Sunday, October 21, 2012

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

  • 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!

  • 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.