Artificial Sweeteners & Liver Cancer - Is There a Link? 6% Increased Risk of Hepatocellular Carcinoma per 330ml of Artificially Sweetened Soft Drink in Human Study

Are we "pouring liver cancer", when we consume soft drinks regularly? Recent data from the EPIC study appears to suggest just that - specifically if the soft drinks are artificially sweetened.

I certainly don't belong to the anti-sweetener faction on the Internet, but the results scientists from the International Agency for Research on Cancer, the University Paris Sud, the Institut Gustave Roussy and the Centre for Research in Epidemiology and Population Health (CESP) in France, the Winship Cancer Institute in Atlanta, the Hellenic Health Foundation and the University of Athens Medical School in Greece, the Harvard School of Public Health in Boston, Aarhus University and the Danish Cancer Society Research Center in Denmark and the Cancer Council Victoria and the University of Melbourne in Australia in the latest issue of the European Journal of Nutrition are serious enough to not to discard them as another unwarranted horror-story of the anti-sweetener lobby (Stepien. 2014).

You can learn more about sweeteners at the SuppVersity

Unsatiating Truth About Artif. Sweeteners?

Will Artificial Sweeteners Spike Insulin?

Sweeteners & the Gut Microbiome Each is Diff.

Sweeter Than Your Tongue Allows!

Stevia, the Healthy Sweetener?

Sweeteners In- crease Sweet- ness Threshold

The aim of the study was to assess associations between intake of combined soft drinks (sugar sweetened and artifiially sweetened) and fruit and vegetable juices and the risk of hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBC) and biliary tract cancers (GBTC) using data from the European Prospective Investigation into Cancer and Nutrition cohort of 477,206 participants from 10 European countries.

After 11.4 years of follow-up, 191 HCC, 66 IHBC and 236 GBTC cases were identified. Hazard ratios and 95 % confidence intervals (HR; 95 % CI) were estimated with Cox regression models with multivariable adjustment (baseline total energy intake, alcohol consumption and intake pattern, body mass index, physical activity level of educational attainment and self-reported diabetes status).

Don't be fooled by the size and name of the EPIC cohort! For the laypress the large cohort size will make this study appear as if the results must be God given. Personally, I am yet not impressed by scientists handing food frequency questionnaires out to almost half a million people (65%-68% correlation with what the people actually eat | Streppel. 2013), but it obviously blurs the errors. Personally, I still wouldn't take this as a complementary ticket for the exuberant consumption of artificially sweetened soft drinks.

As the researchers rightly point out, this makes the study at hand one of the few to study the possible link between soft drink consumption and cancers of the liver and biliary tract, which could - "[g]iven the rising consumption of sweetened non-alcoholic beverages and their likely link to several metabolic disorders that play a role in the development of these cancers" (Stepien. 2014) - be a major contributor to the ever-increasing number of liver carcinoma.

Figure 1: HR (95 % CI) for HCC by categories of soft drink and juice consumption compared to non-consumers in the EPIC cohort | % above the bar indicate risk increase / decrease - all trends are significant, but only the risk increase in the highest consumption group reaches individual significance (Stepien. 2014).

As you can see in Figure 1 (risk increase in % is sign. only for the high consumption), the scientist found a general link between soft drink consumption and hepatocellular carcinoma risk: +83% risk increase for those who consume soft drinks habitually (= more than 6 drinks per week) and +38% for the "juicers" (people who consume fruit and vegetable juices on a daily basis) - those are quite impressive numbers, even if there was no link to any of the other forms of cancer the scientists investigated.

A 6% risk increase does not equate a risk of 6%! I just realized on Facebook that people are still misinterpreting risk increases as absolute risks. If you have a risk increase of 6% of a crude baseline risk of 101/476968 [number of cancer patients / number of subjects] = 0.021%, a 6% risk increase will bring you up to a risk of 0.024% which means that 2.24 people out of 10,000 are at risk of developing hepatocellular cancer. This is not an exact calculation, obviously, because I don't have all the data to do it properly, but it gives you an estimate of the absolute risk, which is minimal!

In view of the previously cited way in which the consumption of these drinks contributes to the metabolic disorders that "play a role in the development of these cancers" (Stepien. 2014 | I would even say they trigger them), it is yet not half as surprising as the results of the scientists' sub-group analysis. In spite of that, the data Stepien et al. generated suggests that it's not the consumption of the "bad" + obesogenic sugary version of the drinks which shows an incremental risk increase of +6% for heaptocellular carcinoma on a per serving base, but its artificially sweetened cousins!

Figure 2: Spline regression models for the intake of soft drinks (left) and juices (right) in relation hepatocellular carcinoma risk. Reference 0 mL/ week. Knots correspond to 10th, 25th, 50th, 75th and 90th percentile of intake. The maximum corresponds to the 99th percentile. Solid lines- HR, dashed lines- 95 % CI (Stepien. 2014).

While the data from the spline regression models in Figure 2 clearly indicates that every 330ml serving of soft drinks (+21% in the crude and +22% in the fully adjusted model), and for every 200ml of juices (+3% in the crude model, but no association in the fully adjusted model) was associated with a significant increase in hepatocellular carcinoma risk in this cohort, the difference between artificially sweetened and sugar sweetened soft-drinks surfaced only in a subsequent sub-group analysis:

"In additional analyses by the type of drinks (sugar-sweet ened vs. artificially sweetened), each additional serving of artificially sweetened soft drink was positively associated with HCC risk (HR 1.06, 95 % CI 1.03–1.09, n_cases = 101), while for sugar-sweetened soft drinks, this association was null (HR 1.00, 95 % CI 0.95–1.06, n_cases = 127). The difference between both estimates was borderline significant (p_heterogeneity = 0.07)." (Stepien. 2014)

No such difference was observed for sex, BMI category, alcohol intake pattern, nor the categories of juices (i.e. apple or other fruit juices were not worse than vegetable juice).

Before you panic, you should take into consideration that as large as the total cohort may have been the number of cases of hepatocellular carcinoma in the regular and artificially sweetened soft drink drinkers was N=127 and N=101, respectively. That's not just not half as impressive as the total number of participants (N = 477,206); it also raises the question how reliable the results actually is.

This is particularly true in view of the fact that Previously reported findings from the EPIC cohort have shown that high sugar intakes are positively significantly associated with HCC risk. A result which contradicts the link non-existing link between sugar sweetened beverage (SSB) intake and hepatocelular carcinoma in the study at hand and put another question-mark behind the results of the subgroup analysis.

I wrote only recently about the results of a rodent study by Suez et al. which may trace the increased HCC risk with artificial sweetener consumption back to unwanted changes in the gut microbime | read more

They stand in line, however, with the results presented by Schlesinger et al. (2013) and Romaguera et al. (2013) who found an association between artificially sweetened soft drinks and diabetes risk in their analysis of the EPIC data from France and, in this case more importantly, the results Suez et al. published in Nature recently (Suez. 2014). In said study, about which I also wrote about on the SuppVersity (read more), the researchers found that the consumption of non-caloric artificial sweeteners affects the intestinal microbiota composition in a way that leads to the development of glucose intolerance and could eventually also be responsible for the observations Stepien et al. made when they correlated the intake of artificially sweetened beverages of the 101 HCC patients in their with the intake of the 476978 "healthy" (=HCC-free) study participants.

Overall, I would still say that more research has to be done before we can safely say that the consumption of high amounts of artificially sweetened soft drinks, let alone the consumption of artificial sweeteners, in general, will put you at a significantly increased risk of developing hepatocellular cancer. An absolute risk, by the way, of which my elaborations in the 2nd red box tell you that it is still far below 0.03% | Comment of Facebook!

References: 

• Romaguera, D., et al. "Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct." Diabetologia 56.7 (2013): 1520-1530.
• Schlesinger, S., et al. "Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort." Annals of oncology 24.9 (2013): 2449-2455.
• Stepien, et al. "Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort." Eur J Nutr (2014). Ahead of print. 
• Streppel, Martinette T., et al. "Relative validity of the food frequency questionnaire used to assess dietary intake in the Leiden Longevity Study." Nutr J 12 (2013): 75. 
• Suez, Jotham, et al. "Artificial sweeteners induce glucose intolerance by altering the gut microbiota." Nature 514.7521 (2014): 181-186.

It's in the Peel - The Protective Hull of These 61 Super Fruits Can Ward Off Cancer: Prunes, Plums, Jujube, Kiwi, Pitaya, Apple, Banana, Lemon, Cherry, Kumquat, Pomelo,...

Peru Ground Cherries could be among the most potent fruity anti-cancer agents nature has to offer.

In all the hoopla around "anti-nutrients", people tend to forget that the majority of the hailed phenols, flavenoids etc. serve the very same purpose, they protect the fruit of certain plants. For a recent study from the School of Public Health and the Chinese Academy of Sciences in Guangzhou, as well as the Peking Univerity Fang Li et al. have now compiled an extensive list of fruits, their peels, pulp and seeds and the corresponding anti-proliferative activity, you may want to use as an anti-cancer shopping guide, when you are grocery shopping... and if you do so, don't peel them: the protective peel is where nature stores most of the stuff that kills cancer cells by having them suffocate in their own reactive oxygen species!

Keep in mind, while the fruits can kill cancer in the petri dish you would be asking too much if you expect to cure existing cancer by just eating one or to servings of the top items on the list below per day. In conjunction with the nutrition & exercise tips you receive on the SuppVersity every day, they may yet contribute their share to render you "cancer proof".

Table 1: Anti lung-, breast-, liver- and colon-cancer activity of 61 fruits,  or rather their pulp, their peel and their seeds; marked in green are all values that are larger than the mean + 60% of the standard devidation (Li. 2013)

I have been thinking for quite some time about the optimal way to present the data, to pick a TOP10 or to come up with a selection and then realized that I - if I were in your position - would like to take a look at the data myself.

Instead of telling you what I thought were the most remarkable results I did thus decide to simply confront you with the complete data marking every value that is at least 60% above the mean + one standard deviation in green and ordering the data by the mean protective effect against the three different cancer types (lung, breast, liver, colon cancer) the researchers have tested for.

If you just take a cursory look at the data, the most striking observation the scientists made is unquestionably, the overall potency of the fruit polyphenols. What you have to keep in mind though is that we are talking about in-vitro studies and direct exposure to dosages of 50.09–141.79 mg/mL, as they were necessary to actually kill breast cancer cells are probably something you will never achieve no matter how many Peru ground cherries you eat. With the latter being among the most potent fruity anti-cancer "meds" we have, it is obvious that the question we will still have to answer pertains to the effects of actually eating any of these items.

It appears out of question that it's not going to hurt you. It should also be obvious that eating a packed of cherries is not going to rid you of existing cancerous growth. On the other hand, there is already plenty of evidence that

• cherries (in this case tart cherries) administered in an extract form, can reduce the risk of colon cancer in rodent models (Kang. 2003)
• polyphenol-rich cloudy apples juices can protect against gastric diseases associated with cancer formation (Graziani. 2005)

etc. The picture that's emerging though is that the in-vivo effects of the above and other fruit polypenols are more or less locally, namely in the gut, where the individual cell is directly exposed to a high amount of the active ingredients in the respective fruit. To achieve maximal benefits and actually battle cancer in other parts of our body than the gut, it may thus be necessary to isolate the molecules, compound them and inject them locally in the the cancerous tissue...

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Bottom line: While consuming high amounts of these anti-cancer fruits will have a plethora of health benefits, which will eventually protect you from cancer in all parts of your body, using them as a druglike medicine in our "war against cancer" would warrant extraction and isolation procedures that allow us to apply them in high concentrations to certain parts of our bodies.

I would bet money that all of the "superfruits" in the list above, also help to avoid prostate cancer

Suggested read & podcast: Last weeks' special issue of the SuppVersity Science Round-Up on prostate cancer is certainly something you either have remembered, when you went through the items on the list. And yes, while the scientists did not test for it, you bet that all of the "superfruits" in the list will also be good for your prostate. And just in case you missed the last installment of the Science RoundUp, I'd highly recommend you briefly go back to the corresponding seconds to read and listen to all the details | learn more about prostate cancer...

Although I doubt that isolating the nutrients and developing corresponding delivery systems entails insurmountable technical difficulties (in fact corresponding nano-technology would probably be available, already; cf. Khandelia. 2013), I am pretty sure nobody is going to do this; after all, the compounds themselves would not only be non-patentable, because naturally sourced, they would also compromise the sales of conventional cancer drugs and are thus a red rag to any of the big players in the business public health has become.

References:

• Graziani G, D'Argenio G, Tuccillo C, Loguercio C, Ritieni A, Morisco F, Del Vecchio Blanco C, Fogliano V, Romano M. Apple polyphenol extracts prevent damage to human gastric epithelial cells in vitro and to rat gastric mucosa in vivo. Gut. 2005 Feb;54(2):193-200.
• Kang SY, Seeram NP, Nair MG, Bourquin LD. Tart cherry anthocyanins inhibit tumor development in Apc(Min) mice and reduce proliferation of human colon cancer cells. Cancer Lett. 2003 May 8;194(1):13-9.
• Khandelia R, Jaiswal A, Ghosh SS, Chattopadhyay A. Gold Nanoparticle-Protein Agglomerates as Versatile Nanocarriers for Drug Delivery. Small. 2013 Feb 27. 
• Li F, Li S, Li HB, Deng GF, Ling WH, Wu S, Xu XR, Chen F. Antiproliferative activity of peels, pulps and seeds of 61 fruits. Journal of Functional Foods. 20 May 2013.

Vitamin A Regrows Liver Tissue. Polydextrose Makes Dieting a Breeze. Exercise Blunts Negative Effects of High Fructose Diet. Diabetes Precipitates Female Sexual Dysfunction.

I did miss my own 1000-posts jubilee!

This week it's pretty easy to find the SuppVersity figure of the week. It's 1011 and that's the number of individual posts this "blog" currently holds. Actually, the very moment I hit the "publish" button on this one, it's going to be 1012 (see image on the right). I guess, I should have 'celebrated' that twelve posts before, but you know how I am, it's about the quality, not the quantity and though I am aware that the latter is unquestionably fluctuating, I would hope that each of you has found one or two 'pearls' - I mean, if you didn't why are you coming back regularly, then?

Apropos regularly, it's Saturday and thus about time for a couple of "On Short Notice" items. So let's not waste any time flattering and get to the science news business:

Vitamin A essential for liver regeneration. Plus: β-carotene and cancer even in non-smokers

So much for the vitamin A vs. D antagonism - in fact, one can't go without the other: Vitamin A & D synergize against liver cancer and increase survival rates by more then 75% (read more)

(Blaner 2013) -- Other than SuppVersity readers, the average slef-proclaimed health-conscious citizen probably thinks of (false) horror stories about vitamin A laden polar bear livers killing a handful of ravenous arctic explorers. The fact that the active form of vitamin A is actually one of the most important hormone-like substances in your body that's essential for the maturation process of stem cells, on the other had, got lost at least since vitamin D the supposed vitamin A antagonist became all the rage in the past decade. Scientists from the Coumbia University in New York and the Chernivtsi National University in Chernivtsi, Ukraine, are now going to publish a paper that should remind everyone (including the science community) that the contemporary black and white painting on D & A may well impair the progress we make in our understanding of our own physiology.

Missing half your liver? Not a problem if you got enough "liver building" vitamin A ;-)

In a mouse model which has been genetically modified so that the rodents weren't able to store adequate levels of retinoids  (yeah, there is a whole family of "vitamins A") in the liver, showed a delayed and incomplete regenerative response to partial hepatectomy (cutting away parts of the liver; PHE). As the scientists point out,

"[t]he requirement for proper retinoic acid signaling to allow for normal liver regeneration is underscored by studies of hepatocyte-specific RXRα-null mice [mice lacking the retinoid receptor]. When RXRα is ablated there is reduced hepatocyte lifespan, which is accompanied by premature hepatocyte death and the appearance of necrotic areas. RXRα ablation also results in delayed hepatocyte proliferation following PHE." (Blaner 2013)

At first sight this observation goes again the often cited liver-toxicity of vitamin A. In view of nature's favorite dose-response curve, which is bell-shaped and indicates that bad things (often similar or even identical ones) happen in both deficiency and toxicity states, it's only logical, though. Plus, similar effects have been observed for wound-healing decades ago (Gerber. 1982) and Ehrlich and Hunt report in a 1968 paper in the Annals of Surgery that the administration of vitamin A blunts the negative effects on cortisol on wound healing and appears to be necessary for optimal tissue regeneration (Ehrlich. 1968).

So, another good reason to pop vitamin A supplements?

Supplementation with very high doses of isolated beta-carotene could in fact induce a state of "vitamin A resistance" in response to the formation of a metabolite that blocks the RXR receptor just like a SERM like clomiphene citrate block the estrogen receptor (read more).

For a healthy person living on a paleo-esque diet supplements should not be necessary. The amount of vitamin A and its pre-cursor beta-carotene you get from a whole-foods diet is usually adequate, even if you don't consume liver or organ meat on a regular basis. The use of what you will generally get, when you go to a healthfood store and buy a "vitamin A" supplement, i.e. a high dose beta carotene, only, product is probably counter-indicated not just for smokers, where it appears to increase the risk of lung cancer development, but also in normal healthy individuals who usually get plenty of beta-carotene from the myriad of fortified foods your local supermarket has to offer - after all, one of the most recent meta-analyses showed that 20-30mg/day increase everyone's risk of lung cancer development by 16% and that of stomach cancer by 34% (Druesne-Pecollo. 2010).

Polydextrose has non-noticeable, but significant satiety effects

(Astbury. 2013) -- I know the headline sounds confusing, but basically that's the long and short of the results, Astbury, Taylor and MacDonald present in their most recent isse in the British Journal of Nutrition. The scientists fed 12 male and 9 female healthy university students (mean age 23.2y; BMI 22.3kg/m²) who had consumed identical breakfasts at 8:00am with isocaloric (210kcal) "preload" mid-morning snacks at 10:45am and 90min before they had a pasta-based test meal, of which they were supposed to eat as much as it would take to feel comfortably full.

Figure 1: Food intake (in kcal) after mid-morning snack with different amounts of polydextrose (left); caloric intake on the subsequent meals of the day (right; Astbury. 2013)

As the data in figure 1 indicates, the consumption of the liquid preload which contained either 0, 6.3, 12 or 21g of the sweet tasting polysaccharide that reaches the colon largely undigested, where 50% of the polydextrose molecules will be fermented to yield CO2 and volatile SCFA such as propionate and butyrate and the rest will be excreted intact in the feces lead to dose-dependent reductions in the amount of food that was consumed in the subsequent meal.

50% energy availability, a source of SCFA, tasty & easy to process - perfect diet 'food'?

With only 50% energy availability and 50% being fermented to short chain fatty acids (SFCA),  the 89% dextrose, 10% sorbitol & 1% percent citric acid molecule, polydextrose could actually be a better choice for dieters than WMHDP (learn more about the SCFA based fat burning effects of resistant starches and how to make fat burning pancakes)

Interestingly, the reduced energy intake was not brought about by a consciously noticeable reduction in either fullness, hunger or desire to eat in response to the test meal (the scientists assessed that by questionnaires). And despite the fact that the effect was only transient, it's actually good and important news that the men and women did not accommodate for the 12-23% (male participants) and 6-18% (female participants) reduction in energy intake on the subsequent meal.

If that worked with every meal and you could achieve a ~20% reduction in energy intake, this alone should help you shed some weight pretty effortlessly. And as if that was not enough, already the polydextrose drinks was even more palatable than the sugary original; with the highest polydextrose content being perceived as most "creamy" - bon appetit ;-)

Even shorter news - "On real short notice", so to say  ;-)

I am well aware that what began as short news has as of late turned into a bunch of regular news - well, almost. So I decided to try and cut the last two items in today's installment short, in order to have them fit into what you would actually expect from a "on short notice" ;-)

• Exercise nullifies bad effects of high fructose diet (Moraes-Silva. 2013) -- A paper by scientists from the University of Sao Paulo puts the "lack of exercise / insuficient activity" hypothesis of obesity back on the radar. Even with an otherwise highly detrimental liquid fructose overload of 100g/l in their drinking water, the rodents in the study Moraes-Silva et al. conducted, did have normal (within statistical limits) glucose tolerance, blood pressure and heart disease risk as the rodents in the sedentary and the exercised control groups.

  

  Figure 2: Regular exercise maintains insulin sensitivity, cardiovascular disease risk and blood pressure even in the presence of pathologically high liquid fructose ingestion (Moraes-Silva. 2013)

  The regular treadmill running also blunted the autonomic dysfunction that was characterized by "an approximate 50% decrease in baroreflex sensitivity and 24% in HR variability", as well as increases in sympathovagal balance (140%) and renal sympathetic nerve activity (45%). Now you tell me "it's all about diet", only. Let alone: "Exercise just makes you hungry!"

• Diabetes and female sexual dysfunction correlate (Pontiroli. 2013) -- We already know that diabetes is a, if not the #1 risk factor for male sexual dysfunction, these days. Now a recent meta-analysis that's going to be published in one of the future issues of The Journal of Sexual Medicine found a 150% increase in sexual dysfunction in type II diabetes. Whether or not this was related to the higher depression rates in diabetic women cannot be said. What is certain, though, is that the BMI was a positive predictor of the effect size. In other words, the negative impact on sexual function increased with the degree of adiposity.
  
  Additional read for those women who feel it's their husband's performance that's to blame for their anorgasmia: "Pedalium murex Linn. fruits more effective than sildenafil in the long run and increases testosterone by 125%" (read more)
   

Now that's it for today, but I am now going out on a limb and promise another serving of short news with a focus on exercise early next week - something like the previous "Health & Exercise"- or the "Get Lean & Stay Lean" quickies and for once I can even tell you about one news that's definitely going to be in there - something about working out with and without breakfast.

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The obligatory reminder: In the mean time I'd suggest you devour the latest SuppVersity Facebook News @ www.facebook.com/SuppVersity. As usual they will receive a couple of updates way before the next official SuppVersity post is going to see the light of the day. Let's see, some of the most recent news are even remotely related to the On Short Notice items of today:

• Penis pumps - Scientists believe they are going to make a revival as a means of penile rehabilitation after surgery for prostate cancer (read more)
• Stress renders cancer immortal - What has just been observed in a rodent model of prostate cancer could have important implications for other cancers, as well (read more)
• PDE5 inhibitor for him, PDE-4 inhibitor for her? Study suggests: PDE-4 inhibitors could improve female sexual function (read more)
• Goose liver for the liver - When it's high in selenium goose liver could protect your liver from the assault of excessive alcohol consumption (read more)

As promised, there will be more. So in case you have not done so already,  you best like the SuppVersity right now so that the latest news will always appear in your news-feed.... ah, and about all that geeky science reading, don't forget that there is more to life than dieting and working out ;-)

References:

• Astbury NM, Taylor MA, Macdonald IA. Polydextrose results in a dose-dependent reduction in ad libitum energy intake at a subsequent test meal. Br J Nutr. 2013 Jan 23:1-9.
• Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S. Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials. Int J Cancer. 2010 Jul 1;127(1):172-84.
• Ehrlich HP, Hunt TK. Effects of cortisone and vitamin A on wound healing. Ann Surg. 1968 Mar;167(3):324-8.
• Gerber LE, Erdman JW Jr. Effect of dietary retinyl acetate, beta-carotene and retinoic acid on wound healing in rats. J Nutr. 1982 Aug;112(8):1555-64.
• Moraes-Silva IC, Mostarda CT, Moreira ED, Silva KA, Dos Santos F, De Angelis K, Farah VD, Irigoyen MC. Preventive role of exercise training in autonomic, hemodynamic and metabolic parameters in rats under high risk of metabolic syndrome development. J Appl Physiol. 2013 Jan 17.
• Pontiroli AE, Cortelazzi D, and Morabito A. Female Sexual Dysfunction and Diabetes: A Systematic Review and Meta-Analysis. J Sex Med. 2013 [e-pub ahead of print]

Vitamin A Educates T-Cells, Joins Forces With Vitamin D Against Liver Cancer. Milk Better Than Sugary Electrolyte Solutions for Rehydration? Helicobactor Pylori: Probiotics from Breast Milk & Feces Better Than Amoxicillin!

Lactobacilli are hip, vitamin A is not - at the SuppVersity you still get news on both

1kg! That's the amount of weight you could probably lose if you rid yourself of all the microbes in your gut - from the weight of the bacteria alone, of course. Whether this would be a good idea or not, is however very questionable. On the one hand, we do have the still not fully understood studies on obesity-resistant germ free mice and an accumulating amount of evidence that having the "wrong" bacteria in the gut is at least associated with an increased obesity risk (Blaut. 2012). On the other hand, however, we are seeing new studies on the various benefits of having the "right" gut microbiome being published on an almost daily basis. So what?

Before we take a closer look at a definite benefit of having the "right" gut bacteria, though, let's start out with another likewise gut-related news item on the role of retinoic acid in T-cell education. In a way it's funny, it starts right where the bacteria reside, could have immune-modulatory effects that are way more pronounced and far reaching than probiotics and is still hardly discussed.

Vitamin A is of critical importance to (intestinal) T-cell education

If you have ever asked yourself how the immune cells in your body know what they are supposed to do, Catharine Ross' latest paper that was published in the American Journal of Clinical Nutrition and is based on a short talk the researcher from the Department of Nutritional Sciences at the Pennsylvania State University held at a conference earlier this year may provide at least some additional insides into the role a still way underrated molecule plays in this "T cell education" (Ross. 2012): Vitamin A!

Figure 1: Model of T cell differentiation, from uncommitted naive T cells into different T cell subsets that produce different cytokines and thus promote different functional activities (adapted from Ross. 2012)

As you can see in figure 1, retinoic acid does not simply promote the differentiation of regulatory T cells, which help to suppress inflammatory reactions, it also plays a significant role in normal mucosal immunity (in the gut, the airways and elsewhere) by modulating T cell activation and regulating cell trafficking. Moreover, vitamin A promotes antibody responses to T cell–dependent antigens. Needless to say that

"[...] in a state of vitamin A deficiency, inflammatory T cell reactions may be inadequately opposed and therefore become dominant [...] Although data from human studies are still needed, the framework now developed from studies in mice and rat models suggests that adequate vitamin A status, [...] is  important for maintaining a proper balance of well-regulated T cell functions and for preventing excessive or prolonged inflammatory reactions." (Ross. 2012).

Discovery a beta carotene derived vitamin A receptor blocker is only one of a couple of intriguing findings wrt to vitamin A.

One thing that sticks out from the complex interactions (see figure 1), really is the way by which the interaction of vitamin A with the T-cells in the gut crucially determine the efficiency of the 'fist line defenses' and their downstream effects on the whole organism. It is by no means co-incidental that diarrhea is rampant in areas of the "third world", where a large amount of the population is vitamin A deficient (Beaton. 1994). And in fact studies have shown consitently that

"RA is essential for 'imprinting' gut-homing specificity on T cells activated by intestinal DCs [dendritic cells] and suggested that MLN DCs are a source of RA that drives T cell differentiation toward the gut-homing phenotype" (Ross. 2012)

Moreover, oral tolerance to foreign antigens and thus an allergy free live requires a form of immune suppression, which can be proffered or hampered by sufficient and insufficient vitamin A intakes. In that, the exact effects of vitamin A will depend on the cytokine milieu the T-cells are exposed to. Examples are...

• an exaggerated IL-17 response with vitamin A deficiency, on the one hand, and
  
• an increase of the inflammatory response due to high vitamin A in an IL-15 environment 

Based on these observations, Ross rightly points out that "when RA is used for therapeutic purposes, it should be used cautiously in subjects with various inflammatory bowel conditions and sensitivities to dietary antigens." (Ross. 2012) People with gluten intolerance, celiac and other allergic reactions, for example would probably be better off avoiding the consumption of any form of supplemental vitamin A (on top of what's in their regular diet). Someone with high IL-17 and IL-6 levels as they have been observed in non-celiac inflammatory bowel disease, type 1 diabetes, multiple sclerosis and rheumatoid arthritis, on the other hand, could actually benefit from vitamin A's (especially ATRA) presence during activation of CD4⁺ T cells, because it will - even in the presence of IL-6 - "favor the development of the a Treg lineage at the expense of T cells secreting IL-17" and could thus help reduce chronic inflammation and keep autoimmune reactions at bay (Schambach. 2007; also Ramgolam. 2010).

More news

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  Figure 2: Who cares about cell viability, the survival time (in days) matters

  Combination therapy with vitamin A and a vitamin D (not D3, but calcitriol) analog EB1089 kills liver cancer cells. And it does so more effectively than any of the two molecules alone. That's the actually unsurprising result of a study that has been conducted at the Beijing Army General Hospital in China. The researchers injected nude mice with molecules that made them develop hepatocellular cancer. Afterwards, the rodents received either 10 μmol/L retinoic acid (vitamin A), 10 nmol/L EB1089 or both as a combination treatment.
  
  Compared to vitamin A or the calcitriol analog alone, the combination treatmend resulted in a significanlty higher reduction of the viability of hepatocellular cancer cells. Based on TUNEL analysis, Zhang et al. did also establish that individual cancer cells had a higher apoptotic ratio in the combined drug group than in the groups for which the drugs were used separately. Most importantly, however, the tumor weight was decreased and the mice on the combination treatment lived significantly longer (see figure 2; Zhang. 2012)

• 

  In the same publication, Pritchett and Pritchett recommend 1.0-1.5ml / kg body weight per hour of chocolate milk as the optimal post-workout drink to be consumed in the 2 h after a workout.

  Skimmed milk, the ideal post-workout rehydration formula? According to L James' paper in Lamprecht's compendium Acute Topics in Sport Nutrition, milk is a way better choice then the standard sugar + electrolyte rehydration formulas. Interestingly this is not due to the minerals in the milk, or the sugar, but, as James argues, a direct consequence of the milk proteins, which help restore "fluid balance after exercise-induced dehydration to a greater extent than a carbohydrate-electrolyte sports drink." As James points out it will yet have to be elucidated, whether the simple addition of whey protein to a standard sugar + electrolyte formula would exert similar effects (James. 2013).
• Probiotics to kill Helicobacter Pylori? While not every bacteria stands a chance against the nasty gut bug H. Pylori, certain Lactobacillus spp. strains obviously do. At least, if the results of a recent in-vitro + in vivo rodent study by Pei-Shan Hsieh can be replicated in human studies.

  

  Figure 3: Urease activity in H. pylpori after co-incubation with the specific probiotic and resulting bacteriostatic ratio (100% = bacteria free; data adapted from Hsieh. 2012)

  Lactobacillus acidophilus TYCA08, L. acidophilus TYCA15, L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32 were the most effective strains the researchers from National Chung Hsing University in Taichung, Taiwan, analyzed. And believe it or not, the latter of these, i.e. L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32, both of which are  by the way found in feces, were even minimally more potent effective than Amoxicillin, a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections. L. acidophilus TYCA15, however, steals the show. This probiotic that occurs naturally in breast milk reduced the urease activity of H. Pylori by -97.1% (see figure 3).
  
  In the consecutive rodent study, Hseieh et al. did yet still use 10⁹ CFU/mL of either AP-32 alone, MH-68 alone, or an equal mix of cultures of the two strains and both, "either alone or as a mixture in powder form were effective in reducing H. pylori load in gastric mucosa and help in reducing gastric inflammation and in regulation of gastric acid production." (Hsieh. 2012)

Thats it for today and for this weekend. As mentioned yesterday, there was simply not enough time to do the necessary research for the follow up to the Athlete Triad Series, so that this will have to wait. So don't dig an even deeper whole in the mean time. Maybe you want to do some of the psychomotor tests mentioned in yesterday's news, and check whether you are already overtrained!? How steady are your hands, for example? And whatever the result may be, don't forget to enjoy the rest of the weekend!

References:

• Beaton GH, Martorell R, Aronson KA, Edmonston B. McCabe, G, Ross, AC, Harvey, B. Vitamin A supplementation and child morbidity and mortality in developing countries. Food Nutr Bull 1994;15(4): 282–9.
• Blaut M, Klaus S. Intestinal microbiota and obesity. Handb Exp Pharmacol. 2012;(209):251-73.
• Hsieh PS, Tsai YC, Chen YC, Teh SF, Ou CM, King VA. Eradication of Helicobacter pylori Infection by the Probiotic Strains Lactobacillus johnsonii MH-68 and L. salivarius ssp. salicinius AP-32. Helicobacter. 2012 Dec;17(6):466-77.
• James L. Milk Protein and the Restoration of Fluid Balance after Exercise. In Lamprecht M (ed): Acute Topics in Sport Nutrition. Med Sport Sci. Basel, Karger, 2013, vol 59, pp 120–126. 
• Pritchett K, Pritchett R. Chocolate Milk: A Post-Exercise Recovery Beverage for Endurance Sports. In Lamprecht M (ed): Acute Topics in Sport Nutrition. Med Sport Sci. Basel, Karger, 2013, vol 59, pp 127–134.
• Ramgolam VS, Markovic-Plese S. Interferon-beta inhibits Th17 cell differentiation in patients with multiple sclerosis. Endocr Metab Immune Disord Drug Targets. 2010 Jun;10(2):161-7.
• Ross AC. Vitamin A and retinoic acid in T cell-related immunity. Am J Clin Nutr. 2012 Oct 10.  
• Schambach F, Schupp M, Lazar MA, Reiner SL. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol. 2007 Sep;37(9):2396-9. 
• Zhang J, Zhang H, Zhang X, Yu Z. Synergistic effect of retinoic acid and vitamin D analog EB1089-induced apoptosis of hepatocellular cancer cells. Cytotechnology. 2012 Oct 16.