Supplement Review: Lactulose - Isomerized Lactose With Prebiotic, Anti-Constipation, -Cancer, -Hyperammonia, -Salmonella, -Endotoxin & Pro-Mineral Absorption Effects

Don't worry: There is more than flatulence and diarrhea to lactulose... I mean, why do you think I'd write about it, then?

I am not sure if all of you have already heard of 4-O-β-D-galactopyranosyl-D-fructose aka lactulose, a synthetic nondigestible sugar you can buy either as a white, odorless powder or as a syrup. It tastes, contrary to what you may expect, pretty good, a bit like hilariously sweet honey, if you asked me, and sweet enough to be used as an "artificial" sweetener. A sweetener that has traditionally been sold as a medicinal drug for decades but is not appearing on an ever-increasing number of ingredient lists of so-called "functional" food products. Despite the fact that the market has grown appreciably over the last 10 years (Panesar & Kumari. 2011), lactulose is after all not yet as "popular" as inulin and the rest of its prebiotic brethren.

From drug, to supplement to food additive

The mere fact that the easiest but certainly not cheapest way to acquire lactulose is still the pharmacy obviously doesn't imply that you can use it as any other over-the-counter (it is OTC, even in Germany ;-) supplement. And that's true in spite of the fact that your doctor may actually prescribe it, if you are suffering from hepatic encephalopathy, constipation, or salmonella (Schumann. 2002).

Lactulose content (mg/l) of milk (Marconi. 2004)

There is "natural" lactulose in milk: Due to the fact that lactulose can be produced by the heat-induced isomerization of lactose (see inset in figure to the left for a reaction curve for milk that's heated at 130°C), all varieties of heat treated milk, even the low-temperature pasteurized variety will contain a certain, albeit low amount of lactulose (see figure to the left).

If that was all lactulose was good for, it would yet probably not have made it into the SuppVersity Supplement Review. The latter is rather due to its ever-increasing presence in "functional foods", where it is used as a prebiotic for its impressive beneficial effects on the composition of the colonic microflora.

If lactulose is added to the formula milk, such babies have same composition of the colonic microflora as the breast-fed babies (Knol. 2005).

I see, now you're listening... I would suggest, then, that we take a brief look at other established and suspected benefits lactulose supplements / lactulose-enriched functional foods have to offer:

• Constipation - I already mentioned it in the introduction. If you ask your doctor about lactolose supplements, he will probably raise his eye-brow and say: "Are you constipated?" While the general recommendation is to treat constipation by increasing your water intake, the amount of fibrous foods you eat, etc. lactulose has a long history as an intermediate adjunct to these changes in patients of all ages, including babies.
  
  
  Flatulence Warning: Don't ingest lactulose before your first date with the girl or guy of your dreams ;-)
  Lactulose is an osmotic laxative. This means it will draw more water into the the colon and can thus offer relief of constipation, including chronic constipation within about 24-48h. When it reaches the intestine, the lactulose molecule is still intact. Lactulose is not digested in the small intestine as the specific disaccharidase is lacking.
  
  It transits unchanged to the colon where it serves as an energy source for the carbohydrate-splitting bacteria, predominantly lactobacillus acidophilus and L-bifidus (Saarela et al., 2003; Cardelle-Cobas et al., 2011; Hernandez-Hernandez et al., 2012).

Lactulose "feeds" the good bacteria in your gut: As you can see in the figure to the left, the continous ingestion of 5g of lactulose for 42 days lead to statistically significant increase in the  16 healthy volunteers who were included in Bouhnik et al.'s controlled, randomised, double-blind, parallel group trial (Bouhnik. 2004).

• These bacteria split lactulose into its active components that will then exert the previously mentioned osmotic effect. Unfortunately, the fermentation process, will usually give rise to some gas... especially in people who are not used to the ingestion of fibrous foods this can lead to temporary gaseous social incompatibility (aka flatulence; cf. Blanc. 1992).

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  Table 1: Summary of treatment, comparison and results of studies on the effects of lactulose on PSE that were reviewed by Conn et al. (1977) and Heredia et al. (1987); (+) clinical improvement, (=) no significant difference, (±) treatment lead to improvement in psychometric tests

  Portal systemic encephalopathy (PSE) therapy - According to Prasad et al. (2007) lactulose exerts significant beneficial effects on the impaired neuronal function and cognitive performance of PSE patients. In the corresponding study that involved thirty-one patients received lactulose treatment for 3 months (+30 controls who did not) the lactulose group showed significant improvements in their quality of life and emotional behavior.
  
  It must be said, though that not all pertinent studies were able to detect significant beneficial effects of lactulose supplementation on PSE. In fact, more than 50% of the studies Conn et al. (1977) as well as Heredia et al. (1987) have reviewed (see Table 1) were unable to detect a significant difference between the patients in the lactulose and those in the healthy control group.
• Salmonella - While peer-reviewed studies on the effects of lactulose in patients with nontyphoid salmonella (Schumann. 2002), there is plenty of anecdotal evidence that lactulose at dosages of up to 60 g per day (diarrhea alert!) can kill the intruders by inducing a a sharp drop of the colonic pH, which makes the survival of salmonella difficult.
• Endotoxins - As a SuppVersity reader you know that endotoxins are what you could call the "toxic poop" of the bacteria that colonize your gut. In a 2003 study Koutelidakis et al. were able to show that jaundice patients who had been pretreated with lactulose showed a significantly reduced increase in endotoxins after surgery. These observations are supported by animal experiments that have shown that oral lactulose administration reduced the mortality associated with endotoxin in obstructive jaundice. 

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  Tired, exhausted, had to cut your workout short today? Is it the flu, or just too much BCAAs? | learn more

  Reduction of blood ammonia levels - This effect of lactulose can actually come very handy for the average protein addicted gymrat as well.
  
  You will probably remember the article about the BCAA induced performance decrements from November 2012 ("Chronic High Dose BCAA Supplementation Reduces Endurance Performance by 43% Plus: How Ammonia, Glutamine, Arginine & Low Carb Could be Involved" | read more).
  
  If said effects are actually a consequence of the ammonia accumulation it may come handy to reduce the baseline ammonia influx from the gut by reducing its production via the acidifying effects of lactulose (Wright. 2011).
• Cancer - Not directly gym-relevant, but certainly as important is the protective effect lactulose may have on colon carcinogenesis. This type of cancer usually develops in the presence of high amounts of secondary bile salts, which could partially explain the reported lower rate of cancer recurrence in colon cancer patients who were treated with lactulose. Rodent studies by Verma & Shulka also suggest that lactulose has a direct protective effect on the DNA of the colon mucosa of rats (Verma. 2013; note: on a per gram basis inulin, which was also tested in this study was a more effective DNA protector).
  
  In addition to its (more or less) direct effects, the lactulose induced increase in bifidobacteria may also have cancer protective effects - not just in the colon, but in the mammary gland and liver, as well (Reddy. 1993)
• Enhancement of mineral absorption - When you surf through the blogosphere you will be confronted with horror-stories about the inhibitory effects all sorts of food products are supposed to have on the absorption of calcium, magnesium iron and co. Against that background it's almost relieving to know that lactulose can significantly augment the absorption of calcium, magnesium, zinc, copper, iron (Seki. 2007).

  

  Figure 1: Effects of 2g and 4g lactulose added to a standardized test meal on the absorption (measured by urinary excretion) of calcium and magnesium in 24 healthy volunteers (Seki. 2007)

  Pometto al. report that the effects are sufficient enough to exert anti-osteoporotic effects in a rodent model (Pometto. 2006). Whether the same goes for human beings hasn't been established, though.

If you review the overall effects, I guess you will be able to trace most of them back to the prebiotic properties of lactulose. The latter is a good thing, but in view of the fact that lactulose is by no means the only prebiotic with promising health effects the question is.

A word of caution to everyone out there with existing intestinal problems: As you may remember from the SuppVerstiy Facebook News Whelan et al. have only recently published a paper that reviews the the evidence that some prebiotics in high doses worsen functional symptoms in IBS and Crohn's patients. (Whelan. 2013 | cf. SvFb Post).

Do we actually need lactulose? As I pointed out in the previous paragraphs, lactulose has plenty of health benefits. It is yet questionable which, if any are "exclusive" to the isomerization product of lactose which has the nasty tendency to produce socially unwanted side effects and highly impractical such as flatulence and diarrhea.

If you don't overdo it (1-2g/day is a good starting dose) you should however be able to avoid loose stools and control the gas production. In this case lactulose can more very handy as one out of many tools you can use to increase the prebiotic content of your diet. Plus: Contrary to most other prebiotics lactulose tastes actually pretty good and can be used as a tasty and healthy sweetening agent in all sorts of products. The latter is also the reason that I expect that you will see it on more and more ingredient labels of commercially available food products in 2014 and beyond.

References:

• Aït-Aissa, A. and Aïder, M. (2013), Lactulose: production and use in functional food, medical and pharmaceutical applications. Practical and critical review. International Journal of Food Science & Technology
• Blanc, P., Daures, J. P., Rouillon, J. M., Peray, P., Pierrugues, R., Larrey, D., ... & Michel, H. (1992). Lactitol or lactulose in the treatment of chronic hepatic encephalopathy: Results of a meta‐analysis. Hepatology, 15(2), 222-228. 
• Knol, J., Scholtens, P., Kafka, C., Steenbakkers, J., Gro, S., Helm, K., ... & Wells, J. (2005). Colon microflora in infants fed formula with galacto-and fructo-oligosaccharides: more like breast-fed infants. Journal of pediatric gastroenterology and nutrition, 40(1), 36-42.
• Koutelidakis, I., Papaziogas, B., Giamarellos-Bourboulis, E. J., Makris, J., Pavlidis, T., Giamarellou, H., & Papaziogas, T. (2003). Systemic endotoxaemia following obstructive jaundice: the role of lactulose. Journal of Surgical Research, 113(2), 243-247.
• Marconi, E., Messia, M. C., Amine, A., Moscone, D., Vernazza, F., Stocchi, F., & Palleschi, G. (2004). Heat-treated milk differentiation by a sensitive lactulose assay. Food Chemistry, 84(3), 447-450. 
• Reddy, B. S., & Rivenson, A. (1993). Inhibitory effect of Bifidobacterium longum on colon, mammary, and liver carcinogenesis induced by 2-amino-3-methylimidazo [4, 5-f] quinoline, a food mutagen. Cancer research, 53(17), 3914-3918. 
• Panesar, P. S., & Kumari, S. (2011). Lactulose: production, purification and potential applications. Biotechnology advances, 29(6), 940-948.
• Pometto, A., Shetty, K., Paliyath, G., & Levin, R. E. (Eds.). (2005). Food biotechnology. CRC Press.
• Seki, N., Hamano, H., Iiyama, Y., Asano, Y., Kokubo, S., Yamauchi, K., ... & Kudou, H. (2007). Effect of lactulose on calcium and magnesium absorption: a study using stable isotopes in adult men. Journal of nutritional science and vitaminology, 53(1), 5-12.
• Schumann, C. (2002). Medical, nutritional and technological properties of lactulose. An update. European Journal of Nutrition, 41(1), i17-i25.
• Van Boekel, M. A. J. S. (1998). Effect of heating on Maillard reactions in milk. Food Chemistry, 62(4), 403-414. 
• Wright, G., Chattree, A., & Jalan, R. (2011). Management of hepatic encephalopathy. International journal of hepatology, 2011.