorff, H. H. (2016). Saturated fatty acids trigger TLR4-mediated inflammatory response. Atherosclerosis, 244, 211-215.

Snodgrass, R. G., Huang, S., Choi, I. W., Rutledge, J. C., & Hwang, D. H. (2013). Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. The Journal of Immunology, 191(8), 4337-4347.

Robblee, M. M., Kim, C. C., Abate, J. P., Valdearcos, M., Sandlund, K. L., Shenoy, M. K., … & Koliwad, S. K. (2016). Saturated fatty acids engage an IRE1α-dependent pathway to activate the NLRP3 inflammasome in myeloid cells. Cell reports, 14(11), 2611-2623.

[iv] Reynolds, C. M., McGillicuddy, F. C., Harford, K. A., Finucane, O. M., Mills, K. H., & Roche, H. M. (2012). Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells—implications for diet‐induced insulin resistance. Molecular nutrition & food research, 56(8), 1212-1222.

[v] Kien, C. L., Bunn, J. Y., Fukagawa, N. K., Anathy, V., Matthews, D. E., Crain, K. I., … & Poynter, M. E. (2015). Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-sensitive genes. The Journal of nutritional biochemistry, 26(12), 1599-1606.

[vi] Soto-Vaca, A., Losso, J. N., McDonough, K., & Finley, J. W. (2013). Differential effect of 14 free fatty acids in the expression of inflammation markers on human arterial coronary cells. Journal of agricultural and food chemistry, 61(42), 10074-10079.

[vii] Yang, X., Haghiac, M., Glazebrook, P., Minium, J., Catalano, P. M., & Hauguel-de Mouzon, S. (2015). Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts. Human Reproduction, dev173.

[viii] Gupta, S., Knight, A. G., Gupta, S., Keller, J. N., & Bruce‐Keller, A. J. (2012). Saturated long‐chain fatty acids activate inflammatory signaling in astrocytes. Journal of neurochemistry, 120(6), 1060-1071.

[ix] Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in Health and Disease, 15(1), 186.

[x] Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in Health and Disease, 15(1), 186.

[xi] Mani, V., Hollis, J. H., & Gabler, N. K. (2013). Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia. Nutrition & metabolism, 10(1), 6.

[xii] Mani, V., Hollis, J. H., & Gabler, N. K. (2013). Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia. Nutrition & metabolism, 10(1), 6.