Sunday, March 17, 2013

Artificial Sweeteners and Crohns/Ulcerative Colitis

Aspartame, Sucralose, and Saccharin



Artificial sweeteners are one of the more controversial dietary topics.  They have been vilified as having causal relationships to everything from cancer to weight gain.  They have also been bandied about in relation to inflammatory bowel disease.  The speculation ranges from blaming artificial sweeteners for IBD due to their prevalence (and IBD’s prevalence) in more developed societies, to being patented as a treatment for IBD.  No, seriously – Coca-cola patented an artificial sweetener delivered mechanism for “treating” autoimmune disorders back in 2007.(1)  What does the evidence say about artificial sweeteners and IBD?

Artificial sweeteners are sugar substitutes made chemically (as opposed to being extracted from a plant source).  For the purposes of this entry, I will not include things like corn syrup, sorbitol, Stevia, or xylitol in the discussion as they are (relatively) direct extracts of plants, nor those that are banned in the US for good reason (like lead acetate – very sweet and low calorie, but the side effect of lead poisoning really ruins the experience).  There are two primary concerns surrounding IBD that are commonly voiced related artificial sweeteners – first, that they are related or exacerbate IBD.  Second, that they cause diarrhea or other gastrointestinal upset.

There are 3 primary artificial sweeteners in the US market – Aspartame (Nutrasweet, Equal), Saccharine (Sweet’N’Low) and relative newcomer Sucralose (Splenda).  They all add “sweetness” to products without the calories of sugar, and have varying properties related to heating/storage/etc as differentiators.  Unfortunately, they have recently been “linked” to IBD by a paper in the World Journal of Gastroenterology – “Etiology of inflammatory bowel disease: A unified hypothesis” by Qin, which has been reported in many news sources. (2)

In his article, Qin hypothesizes that “it is proposed here that saccharin and sucralose might be the key causative factors for IBD”, in addition to suggesting that Ulcerative Colitis and Crohns Disease are actually two manifestations of the same disease (I won’t cover that in this entry, but I will look at the causative nature of sucralose and saccharine in IBD).

The first step in analysis is the plausibility of the mechanism of action.  Qin provides the mechanism of action that is consistent with the current complexity model of IBD – namely that it is a combination of genetics and environmental factors.  One factor cited by Qin in his hypothesis is the increased intestinal permeability in not only IBD patients but relatives and spouses, who would share a common environmental factor.  This holds for Crohn’s Disease, but recent work on UC points toward no increased permeability for spouses (supporting a genetic factor for permeability and potential predisposition.)  The recent work is still on a small scale, but the research for increased permeability in co-habitating non-relatives in UC is sketchy at best. (3) 

The second part of the mechanism cited is the increased dietary intake of saccharine and sucralose causing a reduction in gut bacteria.  There is no valid evidence that sucralose reduces gut bacteria, even in rats.  The cited study (4) was discredited for major deficiencies shortly after publication.(5)  In general, the most current review shows that early animal models didn’t translate well to human studies, with no major biological impact based on normal consumption of artificial sweeteners, including saccharine and sucralose, in humans.(6)  An even larger trial on the metabolic effects of sucralose is currently underway: http://clinicaltrials.gov/ct2/show/NCT01200940, and includes effects on stomach emptying.
Because the mechanism for action is not supported by the current research, it would tend to disprove any correlation epidemiologically having a causative relationship (at least by the mechanism described).  That said, let’s look at a few contrarian epidemiological results:

·         The incidence rate in Alberta between 1977 and 1981 was one of the highest ever for Crohn’s, recorded at 10 in 100,000, with UC at 19.6 out of 100,000.  This was after saccharine was banned but before sucralose was introduced.(7)  No commensurate change was seen in the followup study a decade and a half later.
·         Crohn’s and UC have been either increasing or stable everywhere since 1980.  Sucralose was not introduced until the early 1990s (up to the mid-2005s for Europe), and took a while to increase in usage, which saccharine usage was overtaken by Aspartame in 1986/1987.(8,9)
·         One of the key markers in the consumption of artificial sweeteners was the removal of saccharine by Coke and Pepsi in 1984/1985.  Consumption was predominantly female at the time, yet no drop was seen in incidence after this action.  Additionally, the female to male ratio for UC is less than one, inconsistent with an expected dose-response (though it is greater than one for males)(10)

The epidemiological data is not supportive of the hypothesis, and further research would not likely be a valuable course to pursue without a stronger mechanism for action or better dose-response epidemiological data.  Qin, hypothesis was interesting (and his papers though provoking), and keeping an open dialog is valuable, but the work isn’t supported by the research.  If this isn’t a basis for avoiding artificial sweeteners, what about potential GI side effects?

Artificial sweeteners have many unproven rumors that about related to their use.  Saccharine was the subject of a major controversy based on research showing increased cancer rates in rat studies in the mid-1970s (and the subject of controversies in the early part of the century largely due to industrial battles).  Later studies showed that the rat models did not translate to humans, and there were no deleterious side effects on human consumption, with the National Cancer Institute concluding “Human epidemiology studies (studies of patterns, causes, and control of diseases in groups of people) have shown no consistent evidence that saccharin is associated with bladder cancer incidence”.(11)  Because of this, saccharine and other artificial sweeteners have been the subject of many conspiracy theory mechanisms of effect, but there is no evidence of any of the three major sweeteners having a causal relationship with cancer.

The other place that artificial sweeteners get a bad rap is from the products of digestion they produce.  The general digestive impacts of the three most common artificial sweeteners would be based on their breakdown in the GI tract, which is well understood:
·         Aspartame.  Breaks down into constituent amino acids aspartate and phenylalanine, as well as methanol.  Individuals with phenylketonuria (the inability to metabolize phenylalanine) may have issues with aspartame, but there are no other concerns.  A comprehensive review in 2002 found “When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.” (12)
·         Saccharine.  Saccharine is absorbed in the intestines without being broken down into constituent components (hence the lack of associated calories).  The absorbed saccharine is excreted in urine, and does not accumulate in tissues over time.(13)
·         Sucralose.  Sucralose is made from sucrose with chlorine atoms substituted for three hydroxyl groups.  Rumor-mongering makes reference to the toxicity of chlorine, but sucralose isn’t actually broken down by the body and is released (in feces and urine) intact.(14)
The final issue with the major sweeteners is confusion with the sugar alcohols, like sorbitol and mannitol.  Most sugar alcohols are strong laxatives (mannitol was used as a medical laxative), and have numerous GI impacts ranging from diarrhea to bloating.  As little as 5g of sorbitol can cause symptoms, with most individuals showing distress after 20g of consumption (a stick of gum has approximately 1.5g).  While there are products that have both a sugar alcohol and another artificial sweetener (for example, many sugar free gum products and ice creams have sucralose and sorbitol), the GI upset has been shown to be caused by the sugar alcohol when isolated.(15,16) 

Bottom Line


·         There is no evidence that the artificial sweeteners (sucralose, aspartame, saccharine) are linked to causing IBD or exacerbating it.
·         None of the major sweeteners (sucralose, aspartame, saccharine)  have ever shown in a controlled study to have negative GI side effects (IBD-related or otherwise). 

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1.       Prakash, Indra, and Grant E. DuBois. "High-Potency Sweetener Composition for Treatment and/or Prevention of Autoimmune Disorders and Compositions Sweetened Therewith." U.S. Patent Application 11/556,118.
2.       Qin, Xiaofa. "Etiology of inflammatory bowel disease: A unified hypothesis."World Journal of Gastroenterology: WJG 18.15 (2012): 1708.
3.       Büning, Carsten, et al. "Increased small intestinal permeability in ulcerative colitis: Rather genetic than environmental and a risk factor for extensive disease?." Inflammatory Bowel Diseases (2012).
4.       Abou-Donia, Mohamed B., et al. "Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats." Journal of Toxicology and Environmental Health, Part A 71.21 (2008): 1415-1429.
5.       Brusick, David, et al. "Expert Panel report on a study of Splenda in male rats."Regulatory Toxicology and Pharmacology 55.1 (2009): 6-12.
6.       Brown, Rebecca J., and Kristina I. Rother. "Non-nutritive sweeteners and their role in the gastrointestinal tract." Journal of Clinical Endocrinology & Metabolism 97.8 (2012): 2597-2605.
7.       Pinchbeck, B. R., J. Kirdeikis, and A. B. Thomson. "Inflammatory bowel disease in northern Alberta. An epidemiologic study." Journal of clinical gastroenterology 10.5 (1988): 505.
8.       Molodecky, Natalie A., et al. "Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review."Gastroenterology (2011).
10.   Russel, Maurice GVM, and Reinhold W. Stockbrügger. "Epidemiology of inflammatory bowel disease: an update." Scandinavian journal of gastroenterology 31.5 (1996): 417-427.
11.   http://www.cancer.gov/cancertopics/factsheet/Risk/artificial-sweeteners
12.   Butchko, Harriett H., et al. "Aspartame: review of safety." Regulatory Toxicology and Pharmacology 35.2 (2002): S1-S93.
13.   Renwick, A. G. "The fate of intense sweeteners in the body." Food chemistry16.3 (1985): 281-301.
14.   Molinary, S. V., and M. E. Quinlan. "8 Sucralose." Sweeteners and Sugar Alternatives in Food Technology (2008): 130.
15.   Meihoff, Walter E., and Fred Kern Jr. "Bile salt malabsorption in regional ileitis, ileal resection, and mannitol-induced diarrhea." Journal of Clinical Investigation47.2 (1968): 261.
16.   Hyams, Jeffrey S. "Sorbitol intolerance: an unappreciated cause of functional gastrointestinal complaints." Gastroenterology 84.1 (1983): 30.

7 comments:

  1. This is Xiaofa Qin, the author of the paper that suspected the possible link between dietary chemicals like saccharin and sucralose and inflammatory bowel disease (1). Thanks for the interest and critiques. Indeed, this remains a hypothesis awaiting more vigorous test. It seems we share the same belief that the truth lies inside the facts and thus we all have a great respect for evidences. However, it is not easy to get to the right evidence and make the right judgment. Back to 270 BC, Aristarchus had found evidence suggesting the earth turning around the sun and constructed the model of heliocentric system, but this simple truth was only accepted after another two thousand of years. People may make their own explanation even on the same evidence. This is how people may have different opinions. Frankly, I also have some disagreements with your conclusions here such as:

    1. Your conclusion:“there is no valid evidence that sucralose reduces gut bacteria, even in rats”.

    My opinion: The study by Abou-Donia et al (2) clearly showed significant reduction in fecal bacteria such as total anaerobes, total aerobes, bifidobacteria, lactobacilli, Bacteroides, etc (Fig. 2 of the paper) in rats treated with splenda. Do you have more strong evidence against this?

    2. Your conclusion: The incidence rate in Alberta between 1977 and 1981 was one of the highest ever for Crohn’s, recorded at 10 in 100,000, with UC at 19.6 out of 100,000. This was after saccharine was banned but before sucralose was introduced (7). No commensurate change was seen in the followup study a decade and a half later.

    The fact: IBD incidence in Alberta increased from 3.1 (UC 1.2, CD 1.9) per 100,000 in 1966 to 17.3 (UC 6.2, CD 11.0) in 1978, then decreased to 13.3 (UC 5,3, CD 8.0) in 1981 (3) (I wonder where you got the data of 19.6 for UC during 1977-1981?). Then it increased again to 27.5 for IBD (UC 11.0, CD 16.5) during 1998-2000 (4). The temporary decrease of IBD after 1978 was in accordance with the ban of saccharin in Canada after 1977. Do you have any better explanation for this?

    3. Your statement: One of the key markers in the consumption of artificial sweeteners was the removal of saccharine by Coke and Pepsi in 1984/1985, yet no drop was seen in incidence after this action.

    The fact: According the study in Monroe County, New York, IBD cases dropped from 85 in 1978 to 64 in 1983, 20 in 1985 and 7 in 1986 (5) (I also clearly demonstrated it in Figure 2 in my paper (1)). This would be a good study as they have the yearly record back to 1920s. Do you have any evidence better than this?

    After the emergence and becoming epidemic of IBD during the last century, the extensive research on IBD have generated enormous evidences, but many being contradiction, confusing, or proved erroneous. Despite that, the clue would be still hidden among this massive mess of evidences. Even Einstein made some misjudgments. Hope our discussion may make our thoughts clearer and help us finding out the right evidence and clue that may shed light to the real cause and root mechanism of IBD. There is also some fervent discussion at the Crohnsforum (http://www.crohnsforum.com/showthread.php?t=36726) regarding the unified hypothesis on the etiology of IBD published in World Journal of Gastroenterology. If you like, we may also continue our discussion there.

    REFERENCES

    1.Qin X. Etiology of inflammatory bowel disease: A unified hypothesis. World J Gastroenterol 2012;18:1708-22.
    2.Abou-Donia MB, et al. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A 2008;71:1415-29.
    3.Pinchbeck BR, et al. Inflammatory bowel disease in northern Alberta. An epidemiologic study. J Clin Gastroenterol 1988;10:505-15.
    4.Bernstein CN, et al. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am J Gastroenterol 2006;101:1559-68.
    5.Stowe SP, et al. An epidemiologic study of inflammatory bowel disease in Rochester, New York. Hospital incidence. Gastroenterology 1990;98:104-10.

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  2. Dr. Qin,
    First off, thank you very much for your posting and for the research work you are doing on IBD. If I recall from other postings, you are at least partially self-funded, and the community appreciates anyone that dedicates their own time and money toward combating IBD.
    There isn’t much out there on the gut and sucralose. There are quite a few articles on glucose, and some old work on saccharin and recent on xylitol, but I agree sucralose still has research gaps. I am familiar with the Abou-Donia study – I’m not sure the results show a reduction due to sucralose for a few reasons:
    • There is a reduction in the overall gut bacteria in most categories in both the control group and all of the sucralose groups. I’d be interested to know if they isolated an environmental factor, of if the rats were on a different diet a few weeks prior to starting the protocol, and the pellets resulted in the drop. I would have expected the control to stay stable. As such, the drop in the control would need to be accounted for (and subtracted) from the drops in the sucralose groups, leading to a minimal if any effect.
    • There does not appear to be a dose-response effect going on as would be expected with the sucralose (positive or negative). Check out the clostridium numbers especially – the highest is the highest sucralose dosage, which would be very disturbing and might indicate a higher risk for C. Dif infection with sucralose. Instead, the lowest clostridium numbers come from the second highest sucralose dosage. This would indicate a poor test protocol or a factor outside the sucralose is present (though I’d probably do another round of testing focused just on this effect).
    • They did not isolate the maltodextrin nor the glucose. Between the two, they are present in doses 95x higher than the sucralose. It would be more plausible that they were contributing to the effects by the digestion of the additional glucose (and the broken down glucose from the maltodextrin), which were not provided to the control group. Any large dosage of glucose sugar would have a likely impact on gut flora. I would have expected the researches to provide the controls with maltodextrin/glucose combinations at the same levels in their water supplies to isolate any sucralose effects.
    That study was largely discredited by (1) below (they cover a few more issues with the study) concluding:
    The Expert Panel found that the study was deficient in several critical areas and that its results cannot be interpreted as evidence that either Splenda, or sucralose, produced adverse effects in male rats, including effects on gastrointestinal microflora, body weight, CYP450 and P-gp activity, and nutrient and drug absorption. The study conclusions are not consistent with published literature and not supported by the data presented.
    Schiffman and Abou-Donia did a follow-up paper that may have new information(2), but none of the scholarly databases I have access to have published it yet.
    I’ll followup on the second half in another post, but I appreciate the thoughtful and well referenced comments.


    1. Brusick, David, Joseph F. Borzelleca, Michael Gallo, Gary Williams, John Kille, A. Wallace Hayes, F. Xavier Pi-Sunyer, Christine Williams, and Wesley Burks. "Expert panel report on a study of Splenda in male rats." Regulatory Toxicology and Pharmacology 55, no. 1 (2009): 6-12.
    2. Schiffman, Susan S., and Mohamed B. Abou-Donia. "Sucralose revisited: Rebuttal of two papers about Splenda safety." Regulatory toxicology and pharmacology: RTP (2012).

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  3. So Informative aгtiсle about Splenda Sugar Alternative. Thanks for sharing it!!

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  4. I have been to visit son which is having headaches been battling anxiety for awhile etc. Also always has been an over gifted child from early on. I find out today for the longest time while he works and.at home he drinks no less than 6 pack of Pepsi Max everyday. Also my son not linking any of this together had to have his colon removed 4 yrs.ago from ulcerative colitis no family history of any thing like this. Not to mention anti -depressant he has had to take.to combat anxiety etc. What is this, another money racket for drug administration & Dr.. What is wrong with this country all these teenagers drink these aspartame drinks trying to stay skinny consuming more and more when in reality makes weight gain. Maybe it's why we r a obeast country. But Rather blame Mc Donalds for super sizing. Do u now how many young marriages .don't make it from issues with these symptoms and trial & error of a course medication. Wonder how many in psyc.ward issues started from drinking that aspartame in hand all day and didn't know better or maybe pregnant mom guzzling to not get fat. It all fits I remember when my son started diet drinks. My God his colon removed 30 yrs old. I'm starting to wonder about this so called not a communist country but May the ones who think a dollar is more important than letting our young people drink aspartame not being awear of what it's doing or.why they might be having anxiety attacks brain fog.My the ones who allow this answer to God for thinking making a dollar is more important than our kids. Just as well let them buy beer at lease my son would have his colon and life back to normal. Just look at our Drug & FDA system or 10 yrs GM pays out little money for all people killed with factor flaw last 10yrs. & knew is this not around aboutt a way called murder for.a dollar.After their money is made Should they get off just by pushing money for.lives.What has our Country come to. But Lord knows let's don't Make canapés medical legal in our state it might save a few anorexic people dying of not eating, or help a dying cancer patient with nausea. Or arthritis patients nerve pain.or back etc. not use that man made drug that's damaging something else while taking.Then how many people have been shot and killed do u hear from smoking a joint . But the women who r beat children and family die from alcoholic people. It should not even be legal. But it's always the dollar not God's people by no means most important I am really starting to wonder if there is a cure for cancer & alhimerzers but our Medical & Drug Field would lose to much money by it being known. I was going through deleting all old meds from over a period of time. I had 5 in container that had been pulled of market from people dying.. Darvacet how long on market after knowing people were having heart attacks. I Thank God I had enough sence to stop taking Viox before it was finally pulled it helped my pain so much but I realized causing me to hurt in chest so I chose to quit taking quite a while before pulled. I know this is irrelavent but just like all them poor trees lost by napkins at fast food places My Lord do u think the Napkins come close to a needle in haystack if u could delete our junk mail each wk. It is half of trash that goes out but I guess those trees aren't important there's a dollar might be made. I Pray to God That some how he sends some kind of sign to wake up this non communism country poisoning our kids with aspartame ruining their brains to point of having to be forced to take anxiety meds. Anti- depressant. Ever who makes these decisions let their kid and grandkids colon be taken or end up in psych ward from reaction of try to get right med to straighten out that drink they think is keeping body skinny. I'm sorry for this but I can't believe money is more important than human health. What is wrong with ones that are making these decisions May God Wake this Country we might not be communist as we know but in some aspect are we Not?

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  5. Well... my entire support group for Military Men with UC have all had horrible experiences with sucralose/Splenda. I am in remission now. If I eat a couple of packets of splenda I will be immediately on a completely crippling flare up. Same with the other 9 guys in my group. So that's 10/10 have instant complete relapse from using splenda. Oh, I've had UC for about 7 years now. Was at the point of hospitalization early on. Well, now I walk around symptom free without any crazy prescription meds. As long as I take my probiotic gummy bears, 3 table spoons of Metamucil, vape some nicotine, and STAY AWAY from sucralose/splenda then I am a 100% functioning soldier. Worst part is, irs hard to get back into remission. Yes that crappy splenda shit. Doesn't get absorbed by your body, your right, but it doesn't always get passes out through your feces.... sometimes it just accumulates in your gut and screws with the your intestinal environment.

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  6. In my opinion, a person should abstain from sugar at all cost. Even though he is fit yet, he should not consume sugar. Neither sugar nor any sugar substitute. I have heard from many health professionals that drinking a glass of Pure Noni Juice can help you get rid of diabetes and other related disorders. What do you want to say about this claim? Thanks for sharing this article. I found it very interesting.

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