Today I want to briefly review two research papers examining the role of increased intestinal permeability (leaky gut) and visceral fat accumulation.
Visceral fat, otherwise known as central obesity, is a recognized risk factor for the development of fatty liver, type 2 diabetes and cardiovascular disease. This type of fat is packed in and between organs in the abdominal cavity.
Visceral fat differs from subcutaneous fat which is fat under the skin. Subcutaneous fat is not associated with disorders classified under metabolic syndrome.
The first paper I want to cover is a Spanish study that appeared in the literature early last year. It’s entitled Circulating Zonulin, a Marker of Intestinal Permeability, Is Increased in Association with Obesity-Associated Insulin Resistance. You can grab a free copy of it here if you like.
The aim of this study was to see if obese men expressed higher levels of zonulin, the intestinal tight junction protein, in their blood serum. As you recall from the last post, zonulin is what was likely up-regulated in our gluten-eating mice.
In the 123 men studied, zonulin levels were significantly increased in the obese men in contrast to the non-obese participants.
Increasing levels of circulating zonulin correlated with glucose intolerance, increased BMI, waist to hip ratio, fasting insulin levels, fasting triglycerides, uric acid and the inflammatory cytokine interleukin 6 (IL-6). Had these researchers measured tumor necrosis factor alpha, I have no doubt they would have also noted high levels of this inflammatory cytokine.
In subjects with normal glucose tolerance, increased zonulin was associated with elevated uric acid levels, higher hemoglobin A1c (a marker of glycated hemoglobin), increased circulating IL-6 and low HDL cholesterol.
Later in the paper, the authors point to a couple of studies showing how a high-fat diet changes gut flora and promotes endotoxemia. What they don’t mention is that these studies were conducted using rodent chow that was 60% fat and fed to strains that are known to put on weight when fed these types of diets. These are the red-line rodents that I talked about in the last post.
Nor do they mention what kinds of fats are typically used in these rodent chows. I briefly covered that topic here.
No mention is made of gluten in this paper. Sad, but not surprising.
Fat, especially saturated fat, is the dietary whipping boy of scientific research and nutritional advice. Rarely are researchers cognizant or motivated enough to look for other dietary explanations for increased permeability. Nor are many aware of what small intestinal bacterial overgrowth is, let alone how it can explain many of the findings in their studies.
Nonetheless, the growing recognition of “leaky gut” as a primary cause of glucose and lipid dysregulation and visceral fat accumulation is a welcome development. I look forward to more studies along these lines.
This Spanish study corroborates the findings of an earlier Swedish study conducted at Göthenburg University which also looked at the association between increased intestinal permeability and fat accumulation. However, this study examined visceral fat accumulation in women. (1)
What got my scientific freak flag all a flutter about this paper was that it didn’t just study obese subjects. These researchers were no doubt aware that it is quite possible to be normal- or slightly over-weight and yet have a body with elevated levels of visceral fat.
What they were interested in finding out was whether increased intestinal permeability, independent of BMI, associated with visceral fat. To do that, healthy women displaying various levels of abdominal fat were recruited.
Women were excluded from this trial if they had any of the following health conditions: type-1 diabetes, receiving insulin treatment, ongoing infection, pancreatic disease, impaired renal function, heart failure or cardiovascular disease, serious systemic disease, evidence of alcohol and substance abuse, history of bariatric surgery, post-surgical adhesions, history of or current gastrointestinal disorder or distress, receiving weight-loss drug therapy, or experiencing gastroenteritis within one month of study commencement.
Sixty-seven women were eventually selected. Height, weight and waist circumference for each participant were noted.
Both subcutaneous and visceral fat in the abdominal region were measured using computed tomography scans. Liver fat was estimated via this method as well. Total body fat was also calculated.
After an overnight fast, participants were given a sucralose and mannitol drink. As these substances can’t be digested in the small intestine, they are normally fermented in the colon by bacteria or excreted in feces. If they are found in urine, this is a pretty good indication that intestinal permeability exists.
Urine was collected throughout the nine-hour period after ingesting this drink and screened for the presence of both sucralose and mannitol. Also measured were plasma levels of glucose, insulin, HDL cholesterol, triglycerides and C-reactive protein, a marker of systemic inflammation. Blood work for all participants came back within normal ranges.
Thirteen months later, these women were again asked to undergo the same procedure. Of the original 67 participants, 55 came back for the second half of the study. This time, though, urine was collected for twelve hours after ingesting the test beverage.
Once again, plasma levels of the aforementioned blood variables were collected and found to be in normal ranges for all 55 women. Assessments of visceral, subcutaneous and total fat were once again conducted.
Participants were divided into four groups or quartiles according to their level of measured intestinal permeability. Those with no or the lowest intestinal permeability were grouped in the 1st quartile. Those with the most intestinal permeability were grouped in the 4th.
This chart graphs the results. Those with the highest intestinal permeability exhibited the highest levels of visceral fat accumulaton. Visceral fat levels in the fourth quartile were 56% higher than in subjects with the lowest permeability.
A positive association of sucralose/mannitol in urine and visceral fat was most likely to be found in the urine samples that were collected between hours 6 and 12 after the test beverage was drunk. This implies that the intestinal region experiencing increased permeability was situated in the mid to last part of the small intestine or the colon.
The researchers noted that future tests would need to be conducted to answer with any certainty where exactly these substances were crossing the gut wall.
Given the lack of evidence for ulcerative colitis in any of these women, my guess is that the women experiencing intestinal permeability did so because of “leakiness” in the small intestine. Zonulin is expressed here and not in the colon.
I need to point out that gluten, or to be precise gliadin, is not the only thing that up-regulates zonulin and intestinal permeability. Zonulin is also up-regulated by pathogenic bacteria and yeast that have colonized the small intestinal gut wall. This in turn causes compromised gut-barrier function and chronic inflammation. Once that occurs, stimulation of the HPA axis, cortisol release and elevation of inflammatory cytokines is a foregone conclusion.
If you haven’t done so already, you may want to consider downloading and reading Dr. Fasano’s excellent paper Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. It is a bit technical at points but well worth the read if you have the time. You can download a free copy here.
As the authors of this Swedish study wrote:
“When gut barrier function is impaired, the “leakage” of gut-derived antigens to the adjacent visceral adipose tissue may lead to hyperplasia [proliferation of cells], inflammation, and other metabolic dysfunctions of the fat depot. Lipopolysaccharide, a major bacterial endotoxin, has been shown to induce hyperplasia, insulin resistance, and the expression of inflammatory mediators in adipocytes. Impaired gut barrier function also increases the delivery of gut bacterial products to the liver via the portal vein which may subsequently promote hepatic lipid deposition [fatty liver]. A 4-week infusion of lipopolysaccharide has been shown to increase liver weight and triglyceride concentration in mice, an effect attributed to the endotoxemia-induced insulin resistance and inflammation.”
I couldn’t have said it better.
This study is a breath of fresh air because it recognizes that increased intestinal permeability, and early onset visceral fat accumulation, can be found in otherwise normal- or slightly overweight people. The mean BMI of the lowest visceral-fat group was 25.9 in contrast to 25.25 in the quartile with the most.
Looking at these women or measuring their weight would have gotten you nowhere in predicting who was on the road to future ill health.
If the intestinal permeability in the women in the fourth quartile is not corrected, there is a strong chance that most of these women will gain lots of stubborn-to-lose fat and develop serious medical disorders. Those women in this highest quartile who don’t put on the weight because of genetic, hormonal or other reasons will likely die sooner from the ensuing medical disorders than their weight-gaining counterparts. The obesity paradox writ large.
Diet composition affects this equation by its impact on gut flora populations and tight junction integrity. While changing diet may be enough for some, in many others it isn’t. Any underlying gut infection, whether bacteria or yeast, but likely both, will need to be treated before chronic endotoxemia ceases.
Limiting or avoiding foods that either promote small intestinal bacterial overgrowth and/or increase intestinal permeability is a necessary precondition for maintaining gut health. So too ensuring healthy gut flora populations.
Remember that beneficial bacteria prevent the colonization of the gut wall by pathogenic species. They are essential for guarding against metabolic endotoxemia.
How you maintain robust colonies of friendly gut flora is ultimately up to you. But do it you must or you will suffer the health consequences.