Shedding Some Light on the Leaky Gut <> Exercise Connection. Plus: 20+ Things You Should or Shouldn't Do to Protect and Restore the Integrity of Your Intestinal Wall

Have you ever felt nauseated after a workout? Or does your protein supplement gives you diarrhea only if you take it right after a workout? Both can be related to the toll  exercise can take on the integrity of your intestinal tract.

To be honest, I was quite surprised that I did not get a hell lot of hatemail in response to the the 'MSG heals the gut study' I posted last Sunday... Be that as it may, I feel sort of awkward to have opened Pandora's box without proving you with some betters tools than mono-sodium glutamate (MSG) to seal the box, or rather your leaky gut, again. Therefore I decided to post this mini-feature on a particular issue all of us will be dealing with: An exercise induced increase in gut permeability. As you are going to see, there are a lot of similarities to the 'classic' leaky gut, which is often implicated in the etiology of chronic inflammatory bowel diseases. In order to understand these similarities, but also the few, yet important differences, we will have to lay some theoretical groundwork.

"What exactly is a leaky gut?"

The easiest way to answer this question would be to say: "That's what everybody and his mama is talking about these days". This definition as concise (and precise) as it may be, is yet about as productive as the talk that's at its heart. So, instead of relying on hearsay, let's rather briefly recap how intestinal wall actually works.

Since the intestines are meant to let nutrients and fluid pass, a certain degree of leakiness is absolutely natural. Problems arise only, when the self-regulatory system is broken and/or the permeability exceeds a normal / healthy threshold (img. by Mariana Ruiz).

The mucosal layer of the intestinal tract is made up of epithelial cells, so-called enterocytes which are connected to one another by specialized proteins. These proteins form the tight junctions (TJ) - a term, you will probably have encountered numerous times before. The main constituents of this kit in between the enterocytes are proteins such as occludin, zona-occludens and claudins. Together, the array of enterocytes and the tight junction form the the intestinal barrier, which allows the absorption of nutrients and water, while preventing the translocation of harmful substances from the gut into the bloodstream.

The integrity of this barrier is influenced by the phosphorylation state of the proteins within the tight junctions.The exact interactions are compilcated and can be looked up elsewhere (Banan. 2005). What's important for you to realize is that during prolonged exercise which is necessarily accompanied by an increase in core temperature, cardiovascular and thermoregulatory responses compromise intestinal blood flow.

With the core temperature usually being lower than the temperature in your intestines, the temperature of your gut can easily approach 41°C during a workout.That's more than your epithelial cells can handle and can lead to structural damage of the 'patches' in the tight junctions + epithelial cell layer (Lambert. 1985).

HIIT veterans or weight lifters are not off the hook

Now, the last paragraph may have sounded as if only long endurance workouts like 10k-runs or marathons could entail damage to the intestinal cells. That's however not the case, since the redirection of the blood away from the splanchnic arteries and to the working muscle that's even more pronounced in high(er) intensity exercise, will initiate an ischaemia reperfusion cycle which can entail oxidative damage not during, but interestingly after the the workout, when the blood rushes back into the intestines (Wijck. 2011).

Take home message: There are two distinct pathways that contribute to the leaky gut during and after a workout (a) heat and (b) ischaemic/reperfusion stress. Both influcne the phosphorylation state of the proteins in the tight junctions and will thus increase the permeability of the gut lining.

It stands to reason that the combination of high intensity and long durations, as you will find it in an ultra-marathon runner, for example, is particularly detrimental to the integrity of the intestinal wall, so that it is not exactly surprising that (ultra-)endurance athletes have the highest prevalence (60-90%) of gastrointestinal distress that which manifests in the form of diarrhoea, nausea, stomach problems, bloating and intestinal cramps (Worobetz.1985; Peters.1999; Jeukendrup.2000)

There is more than one thing you can to to protect, heal and restore your gut integrity

The fact that a "leaky gut" is like an open door not just for exogenous toxins or live bacteria, but also for their 'endotoxic poop' is probably no news for you. In fact, it is also the reason why you want to either prevent the pathological increases in gut permeability, in the first place, and/or (re-)seal the gut as soon as possible after your workouts. In this regards, there are three fundamental and easily implementable strategies that should always be employed before you even think about using specific supplements:

• 

  Figure 1: HSP 70 offers protection against endotoxins (LPS) in vivo (top) and in vitro (bottom; Dokladny. 2010)

  Despite the possible ischaemic / reperfusion stress short high intensity exercise bouts like sprinting are generally less taxing on the integrity of the tight junctions than longer duration medium intensity aerobic workouts. Avoiding these particularly gut-stressing workouts and/or taking special precautions before and after marathons and other endurance events would thus be strategy #1 to keep the epithelial cell layer intact and pathogens and toxins from entering the circulation.
• The natural intracellular expression of heat shock proteins (HSPs) can protect the tight gut junctions during and/or help their restoration after a workout. Just like all our endogenous protection systems the production of HSPs can be trained. Giving your body the time it needs to accommodate by making small, but consistent steps towards longer and/or more intense workouts would therefore be strategy #2.
• That leaves us with strategy #3, of which I hope all of you will be using anyway - even if you have not been aware of its gut protective effect, yet: The provision of adequate fluid supply before, during and after a workout (Lambert. 2008).

As the workout durations become longer and longer and/or the respective intensities higher and higher, solely relying on your bodies self-healing capacity and adequate hydration may seize to work, though. Despite the fact that our bodies accommodate to the ever increasing demand for intracellular protection against heat stress by upregulating the HSP expression (athletes have higher HSP expression to a standardized endurance training protocol than normal individiuals; cf. Fehrenbach. 2000), there is - just as with about every adaptive response - a certain threshold, when hormesis, i.e. the beneficial adaptation to a manageable amount of stress, is no longer an option.

From "A" as in arginine to "Z" as in zinc - a list of things to keep the gut lining intact

While there has been quite a lot of research as of late into which dietary supplements and even regular foodstuff would be able to modulate the heat shock proteins in order to prefer the desired downstream benefits on gut integrity, the number of compounds of which it is reasonable to assume that they can actually make a difference is still very small:

• Colostrum supplementation to cell cultures has been shown to increase the expression of HSP-70 in human epithelial cells; studies with human subjects are rare and ambiguous:  While Marchbank et al., have been able to show that bovine colostrum truncates the increase in gut permeability caused by heavy exercise in athletes (Marchbank. 2011), Buckley et al. actually observed detrimental effects of 8 weeks of bovine colostrum supplementation on the exercise induced gut permeability in runners (Buckley. 2009).The explanation for these discrepencies is not clear, but may be related to the longer duration / different intensity of the exercise protocols, or differences in the immunoglobolin, peptide or amino acid composition of the supplements.
• Zinc in general and specifically polaprezinc, a zinc based anti-ulcer drug, which has primarily been used in Japan as a means to seal leaky Japanese guts, show some promises, as in the treatment and prevention of increased intestinal permeabilty (Zhang. 2009). It is thought that zinc is critical for tight junction assembly and has been shown to be critical in the protection of the gut lining from the chronic toxic assault of alcohol (Zhong. 2010). That being said, you should keep in mind that alcohol will deplete your bodies zinc stores, so that it cannot be said, if someone with an adequate zinc intake would benefit to the same degree as a zinc deficient alcoholic. Moreover, as "natural" as they may be, even essential minerals like zinc don't come without potential side effects (cf. "After 120 Days Rodents on Diets Containing 2xRDA of Zinc Develop Metabolic Syndrome", read more).
• Glutamine has been used as treatment for patients suffering from irritable bowel syndrome and Crohn’s disease and has been shown to actively increase the expression of HSP70 in critically ill patients (Jonas. 1999; Ziegler. 2005).  
• Berberine could be an ideal addition to glutamine (thx to Maxim Okhrimenko for pointing that out in the comments); berberine does not only modulate the TNF-alpha response in the intestines and increases AKT, but has also been shown to maintain / rescue intestinal glutamine transport and glutaminase activity (Gu. 2009; Amasheh. 2010; Li. 2010; Niu. 2011)
• Probiotics are still an 'under-researched' newcomer and though there is some preliminary evidence pointing to the efficacy of probiotic therapy as a means of improving gut function and enhancing the integrity of the intestinal tight junctions, the ideal supplement regimen, as well as its long-term effects will still have to be elucidated in human studies. Studies by Ewaschuk et al. have yet already shown that the impact factors released from Bifidobacteria infantis can offer a certain degree of protection against experimentally induced colitis in rodents (Ewaschuk. 2008). As far as exercise specific studies are concerned, a recently published paper by Lamprecht et al. is probably the first peer reviewed human study to report allegedly "borderline significant" beneficial effects on gut permeability (measured only indirectly by quantifiying the zonolin conent of the feces) and TNFalpha expression in response to a multi-species probiotics (1010 CFU/day, Ecologic®Performance orOMNi-BiOTiC®POWER) in 23 trained men (Lamprecht. 2012; the study was partially funded with a grant from Winclov, the manufacturer of the respective supplements).
• Butyrate, yet not all short chain fatty acids, have recently been found to decrease gut permeability (Ferreira. 2012). Both data from human studies, as well as exercise specific data is yet still absent.
• Hydroxypropyl methylcellulose (HPMC), which is a non-fermentable fiber, has been shown to protect rodent guts from a high fat diet induced increase in gut permeability (Kim. 2012), as in the case of butyrate its efficacy (and when you think about athletes, tolerability) will yet still have to be confirmed in human trials.
• L-Arginine (and AAKG) as a source of nitric oxide, which is necessary to protect the gut barrier from invaders could have a protective effect, as well (Quirino. 2012); and though this effect is not exercise specific, we know that arginine requirements increase in states of chronic stress, it would therefore be logical that supplementation with l-arginine, or even better AAKG, which comes with a precursor to glutamine will have beneficial effects on the tightness of the guts of intensely training athletes, as well (suggested read: BCAAs, glutamine and ammonia detox) .
• Oats, maybe due to their beta glucan content and their ability to increase the production of short-chain fatty acids in the large intestine, oats offer protection against alcohol induced increases in tight junction permeability (Tang. 2009); exercise specific studies have yet to be conducted, though.Personally I would yet not be surprised if this would turn out to be very effective (note: as long as they are not cross-contaminated, oats are 100% gluten-free)
• Goats milk (powder) has been shown to be equally effective as colostrum in reducing heat and thus most likely exercise induced gut permeability (Prosser. 2004)
• Lactoferrin, a multifunctional protein of the transferrin family that is present in milk may have protective effects against LPS-mediated intestinal mucosal damage and impairments of the barrier function in intestinal epithelial cells (Hirotani. 2008)
• Vitamin A in adequate amounts is necessary to maintain gut integrity; it is likely that this is all the more true if gut integrity and immune function are additionally challenged by strenuous exercise (Quadro. 2000)

I guess, I could find even more supplements (and foods) that may help you protect or restore your gut lining, but let's be honest: As important and beneficial eating and supplementing the right things may be, all your efforts would be foiled if you eat foods and supplements that will have the opposite effect on your gut lining. So here is the complementary and likewise non-exhaustive list of stuff you'd better avoid (at least in high doses) if you want to keep your tight junctions intact and your gut from becoming leaky:

Figure 2: Gliadin peptides induce the release of zonulin which in turn interacts with the tight junctions and increases the diffusion of small molecules (∼350 Da) across the cell membrane. Whether the tight junctions open up wide enough to allow for free diffusion of whole gliadin peptides, whose molecular weight is at least 2000 Da, remains to be determined, though (Heyman. 2011)

• Alcohol will wreak havoc on the permeability of your intestines; probably in consequence of its depleting effect on ileal zinc concentration (Zhong. 2010).
• Gliadin (in wheat/gluten) does actively promote the release of zonolin and the widening of the tight junctions (see figure 2); whether you will notice that or not, depends on the occurrence and extent of an immune response as it is characteristic for Celiac patients. I guess, it's actually not necessary to say that all sorts of other allergens, respectively the ensuing inflammatory response to being exposed to them will have detrimental effects on the integrity of your gut, as well, right?
• ALA, EPA and DHA the dietary omega-3 fatty which may help sooth tight junction permeability in states of chronic inflammation will actually increase it, when the baseline inflammation is already low or they are consumed in excess (Usami. 2001; Roig-Pérez. 2010)
• Copper and iron increase tight junction permeability of caco-2 cells via distinct mechanisms (Ferruzza. 2002)
• Capsaicin, piperine and other hot spices do not only cause a burning sensation in your mouth, it literally burns your intestinal cell lining, as well (Johri. 1992; Tsakura.2007)
• Quercitin by blocking the increase in HSP-70 will increase the suceptibility of your gut to exercise induced increases in permeablity (Kuennen. 2011)
• NSAIDs like aspirin and ibuprofen increase the permeability of the gut ad amplify the potentially detrimental effects of exercise (Lambert. 2007)

Obviously, only few of the last mentioned offenders are exercise specific, but if you start working out with already compromised gut integrity, you can hardly complain if a couple of grams of glutamine, or whatever else you may have picked from the previous list, don't effectively protect your intestinal wall from damage. What's even more important though is that you understand the Janus-faced nature of anti-oxidants and anti-inflammatory compounds. As beneficial as they may be in situations of chronic or acute pathologic inflammation, NSAIDs, quercitin and even your beloved omega-3 can eventually extinguish the 'controlled fire' your body needs to keep all immune and metabolic functions simmering along nicely (suggest reads: "Are you stressed enough for a longer life?" and "Inflammation is a True Fat Burner").

References:

• Amasheh M, Fromm A, Krug SM, Amasheh S, Andres S, Zeitz M, Fromm M, Schulzke JD. TNFalpha-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFkappaB signaling. J Cell Sci. 2010 Dec 1;123(Pt 23):4145-55.
• Banan A,Zhang LJ, Shaikh M,et al. theta Isoform of protein kinase C alters barrier function in intestinal epithelium through modulation of distinct claudin isotypes: a novel mechanism for regulation of permeability. J Pharmacol Exp Ther. 2005; 313:962–82.
• Buckley JD, Butler RN, Southcott E, Brinkworth GD. Bovine colostrum supplementation during running training increases intestinal permeability. Nutrients. 2009 Feb;1(2):224-34.
• Dokladny K, Lobb R, Wharton W, Ma TY, Moseley PL. LPS-induced cytokine levels are repressed by elevated expression of HSP70 in rats: possible role of NF-kappaB. Cell Stress Chaperones. 2010 Mar;15(2):153-63. Epub 2009 Jun 24. 
• Ewaschuk JB, Diaz H, Meddings L, Diederichs B, Dmytrash A, Backer J, Looijer-van Langen M, Madsen KL. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol. 2008 Nov;295(5):G1025-34. 
• Ferruzza S, Scacchi M, Scarino ML, Sambuy Y. Iron and copper alter tight junction permeability in human intestinal Caco-2 cells by distinct mechanisms. Toxicol In Vitro. 2002 Aug;16(4):399-404. 
• Gu L, Li N, Li Q, Zhang Q, Wang C, Zhu W, Li J. The effect of berberine in vitro on tight junctions in human Caco-2 intestinal epithelial cells. Fitoterapia. 2009 Jun;80(4):241-8.
• Heyman M, Abed J, Lebreton C, Cerf-Bensussan N. Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut. 2012 Sep;61(9):1355-64.
• Hirotani Y, Ikeda K, Kato R, Myotoku M, Umeda T, Ijiri Y, Tanaka K. Protective effects of lactoferrin against intestinal mucosal damage induced by lipopolysaccharide in human intestinal Caco-2 cells. Yakugaku Zasshi. 2008 Sep;128(9):1363-8.
• Jeukendrup AE,Vet-Joop K, Sturk A,et al. Relationship between gastrointestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men.Clin Sci (Lond). 2000;98:47–55. 
• Jonas CR, Ziegler TR. Potential role of glutamine administration in inflammatory bowel disease. Nestle Nutr Workshop Ser Clin Perform Programme. 1999;2:217-30.
• Johri RK, Thusu N, Khajuria A, Zutshi U. Piperine-mediated changes in the permeability of rat intestinal epithelial cells. The status of gamma-glutamyl transpeptidase activity, uptake of amino acids and lipid peroxidation. Biochem Pharmacol. 1992 Apr 1;43(7):1401-7.
• Kim H, Bartley GE, Young SA, Davis PA, Yokoyama W. HPMC supplementation reduces abdominal fat content, intestinal permeability, inflammation, and insulin resistance in diet-induced obese mice. Mol Nutr Food Res. 2012 Sep;56(9):1464-76. 
• Kuennen M, Gillum T, Dokladny K, Bedrick E, Schneider S, Moseley P. Thermotolerance and heat acclimation may share a common mechanism in humans. Am J Physiol Regul Integr Comp Physiol. 2011 Aug;301(2):R524-33.
• Lambert GP, Gisolfi CV, Berg DJ, Moseley PL, Oberley LW, Kregel KC. Selected contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress. J Appl Physiol. 2002 Apr;92(4):1750-61; discussion 1749. PubMed PMID: 11896046.
• Lambert GP, Boylan M, Laventure JP, Bull A, Lanspa S. Effect of aspirin and ibuprofen on GI permeability during exercise. Int J Sports Med. 2007 Sep;28(9):722-6.
• Lambert GP, Lang J, Bull A, Pfeifer PC, Eckerson J, Moore G, Lanspa S, O'Brien J. Fluid restriction during running increases GI permeability. Int J Sports Med. 2008 Mar;29(3):194-8.
• Lamprecht M, Bogner S, Schippinger G, Steinbauer K, Fankhauser F, Hallstroem S, Schuetz B, Greilberger JF. Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial. J Int Soc Sports Nutr. 2012 Sep 20;9(1):45. 
• Li N, Gu L, Qu L, Gong J, Li Q, Zhu W, Li J. Berberine attenuates pro-inflammatory cytokine-induced tight junction disruption in an in vitro model of intestinal epithelial cells. Eur J Pharm Sci. 2010 Apr 16;40(1):1-8.
• Marchbank T, Davison G, Oakes JR, Ghatei MA, Patterson M, Moyer MP, Playford RJ. The nutriceutical bovine colostrum truncates the increase in gut permeability caused by heavy exercise in athletes. Am J Physiol Gastrointest Liver Physiol. 2011 Mar;300(3):G477-84.
• Musch MW, Sugi K, Straus D, Chang EB. Heat-shock protein 72 protects against oxidant-induced injury of barrier function of human colonic epithelial Caco2/bbe cells. Gastroenterology. 1999 Jul;117(1):115-22. 
• Niu L, Qiao W, Hu Z, Li N, Huang Q, Gong J, Li Q, Zhu W, Li J. Berberine attenuates lipopolysaccharide-induced impairments of intestinal glutamine transport and glutaminase activity in rat. Fitoterapia. 2011 Apr;82(3):323-30.
• Peters HP, Bos M, Seebregts L,et al. Gastrointestinal symptoms in long-distance runners, cyclists, and triathletes: prevalence, medication, and etiology. Am J Gastroenterol. 1999; 94:1570–81. 
• Prosser C, Stelwagen K, Cummins R, Guerin P, Gill N, Milne C. Reduction in heat-induced gastrointestinal hyperpermeability in rats by bovine colostrum and goat milk powders. J Appl Physiol. 2004 Feb;96(2):650-4.
• Quadro L, Gamble MV, Vogel S, Lima AA, Piantedosi R, Moore SR, Colantuoni V, Gottesman ME, Guerrant RL, Blaner WS. Retinol and retinol-binding protein: gut integrity and circulating immunoglobulins. J Infect Dis. 2000 Sep;182 Suppl 1:S97-S102.
• Roig-Pérez S, Cortadellas N, Moretó M, Ferrer R. Intracellular mechanisms involved in docosahexaenoic acid-induced increases in tight junction permeability in Caco-2 cell monolayers. J Nutr. 2010 Sep;140(9):1557-63.
• Ruiz M. Wikipedia contributors, 'Tight junction', Wikipedia, The Free Encyclopedia, 10 November 2012, 07:58 UTC, <http://en.wikipedia.org/w/index.php?title=Tight_junction&oldid=522300074> accessed 25 November 2012
• Tang Y, Forsyth CB, Banan A, Fields JZ, Keshavarzian A. Oats supplementation prevents alcohol-induced gut leakiness in rats by preventing alcohol-induced oxidative tissue damage. J Pharmacol Exp Ther. 2009 Jun;329(3):952-8.
• Tsukura Y, Mori M, Hirotani Y, Ikeda K, Amano F, Kato R, Ijiri Y, Tanaka K. Effects of capsaicin on cellular damage and monolayer permeability in human intestinal Caco-2 cells. Biol Pharm Bull. 2007 Oct;30(10):1982-6.
• Usami M, Muraki K, Iwamoto M, Ohata A, Matsushita E, Miki A. Effect of eicosapentaenoic acid (EPA) on tight junction permeability in intestinal monolayer cells. Clin Nutr. 2001 Aug;20(4):351-9.
• van Wijck K, Lenaerts K, van Loon LJ,et al. Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men.PloS One. 2011; 6.
• Worobetz LJ,Gerrard DF. Gastrointestinal symptoms during exercise in Enduro athletes: prevalence and speculations on the aetiology.N Z Med J 1985; 98:644–6.
• Zhang B, Guo Y. Supplemental zinc reduced intestinal permeability by enhancing occludin and zonula occludens protein-1 (ZO-1) expression in weaning piglets. Br J Nutr. 2009 Sep;102(5):687-93.
• Zhong W, McClain CJ, Cave M, Kang YJ, Zhou Z. The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction. Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G625-33. 
• Ziegler TR, Ogden LG, Singleton KD, Luo M, Fernandez-Estivariz C, Griffith DP, Galloway JR, Wischmeyer PE. Parenteral glutamine increases serum heat shock protein 70 in critically ill patients. Intensive Care Med. 2005 Aug;31(8):1079-86

Saturated Fat Kills Gut Bacteria & Modifies Genes in the Distal Small Intestine - Another Reason Why We Get Fat? Plus: Bacteria, Fiber, SCFA, GLP-1 & PYY Revisited

Image 1: Bacteria, there are >100 trillion of them right inside of your digestive track, you can hardly know them all and scientists do neither - the only thing we are beginning to understand, though, is that it may be a good idea to get them to know at least somewhat better ;-)

I guess some of you have already noticed that I was (and probably am now, again) somewhat behind, as far as answering your questions, comments an wise remarks are concerned. Actually it is still more of a coincidence that today's SuppVersity news, which, as you see is not an Adelfo Cerame post (don't forget to keep the fingers crossed for him! This is his weekend!), could actually be interpreted as my somewhat lengthy response to a comment from Vincente on the effects of GLP-1 on chocolate preference in rats and an interesting hypothesis of his, on how this could all relate to my previous post on the fat burning effects of GLP-1 ("Eat More, Burn More and Lose Fat Like on Crack with GLP-1!?"). What, that was Vincente's reasoning, what, if those obese individuals had just messed up their gut bacteria an would lack those beneficial bacteria, which convert the fiber and resistant starch that makes it through your small intestine, right down into your long one to short chain fatty acids?

Does obesity come from within?

I guess by now some of you may already be asking themselves, where all that relates to GLP-1 and eating more, burning more and losing fat like on crack. Well, the missing link if you will is actually not a link, but rather a receptor - the free fatty acid receptor, FFR, which "sniffs" the presence of the short chain fatty acids and triggers the release of GLP-1 and PYY. Those two incretin hormones, of which researchers have found within the past 10 years or so that they are way more than mere "satiety signals. Several research studies in rodents have shown that the anti-obesogenic effects of GLP-1 and PYY are if at all, only partly mediated by reductions in food intake, yet mostly via complex downstream effects on total energy expenditure, glucose and fatty acid oxidation.

Contrary to exogenously administered GLP-1, which is actually being used in the treatment of diabetes an the metabolic syndrome, the in-vivo data from rodent studies, which suggests that high fiber diets protects those little critters from diet induced obesity (Aziz. 2008; Shen. 2008; Zhou. 2008) have, as Robertson et al. pointed out only recently, not yet been confirmed in humans trials (Robertson. 2012). Moreover, the latest results from the Merck Reserach Lab show, contrary to previous evidence from the Cambridge Institute for Medical Research (Tolhorst. 2012), that even our current assumption with respect to the underlying mechanism, could at least be incomplete (Lin. 2012). This does not mean that the short chain fatty acids would not produce the desired increase in GLP-1 nad PYY, but rather that their effects are not solely mediated by  the aforementioned free fatty acid receptor in the gut.

Let's make things even more complicated and bring some long chain fatty acids to the table!

What is yet self-evident though is that the way GLP-1 and PYY modulate energy utilization punches yet another huge hole in the prostrated "calories in vs. calories out hypothesis", one that has little to nothing to o with insulin and one that acquires yet another shade of gray, when we look at the long-chain counterpart of the "bacterial excrements" the dreaded or beloved (depending on the standpoint of the individual) saturated fatty acids (SFA) and a recently published study by scientists from the Wageningen University in the Netherlands (De Wit. 2012), who investigated the long-term effects (8 week, study conducted on mice) of high fat diets with fats from different fat sources

• palm oil - representing the saturated fatty acids,
• olive oil - representing the mono-unsaturated fatty acids, and
• safflower oil - representing the polyunsaturated fatty acids

on body weight gain, liver triglycerides and the whole other standard parameters and their relation changes in the gut microbiome and the amount of fat that "left" the animals undigested.

Figure 1: Fecal fat and energy loss, total energy intake and relative (to control on normal chow) liver triglycerides, oral glucose tolerance and weight gain over the 8 week study period (de Wit. 2012)

A casual look at the data in figure 1 should suffice to see that there is a profound mismatch between almost all classic features of the metabolic syndrome of which we would usually expect that they would be closely associated:

• the rodents in the palm oil group ate the least amount of energy, excreted the greatest amount of fat and total energy in their feces and still gained the greatest amount of body weight and had the highest amount of liver triglycerides (beginning non-alcoholic fatty liver disease)
• the rodents in the olive oil group did not consume significantly more amount of energy or excrete significantly more amount of fat / energy in their feces and still gained ~40% less body weight and did not exhibit similarly high triglyceride storage in the liver as the rodents on the saturate fat (palm oil)
• the rodents in the safflower oil group were comparably ravenous (+20% energy intake), but although they did not excrete more energy and fat than their peers, their bosy weight gain was profoundly reduced and their liver triglycerides were better than in the "non high fat control group" and yet their glucose tolerance was not the best, but the worst of all the three groups

All that does only make sense, when a second parameter, or I should say another 100 trillion bacterial parameters come into play and the SFA induced reduction in microbial diversity and
composition (increased the firmicutes/bacteroidetes ratio) are accounted for, as well. those, this is at least what de Wit et al. believe are namely responsible for the complex changes in genes that regulate the fatty acid metabolism and expression of inflammatory markers, the scientists observed

Chicken or egg, cause of correlation? Or just gut optimization?

Even tde Wit et al. do yet point out that their observations do not provide significant evidence to establish a causal relationship between the bacterial changes, which are a direct result of an overflow of (selectively) antimicrobial saturated fats into the distal part of the intestine, the subsequent disturbances in the bacterial balance and (human!) gene expression in the gut and the  particularly pronounced obesogenic effects of saturated fatty acids.

You could, at least in my humble opinion, even argue that these are simply adaptive effects that ensure that the "host", in this case the rodents, "gets the most" out of his diet - after all, this is exactly what we are seeing here: A modulation of genes related to the conservation and storage of energy, such as the downregulation of the Bcmo 1 gene that predisposes to the development of obesity and non-alcoholic fatty liver disease (Hessel. 2008),  which allows for maximal energy efficiency despite greater fecal energy loss.

Conclusion? Drink safflower oil?

That these results should not be taken as an incentive to guzzle safflower oil (or drop your coconut oil for the latter) should be obvious. Just as obvious, by the way, as the realization that despite all the hoopla and my own excitement about the newly discovered importance of the gut microbiome as one of the possible contributers to the global obesity epidemic. We are understanding way too little about its interactions with its host, i.e. us, to exclude that we are not - yet again - confusing cause and effect, causation and correlation and take our gut microbiome, which is eventually nothing else than a mirror of our healthy or unhealthy lifestyle for the real deal, and try to modulate and fix the mirror image with anti-, pro- or prebiotics without working on what stands right before the mirror: The sedentary, convenience food consumer, who works to jobs and rather watches TV till late at night instead of getting his 7-8h of sleep....

References:

1. Aziz AA, Kenney LS, Goulet B, Abdel-Aal el-S. Dietary starch type affects body weight and glycemic control in freely fed but not energy-restricted obese rats. J Nutr. 2009 Oct;139(10):1881-9. Epub 2009 Aug 19. 
2. Hessel S, Eichinger A, Isken A, Amengual J, Hunzelmann S, Hoeller U, Elste V,  Hunziker W, Goralczyk R, Oberhauser V, von Lintig J, Wyss A. CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice. J Biol Chem. 2007 Nov 16;282(46):33553-61.
3. Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G, Marsh DJ. Butyrate and propionate protect against  diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012;7(4):e35240.
4. Robertson MD. Dietary-resistant starch and glucose metabolism. Curr Opin Clin Nutr Metab Care. 2012 Jul;15(4):362-7. 
5. Shen L, Keenan MJ, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Zhou J. Dietary resistant starch increases hypothalamic POMC expression in rats. Obesity  (Silver Spring). 2009 Jan;17(1):40-5. Epub 2008 Oct 23.
6. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012 Feb;61(2):364-71.
7. Zhou J, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Shen L, Danna SC, Tripathy S, Hegsted M, Keenan MJ. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1160-6.
8. de Wit NJ, Derrien M, Bosch-Vermeulen H, Oosterink E, Keshtkar S, Duval C, de Vogel-van den Bosch J, Kleerebezem M, Müller M, van der Meer R. Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. Am J Physiol Gastrointest Liver Physiol. 2012 Jun 14.
9. Zhou J, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Shen L, Danna SC, Tripathy S, Hegsted M, Keenan MJ. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1160-6. 

Resistant Starch (RS4) Reduces Waist Circumference, Body Fat % & Cholesterol Levels in Lean and Obese Individuals in Randomized, Double-Blind Cross-Over Human Study

Effortlessly lean with RS4? Probably not, but if you're into flour-based products it may be for you.

Some things are resistant to being forgotten. D-aspartic acid, for example, is useless and still around. RS-4, on the other hand, has more or less disappeared from the market, when Scott Connely's and Vince Andrich's last project Myotropics shut its doors. What? Oh, you don't even know what I am talking about? Well, RS-4 stands for "resistant starch", type 4. It's usually made from waxy maize starch, but will - due to its unique structure pass through the gut, more or less undigested (learn more).

RS-4 will thus end up in the long intestine, where it is eaten up and being fermented by your bacterial subtenants to eventually be absorbed by your gut in the form of short-chain fatty acids - readily available energy with a metabolic twist - a twist due to which they will also function as signalling molecules in the complex concert that is your metabolism.

There are dozens of Myths & Truths you can learn about at the SuppVersity

Pasta "Al Dente" = Anti-Diabetic

Vinegar & Gums for Weight Loss

Teflon Pans Will Kill You!

You Can Drum Yourself Lean

You Can Wash Pesticides Away

Milk = Poisonous Hormone Cocktail

These short chain fatty acids have gained quite some attention in the science community as of late and are touted to be the potential anti-obesity + pro-metabolic agents of the future.

Accordingly, seasoned SuppVersity veterans, who obviously knew everything I've just explained, already, will no be surprised to hear that Sailendra N. Nichenametla and colleagues claim in their latest paper in the peer-reviewed scientific journal Molecular Nutrition & Food Research that

"...[i]ncorporation of RS4 in routine diets could offer an effective strategy for public cardio-metabolic health promotion." (Nichenametla. 2014)

The researchers from the South Dakota State University base their assessment of the health benefits of RS-4 flour (Fibersym, MGP Ingredients, Atchison, KS - a sponsor of the study), which had been replaced at a 30% v/v ratio in the diets of 86 US adults with and without metabolic syndrome... and as you can see in Figure 1, the effects of this minimal change were quite enormous.

Figure 1: Changes in HDL and body comp. in all subjects, and subjects w/ and w/out metabolic syndrome (Nichenametla)

The addition of 30% RS-4, which is an artificial resistant starch that passes the small intestine undigested to end up in the large intestine, where it is converted to short-chain fatty acids by the gut bacteria (learn more), to the flour the subjects had to use for all their flour-based products, induced a 7.2% reduction in total cholesterol, a 5.5% reduction of non-HDL, and a 12.8% reduction in HDL of which I must say that I am obviously not happy with it.

Interestingly, similar changes were not observed in normal-weight (No-MetS) individuals. For them the resistant starch worked its previously reported fat loss wonders and lead to reductions in waist circumference (-2.6%; p=0.02) and percent body fat (-1.5%; p=0.03) over the course of the 12 weeks they spent in the active arm of the study (remember: We're dealing with a cross-over study with a two week washout in-between).

Read more about WM-HDP the RS-4 version of Waxy Maize at the SuppVersity | go ahead

Bottom line: In conjunction with the "small but significant 1% increase in fat-free mass was observed in all participants combined (p=0.02)." (Nichenametla. 2014) The study at hand clearly demonstrates that the previously reported metabolic benefits of synthetic resistant starches (RS4 vs. natural RS3) are real. Even if there were no significant changes in glycemic variables and blood pressures. The consumption of improved the dyslipidemia and body composition of the study participants and is thus potentially interesting for both, lean physical culturist and/or obese victim of the standard American diet.

Whether we are going to see corresponding products (e.g. an RS-4 enriched flour) on the supermarket-shelves, soon, is yet something I personally doubt - I mean, it's possible it will be a bit more expensive than the regular flour and those people who would care don't buy the former, anyway.

References:

• Nichenametla, Sailendra N., et al. "Resistant starch type 4‐enriched diet lowered blood cholesterols and improved body composition in a double blind controlled cross‐over intervention." Molecular nutrition & food research (2014).

Eat More, Burn More and Lose Fat Like on Crack with GLP-1!? Roux-en-y Bypass Study Sheds a Whole New Light on Satiety(Hormone)-Induced Weight Loss

Image 1: A gastric bypass should always be the last option; with all the possible complications it is nothing to treat lightly (img medcenterone.com)

Everyone who has read the Intermittent Thoughts on "Goal Setting and Programming Success" with the three somatypes, SuperSize Homer, Peter Griffin and Anorexic Stan, will be aware that I do acknowledge the oftentimes life-saving benefits of surgical anti-obesity interventions, when everything else fails. Until recently, I did however assume that"cutting off" a part of your stomach or using a sling or other devices to reduce its size would simply reduce a patients ability to overeat, thusly reduce hi caloric intake and help him to cut his weight back into a region that is no longer life-threatening. The recent publication of a study by scientists from the Harvard Medical School (Nestoridi. 2012) does yet suggest that the effects of roux-en-y gastric bypasses are in fact way more far reaching than, at least I, had previously thought.

Does a roux-en-y bypass "actively" burn fat!?

In their experiment Erini Nestoridi and her colleagues had observed that the overweight mice in the active arm of their study, i.e. those mice who were not just cut open (sham group), but had also received the roux-en-y gastric bypass (RYGB), did not only lose body fat like crazy, they did also consume significantly more calories, expended significantly more oxygen (a marker of fatty acid oxidation), had a significantly lower respiratory quotient (=burned more fat than glucose for fuel) and wasted almost twice as much energy in the form of body heat than their sham-operated peers, so that their overall energy balance looks like they were on DNP or any other "true" thermogenic fat burner (cf. figure 1)

Figure 1: Energy intake, respiratory quotient (higher levels = more glucose, less fatty acid oxidation), heat production, fat free mass and fat mass during and at the end of the 8-week intervention trial subsequent to either sham or roux-en-y gastric bypass operations on obese mice (data calculated based on Nestoridi. 2012)

In combination with the to-be-expected increase in fecal energy loss (44kcal/day vs. 13kcal/day), which occurred as a consequence of the decreased transit time and ability to absorb nutrients from the chow, these changes explain very well, why, at the end of the 8-week intervention period, the RYGB mice had lost all their unhealthy fat depots, while their sham operated had gained another 6g of body weight.

Gastric bypasses increase the GLP-1 response and thusly restore metabolic health

All that reminded me of some research with regard to the metabolic role of the so-called satiety hormones, CKK, PYY and above all GLP-1 I have been doing as of late. Glucagon-like-peptide 1 (GLP-1), in particular, exerts profound and far reaching metabolic effects, which have little to do with the satiety function its label "satiety hormone" does imply. Interestingly, the restoration of normal fasting blood glucose levels, the  normalization of the glucose response to an oral glucose tolerance test, the increased fatty acid oxidation and even the RYBG mice' profoundly reduced preference of the hypercaloric high fat chow (after the surgery the rodents had free access to normal and the highly palatable "high fat" chow, on which they had accumulated a 50% body fat percentage before the surgery) have all been associated with increases in GLP-1 levels in previous studies. In their 2005 review of the literature, Burcellini et al. even mention the involvement of cerebral GLP-1 in cognition and memory (Burcelin. 2005).

A 2012 case-report in which Myint et al. (Myint. 2012) describe a RYBG patient who suffered from recurrent episodes of hypo(=low)glycemia due to increased GLP-1 levels would support my hypothesis that GLP-1, or rather its increased expression subsequent to gastric bypass operations could be the root cause of all the beneficial metabolic effects in the rodent study at hand and the thousands of human beings whose lives have been saved by this surgical intervention, as of yet. That this is not just a transient or outlier effect, but something we see across the board in all RYGB patients and which remains, even at a10-year follow-up has been confirmed by Mohamad S. Dar and his colleagues from the East Carolina University, who examined the GLP-1 response to oral meal consumption in 5 RYGB patients 10 years after the operation and found that the "exaggerated GLP-1 response [is] maintained [...] despite statistically significant
weight loss".

The fat burning effect of eating to satiety

Image 2: Adelfo's progress during his contest prep are an excellent example for the highly desirable "side effects" of eating to satiety.

Now, it would not only be plain out stupid to get a gastric bypass done, when that is not medicinally necessary, it would also compromise the value of "my" hypothesis that GLP-1 could in fact be the main working mechanism behing RYGB induced weight loss, if it was not (a) increased / higher in the billions of people who do not get obese in the first place and if there were not (b) other most prominently dietary means to increase GLP-1 which trigger similar beneficial metabolic effects. As you may imagine, I would not have proposed this hypothesis, if I had not already come across pertinent research, such as a 2006 study by Nicola Pannacciulli et al. in which the NIH researchers found a statistically significant association between GLP-1 levels and resting energy expenditure in 46 glucose tolerant male and female subjects with BMIs ranging from 18.6-50m²/kg (Pannacciulli. 2006).

A preliminary GLP-1 cheat sheet for the obese and non-obese dieter

The following list of dietary GLP-1 "agonists" is yet still "work in progress" and more of a preview on a future, comprehensive blogposts of the role of the metabolic function of the incretin hormones, I am currently working on (whenever I have 1s of time to spare ;-):

• short chain fatty acids (Tulhurst. 2012) 
• fermentable fiber (Greenway. 2007)
• fermentable resistant starches (Zhou. 2008)
• bile acid (Katsuma. 2005; Parker. 2012)
• egg and meat hydrosolates (Cordier-Bussat. 1998)
• milk proteins (Hall. 2003; Juvonen. 2011)
• fish oil (only if administered interperitoneal; Motoshita. 2008)
• fats, when added to starchy carbs (e.g. Frost. 2003)

Unfortunately, things can become quite confusing, because despite all those "starches" and "fibers" in the list, there are studies, which report the exact opposite effects for some of the classic dietary fibers, like psyllium, for example (Karhunen. 2010). Conflicting results by Wang et al. who report 2x increased GLP-1 levels in response to psyllium or sugarcane fiber enriched high fat diets (Wang. 2007), do thusly raise the question if the GLP-1 response is either (a) species-specific (the Wang study was done on mice), (b) depends on the accompanying nutrients (both studies used rather high fat foods / chow, though), or whether (c) the difference is a simple consequence of the study design, i.e. acute (Karhunen) vs. chronic (Wang) ingestion of fiber-(en)rich(ed) food / chow.

Could it not be about insulin, but about GLP-1?

And although we certainly cannot rule out (a) completely and must acknowledge that (b), i.e. man vs. mouse, will always make a difference, I personally believe that overall (c), i.e. the differences between the acute, the longer term and the chronic effects are, are most likely responsible for the differences in GLP-1 response and the ensuing metabolic effects. After all, fermentable fiber, fermentable resistant starches and psyllium all increase the production of short chain fatty acids in the colon. The beneficial effects the latter have on the amount of GLP-1 that is released will however arise at a very late stage of the digestion process. the decrease in GLP-1 Karhunen et al. report in their study, on the other hand, was measured right after the ingestion of the meal.

Don't forget: In non-insulin resistant individuals, glucose, or rather its transportation via the GLUT-2 receptors is a stimulator of GLP-1 release, as well. It is thusly not really surprising that Lee et al. have recently been able to show that its release is impaired in diabetic rats (Lee. 2012). With an intact GIP response (cf. WMHDP article for more on how GIP is making you fat) diabetics and most likely also "just insulin resistant" individuals are thusly getting all the negative without any of the beneficial effects of carbohydrate ingestion, so that GLP-1 is yet another piece in the "why low-to-no-carb works / may even be necessary for obese diabetics, but is unnecessary for healthy individuals" puzzle, I've been putting together with a whole host of posts over the past couple of weeks.

Given GLP-1's role as a mediator of glucose disposal and fatty acid metabolism, it is thus likely that the long-term health benefits I have hinted at in the context of the gastric bypass study, arise only when we have a steady "elevation" or rather steadily high-normal levels of GLP-1, instead of some punctuated spikes, as Karhunen observed them for "non-fibrous" foodstuff or Juvonen for low viscosity foods (Juvonen. 2009).

If we also take into account that Cheong et al. report that large fluctuations in blood glucose levels exert greater ER stress on rat insolinoma cells than chronic hyperglycemia and that the former, i.e.the large blood sugar fluctuations, yet not chronic hyperglycemia downregulate the GLP-1 receptor expression (which would induce a metablic state we would have to label "GLP-1 resistance") on these cells (Cheong. 2011). We could go as far as to speculate that the ups and downs of the glucagon-like-polypeptide 1 and the subsequent down-regulation of its receptors at the cellular level and not our contemporary scapegoat, insulin, could be at the heart of the diabesity epidemic... but I will get deeper into that in the upcoming incretin hormone special, so stay tuned!

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.

---

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]

Ramp Up Your Short-Chain Fatty Acid Production With Fermentable Starches Within 6 Days. Longterm Fat Loss, Gut Health & Cancer Protection Possible

You cannot handpick several billion lodgers in your intestine, but you can attract the right one by providing them with the foods they like. Contrary to the current probiotic hype, the key to gut and metabolic health lies in the prebiotics you are stuffing down your piehole.

It's quite funny, only 5 years ago, everyone was still smiling at people who spent extra bucks on yogurts and other dairy products that were enriched with certain bacteria strains - strains, which were and obviously still are supposed to have health-promoting effects. The fact that probiotic yogurts and similar stuff have meanwhile made it into the store brand line-up of the large discount-markets (at least here in Germany) is however clear cut evidence that the previously laughed at idea that gut bugs are something you want to foster and promote has meanwhile turned into another of those partly highly questionable, but widely accepted pieces of "nutritional wisdom". The question that remains is, will they join the ranks of other scientific hypothesis that have made it n allegedly oversimplified from the bench to the store-boards before their time was ripe? Hypotheses such as the "cholesterol is bad for your heart", the "pasta and rice will keep you lean" and the "fat makes fat" hypotheses?

Don't worry, I am neither going to rant, nor am I suggesting that the whole idea about the importance of the gut microbiome is similarly flawed as the "eat fat and get fat"-hypothesis. The thing I do yet want to point out, before I tell you more about the latest scientific findings, is that our knowledge about the good and the bad guys in our intestines, about the ways they interact and about the short- and longterm effects of these interactions are so limited that my gut tells me (all puns intended) that everything that goes beyond the classics, i.e. the consumption of a diet rich in various types of fibers and a reasonable amount of fermented foods could well turn against us in a not very distant future.

Feeding the good guys: Does it work? And how does it work?

Based on the currently available evidence, it does however in fact look like the shift towards short-chain fatty acid producing bacteria, the scientists from the University of Minnesota and the scientist from the Fred Hutchinson Cancer Research Center initiated in their 20 study participants (ten men and ten women) who had been recruited via flyers around the University campus (that alone goes to tell you how "mainstream" the notion of beneficial gut bacteria has become). The subjects were health and aged between 18 and 60 years, they were non-smokers and were not taking any prescription meds and contrary to the average American (cf. "How Fat We Have Become") their BMIs were in the normal range.

Table 1: Macronutrient composition of the test meal on day 1 and the supplemental cereal bars and beverages the subjects consumed in the course of the 6-day study period on four occasions every day (Klosterbuer. 2013)

"Participants consumed five treatments in a double-blind, cross-over design with treatment periods of 7 d followed by a 21 d washout period. On day 1 of the study, following a 12 h fast, participants arrived at the GCRC and consumed either a low-fibre control breakfast or one of four fibre-containing breakfasts. Meals consisted of a muffin, hot cereal, and fruit-flavoured beverage. For the next 6 d, participants consumed the study products at home. Treatments were provided as cereal bars and a beverage mix, which was pre-measured into 500 ml water bottles. Participants were instructed to consume four cereal bars and one beverage over the course of each day." (Klosterbuer. 2013)

Obviously the test breakfast, as well as the bars and beverages the dietary composition of which you can see in table 1 contained additional "functional" additives. As indicated by the titles above the respective columns in table 1, these were

• 

  Figure 1: Short-chain fatty acid content of the stools (top), number of stools and consistency (1=hard, 4=diarrhea, middle), gastrointestinal symptoms (bottom, Klosterbuer. 2013)

  for the breakfast, 25 g SCF or RS alone or in combination with 5 g pullulan (SCF+P and RS+P),
• for the beverages and bars in the treatment groups, 20g SCF or RS alone or in combination with 5 g pullulan (SCF+P and RS+P) for the beverages and bars and
• for the beverages and bars in the control group, fully digestible maltodextrin

• the short chain fatty acids (SCF) were produced via hydrolysis of maize starch, followed by
  cooling to form a branched structure, 
• the resistant starch (RS) was a type 3 (RS3) retrograded starch roduced from heat moisture-treated, high-amylose maize starch, and 
• pullulan is a linear glucose homopolysaccharide that's formed during the fermentation of dextrin by the yeast Aureobasidium pullulans.

All test products were provided by Tate and Lyle, Inc. and - as you can likewise see in table 1 matched for macronutrient and energy content. All bars and beverages were meant to be consumed along with participants regular diets.

Astrology was yesterday, feceology (=poopology ;-) is the future!

Aside from the obligatory protocols on the state of their digestive health the subjects also had to collect stool samples, which were then analyzed by the researchers who were looking at the RNA and DNA content of the samples to identify any changes in the makeup of the gut microbiom, without exact quantification of individual strains. What they found was that ...

"[a]mong the treatments, the control was significantly different from the SCF (P<0.001) and SCFþP(P<0.0002) treatments. The SCF treatment was significantly different from the RS treatment (P<0.007), and the SCF+P treatment was significantly different from the RS+P treatment (P<0.002). The GMC [gut microbial community] following the consumption of the SCF and SCF+P treatments was not significantly different." (Klosterbuer. 2013)

Now this certainly does not sound very informative, right? It in fact isn't but let's be honest, what's the additional value of me telling you that the scientists were able to associate a certain peak in the bacterial make up with either Anaero-coccus vaginalis or Parabacteroides goldsteinii and another one with either Parabacteroides distasonis or Parabacteroides merdaeusing anisilico?  Not much, right.

"I know that we know nothing" An adequate description of the "state of the art"

My casual observation that knowing the funky names of the individual bacteria that felt specifically cosy in the acidified short-chain fatty acid loaden milieu that formed in response to the dietary intervention is about as useful to you as knowing all the names of the tiny insects in the Amazon Delta. In view of the fact that this is not much different for the scientists who were not even able to tell exactly which bugs they were looking at here. In fact, we have not even come so far to say "little do we know" - the current state of our "understanding" of the complexity of the gut microbiom is simply far from allowing any reliable prognosis statements on which bacteria we want in which ratios.

Figure 2 (first published in "Waxy Maize Reloaded"): Changes in postprandial energy expenditure (left) and fatty acid oxidation (right) after the ingestion of regular and WM-HPD pancakes (data adapted from Shimotoyodome. 2011)

That being said the net increase in SCFA production that was achieved by all treatments in the study at hand is an endpoint that may provide at least some orientation. After all, you will probably all remember the impressive results of theh Shimotoyodome study from 2011 (see figure 2) I discussed in conjunction with the post on WM-HDP, back in the day. While this is likewise still speculative, it's still highly likely that the increase in fatty acid oxidation the researchers observed in their human subjects after the consumption of pancakes that had been enriched with resistant starch (RS4) is a direct consequence of the increased short chain fatty acid production in the colon.

There is yet an important "on the other hand" we must not forget

GLP-1 is also partly responsible for the profound weight loss after bariatric surgery. In this case it is yet not the rise in short chain fatty acids, but as the scientists speculate the mechanical stretch and the influx of dietary fat that would otherwise have been absorbed earlier during the digestive process that triggers the release of the "satiety hormone" glucacgon-like peptide 1 (GLP-1, read more)

In fact, the aformentioned beneficial effects on the fatty acid metabolism and the concomitant reductions in insulin, which were brought about by an increase in GLP-1 (learn more about the potent fat burning effect of GLP-1) and decreases in GIP, respectively, have recently been traced back directly to the influence of SCFA in the long intestine. In a cleverly designed study, Lin et al. were able to show that the expression of these quasi-hormonal peptides, appears to be mediated by a direct interaction of bacteria-generated (or simply ingested) short-chain fatty acids in the gut with a speficic free free fatty acid receptor 3 (FFAR-3) in the gut lining (Lin. 2012).

As far as this part of the equation goes, we do therefore actually "know" something, what we do not know, but there are obviously a couple of my beloved "on the other hands" we still have to take into account. The most significant of these is unquestionably that impressive results as those that were observed in the very short run in the Shimotoyodome study will only arise in scenarios, in which the regular sugars and starches 90% of the Western population literally lives on are replaced with fermentable alternatives.

As long as you keep on the twinkies and dingdongs diet, the composition of your gut microbiome won't save you - no matter how good the critters are in turning fermentable starches into short chain fatty acids.

Figure 3: Different resistant starch content of various foods (% dry matter; based on Goni. 1996)

After all none of the simple sugars and easily digestible starches will even make it to the colon before they are either directly or after being disassembled by the enzymes in your gut taken up into the blood stream - the couple of  SFCA you either ingest as a supplement or your gut bacteria may be producing from additional pre-biotics (the term used in a very broad sense here and in the following paragraphs) you may be taking won't save you from the "fat" consequences.

Remember: If A → B & A → C, this does not imply B → C

Epidemiological studies such as Layden et al.'s 2012 analysis of the body composition of young, obese women in which the researchers found a negative correlation between body fatness (esp. visceral obesity) and the SCFA production in the colon do therefore not necessarily tell us that having a certain gut microbiome protects you from obesity (Layden. 2012). Observational studies like these, but also all experiments in which the human or rodent "participants" had the chance to compensate for the intake of fermentable starches or other supplements by skipping on foods they'd otherwise consume, simply tell us that eating fermentable starches is better than eating sugary junk - not more, but also not less.

Can saturated fat cause endotexemia? Learn the answer here!

If the ladies with the lower visceral fat in the Layden study consumed a diet that was devoid of fermentable starches, they would not produce any short chain fatty acids no matter how the composition of their gut microbiome may look like (in fact it would soon look like a "ghetto" full of unwanted bacterial tenants not paying their rent in form of healthy SCFA ;-). It should be obvious that the same goes for the anti-cancer effects of the SCFAs butyrate, propionate and acetate (Matthews. 2012), as well as all the other beneficial health effects which have been linked back to the bacterially manufacture two- to six-carbon chain FAs.

All the aforementioned benefits require the reguar ingestion of more than just trace amounts of fermentable starches. These pre-biotics will automatically have the "beneficial" bacteria in your gut get the better of the "bad guys" and it is a necessary prerequisite that any probiotics you are consuming either in pill form or from enriched foodstuff can take full effect. In other words:

Pre-biotics don't support probiotics, it's the other way around. Probiotics can support and accelerate the desired permanent change the regular consumption of prebiotics will bring about.

I know the product descriptions on the shiny websites of the snake oil industry will conceal that, but without a consequent and permanent change in your dietary habits, you can as well flush your super-potent 100 billion bacteria per serving probiotic directly down your toilette.

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Even the nicest subtenants can become a real problem, when they come over without being asked day by day. Unfortunately, all sorts of gut bacteria (even the "good" ones) have as imilarly nasty habit of translocating through a leaky gut wall into parts of your body, where you certainly don't wont them... read about the nasty consequences, here

Long story short: All the current hoopla about probiotics, the tons of "enriched" products on the shelves of the supermarket, the capped super-*place your favorite strain here* with bazillions of "life-bacteria" in them and for which you would have to spend half your monthly salary, if you wanted to consume enough of them to override the baseline effect your diet, all of them are about as useful as a stimulant based fat burner on a hypercaloric diet.

You are what you eat, not what your supplement! The same goes for the composition of the bugs in your gut and if you want them to produce short chain fatty acids for you you better make sure they get the raw materials on a consistent basis. That this works like a charm within no more than 6 days is evidenced by the study publication of which triggered this lengthy discussion.

Whether all the purported health benefits will become visible in the short, long or very long term will yet still have to be elucidated... and that this is probably not going to happen, when you try to get your fermentable starches from bread only (0.25g per slice vs. navy beans 10g per 1/2 cup and even bananas 5g per banana)

References:

• Goñi I, García-Diz L, Mañas E, Saura-Calixto F. Analysis of resistant starch: a method for foods and food products  Food Chemistry. 1996; 56(4):445–449.
• Layden BT, Yalamanchi SK, Wolever TM, Dunaif A, Lowe WL Jr. Negative association of acetate with visceral adipose tissue and insulin levels. Diabetes Metab Syndr Obes. 2012;5:49-55. 
• Klosterbuer AS, Hullar AJH, Li F, Traylor E, Lampe JW, Thomas W, Slavin JL. Gastrointestinal effects of resistant starch, soluble maize fibre and pullulan in healthy adults. British Journal of Nutrition. 2013 [Epub ahead of print].
• Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G, Marsh DJ. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012;7(4):e35240.
• Shimotoyodome A, Suzuki J, Kameo Y, Hase T. Dietary supplementation with hydroxypropyl-distarch phosphate from waxy maize starch increases resting energy expenditure by lowering the postprandial glucose-dependent insulinotropic polypeptide response in human subjects. Br J Nutr. 2011 Jul;106(1):96-104.
• Wroblewska M, Brzuzan L, Jaroslawska J, Zdunczyk Z. Effect of buckwheat sprouts and groats on the antioxidant potential of blood and caecal parameters in rats. Int J Vitam Nutr Res. 2011 Sep;81(5):286-94.