Dog-doing-the-homework

Criminy. Getting fixed was more enjoyable than pooling these P values!

 

Today’s post will cover a meta-analysis (review) of randomized clinical trials that studied prebiotics and their effects on a host of different metabolic markers in humans. Published in the British Journal of Nutrition, this paper covered the results of twenty-six trials that collectively studied 831 subjects. (1)

Studies included in this meta-analysis were restricted to those undertaken between January of 2000 and September of 2013. The authors specifically excluded trials conducted before 2000 that relied solely on culture-dependent assessments of gut bacterial populations.

Only those studies dealing specifically with prebiotics were included for review. Prebiotics were defined as those soluble fibers that contain one or more of the following: inulin, oligofructose, fructo-oligosaccharide or galacto-oligosaccharide. Other trials involving plant-derived fibers like arabinoxylan and β-glucan were excluded.

Also excluded were any studies lasting less than 24 hours. Nor were any studies included that concurrently administered probiotics or synbiotics (probiotic pills or tablets that contain prebiotics) to avoid confounding. Finally, studies that were targeted at HIV+ patients or those suffering from inflammatory bowel diseases were not reviewed.

Of the twenty-six studies, thirteen included participants who were healthy. Five included overweight or obese subjects. One study used participants who were overweight and had metabolic syndrome. Two trials used only subjects who were type 2 diabetic. Two other trials included those with very high cholesterol levels, and one study used subjects diagnosed with non-alcoholic steatohepatitis (NASH), or what is more commonly known as non-alcoholic fatty liver.

Duration of all trials examined lasted anywhere from two days to twenty-eight weeks. Subjects ranged in age from 19 to 99.

OK, time to get to the heart of this meta-analysis. The first group of scientific papers reviewed, five in total, studied the effects of prebiotic supplementation on satiety or hunger.

Of the five, three showed statistically significant decreases in feelings of hunger. (2) (3) (4) The two studies that reported no change in satiety were not included in the analysis as the researchers failed to report vital data or respond to the authors of the meta-analysis when contacted. (5) (6)

This reduction in hunger was only true for subjects who consumed prebiotics daily for a minimum of two weeks. Given the level of gut dysbiosis that undoubtedly afflicts many, this doesn’t surprise me.

Keep in mind that reports of increased satiety were self-reported, meaning we have to take the word of the subjects as only one of the three studies objectively measured food intake. A further limitation of these studies was the small number of total participants (n=81).

Duration of these five trials ranged anywhere from two days to two weeks. Apparently fond of stating the obvious, the reviewers noted that such a short time period was unlikely to lead to any appreciable weight loss.

Moving on to the five studies that measured actual caloric intake in normal-weight, overweight, and type 2 diabetics, three found statistically significant reductions in intake. (2) (7) (8) But when pooled with the two studies that found no to little effect, the meta-analysis failed to confirm these findings. However, of the two studies that found no change in energy intake, one lasted a mere two days! (5)

Really? Honestly? Seriously?

Apparently, the authors of this trial thought that prebiotics might be the latest miracle cure for obesity. What’s next for this research group? A study showing that cutting calories for two days didn’t result in weight loss so why bother? But I digress.

In those studies where subjects supplemented with prebiotics for a minimum of two weeks, levels of the satiety hormone peptide YY were shown to increase. Excluding the questionable two-day study, two trials found increasing levels of another satiety hormone, glucagon-like peptide 1, although this did not reach statistical significance when pooled with the remaining two studies. All trials that measured for ghrelin, the I-gotta-eat-something-right-now-or-I’ll-chew-your-freakin’-head-off hormone, showed significant reductions.

Looking at the effect of prebiotics on weight loss, two studies found significant weight reduction. However, three trials showed no difference leading to an uncertain finding.

But even here, things were not so clear cut. Studies that were longer (lasting between twelve and seventeen weeks) were more likely to show decreases in body weight than those studies lasting four to eight weeks. Again, this shouldn’t be too surprising.

Restoration of beneficial gut flora takes time. Correcting gut dysbiosis and the dysregulating effects of cortisol on hunger and energy expenditure are not going to happen overnight.

Pathogens that have a choke hold on the intestinal ecosystem don’t meekly slink away just because you’ve decided to throw some prebiotics or probiotics down the old food chute for a few days or weeks. There are no miracle cures when it comes to resolving gut dysbiosis, and yes that also includes prescription antibiotics, antifungals and antiparasitics.

Sadly, that last statement will probably torpedo any chances I had of being asked to appear on the Dr. Oz show. Oh well, c’est la vie!

The next four studies measured the effect of prebiotics on glucose concentrations after eating (postprandial). Two of the four studies reported significant declines in blood glucose in both normal-weight and obese subjects. (3) (9) Following this analysis, statistical significance was still retained.

Of the three studies that measured postprandial insulin levels, two demonstrated significant reductions following prebiotic supplementation in participants that were overweight or had very high cholesterol levels. Combined analysis of these three trials continued to show a statistically significant reduction in postprandial insulin levels.

Two of the four studies found significant delays in gastric emptying in men. (10) (11) Recall that in part two of my GERD series, I wrote how high amounts of dietary fiber can cause delays in stomach emptying. While this is useful when trying to lose weight due to feeling full, it can be less than helpful when acid reflux is a problem.

However, in both studies wheat pasta was the food supplemented with inulin. Combining the gastric delaying effects of fiber with opioid peptide digests derived from consuming gluten grains is not such a hot idea when acid reflux is an issue. This is probably what also happens to many who eat “healthy whole wheat,” but with the added gastric-delaying effects of insoluble fiber. Moral of the story: ditch the gluten grains instead of soluble fiber if you suffer from mild to severe gastroparesis.

Studies measuring postprandial glucose and insulin concentrations showed significant declines in both with intake of prebiotics. However, those measuring fasting glucose and insulin were inconsistent. Statistically significant reductions were only seen in healthy subjects after five weeks of prebiotic intake. (10) In women with type 2 diabetes, significant reductions were seen after eight weeks. (7) That said, no reduction was seen in obese women even after three months of taking prebiotics.

This meta-analysis found insufficient evidence to recommend prebiotics for controlling either total cholesterol or LDL levels in the healthy or obese, or in those with chronically raised cholesterol. However, most trials found improvement in other metabolic markers.

Of the eleven studies that studied whether prebiotics lowered triglyceride levels, five reported significant reductions (12) (13) (10) (14) (15), but six did not. (16) (17) (9) (18) (19) (20) Again, these results are too inconclusive to arrive at any evidence-based recommendations.

Regarding non-alcoholic fatty liver, one trial showed a significant reduction in aspartate aminotransferase (AST) levels. (16) However, this study only had seven subjects and changes in AST are not exclusively dependent on liver function.

Nevertheless, this trial does find support in a larger randomized study of sixty-six subjects who were administered a synbiotic of fructo-oligosaccharide with Bifidobacterium longum for 24 weeks. (21) This resulted in the reduction of inflammatory markers, reduced levels of LDL cholesterol, lipopolysaccharides, improvements in insulin sensitivity and reduction of fatty liver as verified by biopsy.

Of the four studies that looked at prebiotics in relation to C-reactive protein (a marker of inflammation), three found a significant decline in the overweight and obese as well as women with type 2 diabetes. (7) (17) (15) Pooled analysis continued to demonstrate a reduction, but one that did not reach statistical significance. Studies looking at other markers of inflammation (inflammatory cytokines) proved contradictory so no definitive conclusions could be arrived at.

Significant increases in measures of antioxidant status were recorded in two trials that examined women with type 2 diabetes and in male cigarette smokers. (22) (23) What I hadn’t known before reading this meta-analysis was that inulin has antioxidant properties that are independent of its effects in increasing beneficial gut flora. (24)

As I wrote in this post, beneficial gut organisms have antioxidant properties. Coupled with ingestion of inulin, I suspect these effects are amplified.

Finally, two studies found significant reductions in circulating lipopolysaccharide (LPS) after prebiotic intake in healthy adults and women with type 2 diabetes. (25) (7)

Conclusion

None of these positive results surprise me in the least given the role gut dysbiosis plays in the cause of metabolic syndrome. Translocation of gut pathogens, especially gram-negative bacteria, across the gut wall will always initiate the Inflammatory-Cortisol Ballet.

Once this occurs, any hope of keeping glucose, insulin, blood lipids, inflammation, nutrient status, metabolism, hunger and cortisol levels under control flies right out the proverbial window. Evidence continues to mount that metabolic syndrome is just a different form of Cushing’s disease. Medicine continues to miss the boat in recognizing this by failing to account for cortisol generation within cells, including, but not limited to, both adipose and liver tissue.

It is true that the hypothalamic-pituitary-adrenal axis is acutely stimulated by translocating gut pathogens leading to transient cortisol spikes, especially in the postprandrial state. However, it is chronic activation of the cortisol-cortisone shunt via this system’s interaction with inflammatory cytokines that underlies development of insulin resistance and elevated circulating free fatty acids characteristic of metabolic syndrome.

To the effect that diet plays a role, and it clearly does, it does so via its actions on commensal organisms, as well as gut wall integrity. So again I reiterate that any dietary or medical interventions that fail to address the role that oral and intestinal organisms play in this dysregulation will also fail to reverse it.

 

References not linked to on the web:

(14) Tovar AR, Caamano Mdel C, Garcia-Padilla S, et al. (2012). The inclusion of a partial meal replacement with or without inulin to a calorie restricted diet contributes to reach recommended intakes of micronutrients and decrease in plasma triglycerides: a randomized clinical trial in obese Mexican women. Nutr J 11,44

 

 

 

 

 

 

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