BMI: body mass index
FPG: fasting plasma glucose
HbA1c: glycosylated hemoglobin
hs-CRP: C-reactive protein
IL-6: interleukin 6
IL-10: interleukin 10
IFN-y: interferon gamma
SIFBO: small intestinal fungal and bacterial overgrowth
TNF-a: tumor necrosis factor alpha
Today’s post will review an interesting study out of Iran that was published in December (1). Conducted at Tabriz University of Medical Sciences, this randomized, placebo-controlled trial sought to investigate if supplementing with prebiotics would affect inflammatory and other markers in overweight women with confirmed type-2 diabetes.
Seventy diabetic women between the ages of 20 and 65 years old were screened for inclusion in this trial. All study participants had to meet the following characteristics:
- having diabetes mellitus for over six months
- maintenance of a stable diet and level of physical activity
- currently taking oral anti-diabetic medications
- having a body mass index (BMI) greater than 25 but less than 35
Anyone who met any of the following criteria was excluded from participating in the study:
- history of gastrointestinal, pancreatic, or cardiovascular disease
- diagnosed with kidney, thyroid, or liver disease
- pregnant or lactating
- anyone currently taking or ingesting prebiotics, probiotics, antibiotics, antacids, alcohol, anti-diarrhea medicine, anti-inflammatory medications, laxatives, statins, or fiber in excess of 30 grams per day
- anyone who planned on changing their oral anti-diabetic medication in the near term
Of the women evaluated, 16 were excluded leaving a total of 54 randomized into two groups of 27 each. The intervention group (those receiving the prebiotic) ingested a total of 10 grams of inulin/FOS per day. The inulin/FOS was derived from chicory.
The placebo or control group was given equal amounts of maltodextrin as a placebo, matched to the prebiotic in texture and taste. Researchers were blinded as to which group was which. The length of the trial was eight weeks.
Of the 54 participants who began the trial, 52 completed it. 27 members in the intervention group and 25 in the placebo group. Following are the characteristics of both groups at the start of the study:
Note that the inulin/FOS group started the study at a higher weight and BMI than the placebo or maltodextrin group. They also had diabetes longer on average. Metformin and glibenclamide, by the way, are anti-diabetic drugs
At the beginning and end of the trial, blood was drawn after an overnight fast for measurement of the following:
- glycosylated hemoglobin (HbA1c), a marker of blood glucose levels over
- fasting plasma glucose (FPG)
- C-reactive protein (hs-CRP), a marker of systemic inflammation
- lipopolysaccharides (LPSs), the outer membrane of gram-negative bacteria
- immune cytokines: tumor necrosis factor alpha (TNF-a), interleukin 6 (IL-6), interferon gamma (IFN-y) and interleukin 10 (IL-10)
After eight weeks, body weight, BMI, FPG and HbA1c remained unchanged in the maltodextrin group. However, in the inulin/FOS group body weight and BMI were reduced. Body weight declined to 72.9 kg and BMI fell to 30.6. Reductions were also observed in fasting plasma glucose along with significant reductions in glycosylated hemoglobin.
Let’s first look at dietary intake. This chart notes the differences in energy intake between both groups at the beginning and end of the study. Note the decrease in calories consumed in the prebiotic group, from 1,624.7 to 1,480.9. This contrasts with the maltodextrin group who actually experienced a slight increase in energy intake.
Contrary to those who claim that carbohydrates are uniquely fattening because of their effect on insulin secretion, the inulin/FOS group experienced insignificant changes while consuming this macronutrient. Total fat consumption significantly decreased in the inulin/FOS group, but as a percentage of calories there was an insignificant downward trend.
Interestingly enough, dietary fiber intake went slightly down in both groups, but this seems to have had no impact on weight loss experienced in the intervention group. Nor was protein intake statistically associated with weight loss in the inulin/FOS group.
The reason these women lost weight can be primarily explained by the decrease in caloric intake. I say primarily because I’m convinced that these women also experienced an increase in basal metabolism and energy expenditure that was unfortunately not monitored in this trial. I’ll explain my reasoning in a bit.
I need to again emphasize that no active dietary intervention occurred in this study. Both groups were instructed to continue eating their typical diet and maintain their usual level of physical activity during the length of the trial.
OK, let’s now turn our attention to blood markers. In the first line across, note the dramatic and statistically significant decrease in fasting plasma glucose observed in the prebiotic group. No such drop occurred in the placebo group.
On the second line, we see that glycosylated hemoglobin levels were significantly lower at the end of the prebiotic intervention. Contrast this to the very slight increase in the maltodextrin group.
On the third line witness how levels of C-reactive protein were also decreased in the prebiotic group. However, the placebo group also experienced a slight decrease.
The next four lines track changes in immune cytokines. Of the four only one, IL-10, is an anti-inflammatory signaling protein. There were no statistically significant changes in this cytokine in either group.
However, there were significant reductions in pro-inflammatory TNF-a, IL-6 and INF-y in the prebiotic group. Again note that in the placebo group no significant change was seen in these immune markers.
Finally, observe the decline in LPS levels (and by definition, endotoxemia) in the inulin/FOS group. No such change was seen in the maltodextrin group. This would explain the unvarying levels of inflammatory cytokines raging in the group of women unlucky enough to receive the placebo.
Before I chime in with my take on this study, let me review some of the mechanisms these researchers hypothesized might be at play here. Firstly, they point to the ability prebiotics have of reducing oxidative stress.
In truth, this property is due to the bacteria that feed off prebiotics. As I wrote in this post, gut flora have anti-oxidant properties.
It should not be surprising then that in those depleted of beneficial bacteria, oxidative stress is a constant companion. As beneficial bacteria help maintain integrity of the gut wall, increasing their numbers would cut oxidation by preventing translocating gut pathogens.
Secondly, these researchers point to the reduction in serum lipopolysaccharides in those who took prebiotics. Again, through the direct encouragement of probiotic growth (predominantly of bifidobacteria) by feeding them the food they thrive on, the chances for gram-negative bacteria to adhere to the gut wall, let alone breach it, are greatly reduced.
Third, these scientists credit the saturated short-chain fatty acids–butyrate, propionate, acetate–produced by bacterial fermentation of these fibers for some of the declines in inflammation. They note how these fatty acids are capable of tipping immune reactions away from inflammatory cascades towards anti-inflammatory pathways.
Fourthly, the researchers mention that declines in insulin levels as a result of better glucose control improves the functioning of resident immune cells in the liver known as Kupffer cells. This in turn makes the liver far more efficient at clearing LPSs from circulation, which also lessens chronic immune activation.
Finally, the authors point to weight loss as a possible reason for reduced inflammation. I find this to be their weakest argument.
I don’t mean to deny the metabolic activity of fat cells. Clearly, these cells exert hormonal effects that are felt both locally and systematically.
However, there are legions of overweight people who never go on to develop diabetes and many thin or normal-weight people who do. And while weight loss can retard or reverse the disorder in certain obese people, this still leaves open the question as to why this is not the case with normal-weight type 2 diabetics.
That said, many of the same mechanisms that drive obesity are also driving development of diabetes, namely increased intestinal permeability, LPS translocation, oxidative stress, chronic cortisol secretion, hunger, insulin-resistance, thyroid hormone dysregulation and systemic inflammation. Any intervention that treats these underlying mechanisms would be expected to affect both obesity and diabetes for the better.
I said above that I was convinced metabolic function improved in the women given prebiotics. The reason I say so harks back to my post on Endotoxemia, Stress and Metabolism.
Endotoxemia is always perceived by the body as a stressor, and for good reason. Threats to our existence do not just come from the external environment. The same hormones that are released when we are confronted with a life-or-death emergency are also released when bacteria and other substances flood across a leaky gut wall.
Lipopolysaccharides in large quantities can dispatch you to the hereafter in no time at all. They, and the intense immune reactions they provoke, are what causes a septic patient to die. I witnessed that agonizing death with my mom and know how fierce that battle rages.
As I explained in my stress post, endotoxins inhibit conversion of T4 thyroid hormone to its more active T3 form, while simultaneously increasing levels of inactive reverse T3. Endotoxins also interfere with thyroid receptor functioning in peripheral tissue.
All this translates into declines in resting metabolic rate, lowering of body heat production and euthyroid sick syndrome. This depression of metabolic rate has far-ranging effects on the body that I don’t have time to get into here. For those that are interested, I’ll refer you to Dr. Broda Barnes classic work: Hypothyroidism: The Unsuspected Illness.
Suffice it to say that depressed metabolic rate makes losing weight an uphill struggle. So in a condition where endotoxemia is slowed or stopped via strengthening of gut-wall barrier function, euthyroid sick syndrome would be expected to lessen or disappear entirely.
Tiredness is a common complaint in those with under-active metabolic function. Advice to increase physical activity to lose weight is likely to fall on deaf ears in folks who are hypothyroid. For many of these people, just getting through a typical day is all the effort they can muster.
I suspect that many of the women on prebiotics experienced improvements in alertness and energy. That would have spontaneously led many to increase their energy expenditure, and probably accounted for some of the weight loss experienced.
Chronic endotoxemia also leads to disturbances in sleep. Someone suffering from persistent bouts of insomnia brought about by elevations in cortisol secretion via chronic activation of the hypothalamic-pituitary-adrenal axis is not likely to have the energy or desire to engage in prolonged physical activity. A well-rested person is far more likely to take the stairs and not the escalator.
Now, while I’ve explained why I believe there was an increase in energy expenditure in the women given prebiotics, what could account for the dramatic reduction in food intake?
As I wrote in part two of my gastroesophageal reflux disease series, prebiotics increase production of glucagon-like peptide 1 (GLP-1). This is one of many satiety hormones produced by specialized cells located throughout the small intestinal brush border.
An increase in GLP-1, both as a direct result of short-chain fatty acids produced by bacterial fermentation, as well as reductions in inflammation, would increase satiety. Those satiety effects are brought about because this hormone slows stomach emptying. A full stomach is a powerful signal to cut food intake.
Other satiety hormones are increased with fermentation of prebiotics, like peptide YY. (2) And as I explained here, small gut dysbiosis interferes with production of all intestinal hormones that regulate food intake. Inflammation resulting from that same dysbiosis also interferes with hormonal receptors in the brain. Reduction in intestinal inflammation and dysbiosis can explain the decline in food intake even though no conscious dietary intervention was necessary for this to occur.
Another cause of disordered food intake is stress. Countless studies have shown that disordered cortisol levels affect appetite. In most, although by no means all, an elevation in stress tends to increase desire for sweet and fatty foods. (3) (4) (5) (6) In those cases where stress does not lead to an increase in hunger, anorexia nervosa is a possible outcome. (7)
And what is true for external sources of stress also holds true for stress generated by the bacterial translocation of gut pathogens to systemic circulation. By maintaining integrity of the gut wall, beneficial bacteria reduce stress emanating from within in much the same way that meditation reduces stress coming from without.
Now, don’t take this to mean that by merely adding prebiotics to your daily regimen you can eat as much as you want and still lose unwanted flab. While it will certainly help control hunger and improve energy levels, weight is ultimately determined by the balance between caloric intake versus energy expenditure.
Eat too much and move too little, and you’ll still be sporting a spare tire regardless of how many prebiotics you ingest. Nevertheless, even in situations where maintaining a caloric deficit eludes you, a reduction in endotoxemia and resulting inflammation would enhance health immensely.
One last point. I was curious to see if the women who took the prebiotics experienced any intestinal symptoms during their two-month experience. According to the researchers no such reactions were reported.
I’m very doubtful of this finding. I’ve yet to meet a type 2 diabetic who does not complain of some intestinal issue: diarrhea, constipation, flatulence and/or bloating, food allergy, fat in stool, gastroparesis, GERD, etc.
Many people who are asked about their gastrointestinal functions are usually quick to say nothing is wrong. That knee-jerk response mainly comes from the fact that their intestinal reactions are as well-known to them as an old pair of jeans or shoes. Not having experienced anything different, they come to accept whatever they experience after eating as normal, and are only prone to complain if symptoms dramatically worsen over time.
Had anyone asked me before I was labeled with having irritable bowel syndrome (IBS) if anything was wrong with my digestion, I would have replied no. Up to that point I prided myself on having a cast-iron stomach that could handle any food I threw at and in it. But looking back at it now, there were obvious signs that things were not quite right.
Nonetheless, I had experienced many of these symptoms since childhood, and knew many people who did as well. As far as I knew, that’s just the way things were meant to work down below and I didn’t really spend much time asking myself if it could be any different.
After all, the many advertisements I saw for stomach and intestinal products told me I was far from abnormal in this regard. However, as I soon came to discover, normal does not magically equate with healthy.
I think that’s what happened here when these women were asked if they experienced any effects from taking 10 grams of prebiotic fiber daily. I suspect that if they had been intensively questioned, they would have reported increases in gas production, more frequent bowel movements, perhaps increases in bloating, possible increases in acid reflux and feelings of stomach fullness.
I believe that everyone with type 2 diabetes has some form of small intestinal fungal and bacterial overgrowth (SIFBO), not to mention colonic dysbiosis. As such, it strikes me as highly unlikely that no changes in bowel symptoms were experienced by these women. Unfortunately, we’ll never know as these researchers didn’t thoroughly investigate the issue.
Nor can we take much solace from exclusion of potential participants due to pre-existing gastrointestinal disease. While the authors of this paper failed to detail what intestinal diseases they specifically screened for, I would imagine Crohn’s disease, ulcerative colitis and IBS made the list.
However, I do know that no screening for SIFBO was done in these women before this study began. But clearly, the results of this trial verify existence of ongoing gut dysbiosis that was dramatically helped by consuming prebiotic fiber and augmenting counts of beneficial bacteria.
What type of dysbiosis afflicts type 2 diabetics will have to wait for other studies where direct sampling of the gut wall throughout the digestive tract is conducted. Sadly, such invasive procedures are both costly and risky. I’m not holding my breath waiting for these types of trials to be conducted anytime soon.
Nevertheless, while we wait for gaps in our knowledge to be filled, the dramatic results of this study should make it clear to anyone who has been diagnosed with type 2 diabetes that prebiotics, not to mention probiotics, should be used to manage it.
I must say it is extremely gratifying to see how quickly medical researchers are catching on to the role gut microbes play in chronic diseases. I look forward to more randomized, placebo-controlled trials of this type in the near future.