Today’s post highlights a research paper out of Italy published this past April. (1) The study compared fasting blood markers for the presence of zonulin, lipopolysaccharides (LPS) and the inflammatory immune protein CD14 between healthy 100-year-olds and two other groups: those under the age of 40 who had the misfortune of having suffered a heart attack and age-matched controls who hadn’t.
To refresh your memory as well as educate those who are new to this blog, zonulin is an intestinal protein that regulates tight junctions in the gut. When up-regulated, it increases gut wall permeability to antigens present in the intestinal lumen.
It is the protein that the cholera pathogen Vibrio cholerae acts upon to increase intestinal leakiness. By acutely increasing zonulin levels, this bacteria causes a flood of water into the intestinal tract that results in copious quantities of diarrhea that if left untreated may result in an untimely death from dehydration and electrolyte imbalance.
It is also the protein that is increased by the ingestion of gluten grains, but most especially in those unlucky enough to have been born with either the HLA-DQ2 or HLA-DQ8 genetic haplotypes. These are the same genes that predispose someone to developing the autoimmune disorder known as celiac disease.
Increase in zonulin levels due to gluten exposure is directly related to the amount and frequency of ingestion. It’s estimated that 50% or so of the current U.S. population are carriers of these genetic variants although no one knows for sure.
To once again quote the world’s leading authority on zonulin:
“The gastrointestinal tract has been extensively studied for its digestive and absorptive functions. A more attentive analysis of its anatomo-functional characteristics, however, clearly indicates that its functions go well beyond the handling of nutrients and electrolytes. The exquisite regional-specific anatomical arrangements of cell subtypes and the finely regulated cross-talk between epithelial, neuroendocrine, and immune cells highlights other less-studied, yet extremely important, functions of the gastrointestinal tract. Of particular interest is the regulation of antigen trafficking by the zonulin pathway and its activation by intestinal mucosa-microbiota/gluten interactions. These functions dictate the switch from tolerance to immunity and are likely integral mechanisms involved in the pathogenesis of inflammatory and neo-plastical [tumor] processes.
The classical paradigm of inflammatory pathogenesis involving specific genetic makeup and exposure to environmental triggers has been challenged recently by the addition of a third element, the loss of intestinal barrier function. Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food-derived environmental triggers [gluten] or changes in gut microbiota all seem to be key ingredients involved in the pathogenesis of inflammation, autoimmunity, and cancer. This new theory implies that once the pathological process is activated, it is not auto-perpetuating. Rather, it can be modulated or even reversed by preventing the continuous interplay between genes and the environment. Since zonulin-dependent TJ [tight junction] dysfunction allows such interactions, new therapeutic strategies aimed at reestablishing the intestinal barrier function by downregulating the zonulin pathway offer innovative and not-yet-explored approaches for the management of these debilitating chronic diseases.” (2) [emphasis mine]
In light of the very important role zonulin plays in regulating the integrity of the gut wall, it should come as no surprise that a leaky gut wall translates into increased permeability to gram-negative bacteria and their lipopolysaccharide components leading to chronic immune activation or inflammation, i.e. endotoxemia. For those unfamiliar with the concept of endotoxemia, please read this.
So with that as introduction, let’s dive into what this study found.
79 disease free Northern Italian centenarians—39 men and 40 women—were studied. All were free from major age-related diseases like cognitive impairment, cancer, coronary heart disease, kidney disease or severe physical impairment. They were, in other words, quite like my late grandmother who on her 100th birthday not only navigated flights of stairs with astonishing aplomb, but could also tell you the history of her extended family including who married and divorced whom all while helping to prepare her own birthday feast! She left this world at the age of 104 after a brief hospital stay due to a fall.
The second group studied was composed of 101 men and 77 women who had suffered an acute myocardial infarction (heart attack) before the age of 40. The third group consisted of 102 men and 76 women also under the age of 40 free from heart or arterial disease, dementia, cancer, autoimmune disorders, kidney disease, liver disorders or psychiatric illness. None of these healthy young Italians had high cholesterol, high triglyceride levels or hypertension. Neither were they obese, although 36% of them did smoke.
So what did these researchers find when markers of zonulin, lipopolysaccharides and CD14 were assessed for all three groups? Well, here are the results:
Of the three markers measured only LPS and zonulin reached statistical significance. Levels of both were significantly elevated in the young heart disease (AMI) patients. They were also both elevated in the healthy young controls in comparison to the healthy centenarians although to a lesser extent. Nevertheless, something tells me that many of those “healthy” controls will soon join the ranks of the unhealthy if they fail to plug up their guts.
That CD14 didn’t reach statistical significance attests to it not being a very reliable marker for endotoxemia. I would suspect that had either tumor necrosis factor alpha (TNF-a) or interleukin-6 (IL-6) been measured the results would have been different. This study adds further confirmation to what I’ve been writing about for years, especially in regards to the development of heart disease.
A few days ago, I highligthed another study on the Gut Critters Facebook Page that found a strong association between depression and coronary heart disease titled Depressive symptoms prospectively predict cardiovascular disease among older adults: Findings from the Maine-Syracuse Longitudinal Study. To quote from this study:
“With respect to chronic depressive symptoms, results suggest that the chronic impact of depressive symptoms over time is associated with future cardiovascular events. Chronic depressive symptoms predicted cardiovascular events during a 10-year outcome period, at 5- to 10-year follow-up. This association was the most robust of all analyses with depressive symptoms accounting for 12.7 percent of the variance associated with cardiovascular events. Importantly, all significant associations between depression and CVD [cardiovascular disease] remained so after adjusting for baseline depressive symptoms, chronic trait anxiety symptoms, age, sex, education, and MAP [mean arterial pressure], with the final model accounting for 27.3 percent of the variance. The interaction between chronic depressive symptoms and gender on CVD was explored. While the occurrence of CVD did not significantly differ by gender, it is speculated that the pattern of results may suggest that males experience a higher likelihood of CVD at lower levels of self-reported depression…
…Depression is an important cardiovascular risk factor with a large impact on public health. The present results, which found that both baseline and chronic depressive symptoms prospectively predict CVD, provide additional evidence in support of depression as a causal risk factor for CVD. Indeed, evidence exists for the mediating role of several biological and behavioral mechanisms related to depression and CVD (e.g. unhealthy lifestyle, metabolic, immune-inflammatory, autonomic, and hypothalamic-pituitary-adrenal axis dysregulation;…).”
In other words, depression can reliably predict heart disease 10 years in advance! And the reason this is so is because both are symptoms of chronic endotoxemia as I’ve outlined here and here. Note that dysregulation of the hypothalamic-pituitary-adrenal axis is one of the causal mechanisms given.
There are, however, major questions left unanswered by the centenarian study. We are given no clues as to why these heathy 100-year-olds had guts that were less permeable than their younger counterparts.
It is possible that part of what we’re seeing here is explained by genetics. I suspect that if tested, these elderly men and women would likely not test positive for either HLA-DQ2 or HLA-DQ8 haplotypes, but that’s pure conjecture on my part.
But the fact that the healthy young controls display fewer leaky gut markers than their heart disease cohorts also speaks to the importance of environmental factors. We know all too well that diet affects gut health, both by its effect on the composition of the intestinal microbiome and by its physical impact on the enterocytes and mucus layer that comprise the gut wall.
For example, I seriously doubt these centenarians are binge drinking alcohol like their younger countrymen and women and staying up to the wee hours dancing and fist pumping to the latest electro house music. Nor are they likely to be as chronically stressed given that many of life’s biggest stressors like holding a job or raising a family are far behind them.
Nor do we know anything about class status. Wealthier people tend to live longer than working class people largely due to differences in diet quality, health care, educational attainment, workplace control, level of stress and differential exposure to violence, quality of housing and environment.
And what of their wheat intake? Did they eat the same amount or less than their younger counterparts? Appetite does tend to decrease as you age so perhaps their eating less of this grain than the “youngsters” accounted for some of what was noted here, but again we have no idea.
And how much fat where these seniors eating on a daily basis? We know that the absorption of long-chain fatty acids increases endotoxemia via transcellular transport, although the type of fats ingested affects how effectively the liver neutralizes these lipopolysaccharides and how they inhibit or exacerbate liver inflammation. See here for a more in-depth exploration of this topic.
And what kind of fats are typical in their diet? Given their age, I’d suspect they are more likely to be consuming olive oil and saturated animal fat and less likely to be consuming “heart healthy” pro-inflammatory and microbiome disrupting omega 6 vegetable oils as their staple fat, but again this is pure speculation on my part.
Given their very low endotoxemia levels, I think we can safely assume that their gut flora is likely more diverse and healthier than that of their younger cohorts. But again what accounts for this?
Do they eat more fermented foods? Are they ingesting larger quantities of prebiotic fiber from their diet? Do they avoid antibiotics unless absolutely necessary? Again, we’re left in the dark as to what’s going on here.
What I can say with great confidence is that the leakier your gut is, the more illness you will suffer and the shorter your lifespan will be. This study just adds more weight to an already solidifying hypothesis.
Now whether endotoxemia manifests as metabolic syndrome (type two diabetes, cardiovascular disease, hypertension) or an autoimmune disorder (celiac disease, Hashimoto’s, lupus, psoriasis, rheumatoid arthritis, etc.) or neurological impairment (Parkinson’s, Alzheimer’s, chronic depression, gluten ataxia, etc.) or organ derangement (fatty liver, cirrhosis, kidney failure, etc.) or various lifestyle related cancers really comes down to your unique genetic makeup, the composition of your gut flora and the makeup of whatever antigens happen to be freely flooding across your permeable gut wall. Regardless, the end result will always be chronic immune activation and cortisol elevation that will manifest itself as damage to some part or parts of your body over time.
So for those of you looking to grow old gracefully, my strong advice is to keep your gut as leak free as possible. And that means maintaining a diverse and healthy gut flora and avoiding those practices and dietary habits that are known to compromise gut wall integrity.
Gut Daddy over and out, but before I go here’s some electro house music to enjoy your alcohol-fueled endotoxemia by 🙂