Bacteria and Sugars: Infections and Glycobiology

• These "resistant" bacteria are able to multiply unhampered by other competing bacteria that have been killed by the antibiotic;
• they are also able to pass that resistance on to other types of bacteria. "What doesn't kill us makes us stronger," said Nietzsche, and it's the same with bacteria.

Pharmaceutical companies are constantly trying to stay ahead of the bacteria by developing more and better antibiotics, but the bacteria seem to learn almost as fast as the FDA approves the new antibiotic.

• In some cases, because of animal testing and use, there have been resistant bacteria even before the antibiotic was released for humans.
• The primary cause of this problem is our overuse of antibiotics. Doctors on the front lines want to help their patients get better and patients wanting to get better expect antibiotics to help. So we prescribe a lot of antibiotics.
• Yet infectious disease specialists tell us we need to be more judicious in our use—"our tactical decisions are hostile to our strategic interests."
  • These could have been the words of any infectious diseases specialist, but they come from Lt. General Moshe Yaalon of the Israeli Ministry of Defense.
  • There are many similarities between bacterial and human levels of warfare, but their common ground is that violence promotes resistance on both levels.
    

Our point is that we desperately need another option in our warfare. In countries where antibiotics are used more sparingly they do not have as much of a problem—the bacteria rapidly lose their resistance when they are not challenged.

Biologists approach this problem in the same way that they address symptoms that arise because of manipulations of bacteria that are discussed elsewhere. Manipulations need to be blocked—like we block malaria by using mosquito netting when we sleep or screens on our windows. Or like we block the spread of sexually transmitted diseases by using condoms, or a variety of communicable diseases by washing our hands regularly. Blocking the spread of bacteria in these simple ways means that they have to survive in their current host without destroying it and over time tends to promote less illness producing bacteria.

One area of research that will help reduce this problem is from the field of glycobiology ('glyco' comes from the word for sugars and 'biology' comes from life so this field studies the role of sugars in living animals). Some people in this field look at how bacteria attach to cells in the body.

• Attachment is necessary before bacteria can cause any kind of infection. If they are not attached to cells they are just washed away by the body's normal cleansing processes and don't cause any problems.
• This approach uses the same strategy of blocking the manipulation described above, but it puts it on an individual level—very much like washing our hands.
• The overwhelming majority of bacteria have what are called receptor sites or lectins that they use to hold on to cells in our bodies.
• These lectins are like hands that fit specific sugar complexes on the surface of cells and this is how they hang on to them.
• Again, this attachment is the first step in starting an infection—if the bacteria are not attached they are washed out and don't cause problems. [I know I've said this a jillion times, but I'll say it another jillion if it helps people understand that this science is really an untried option in our war with bacteria.]

Nathan Sharon is a researcher who has been looking at this attachment for the past thirty years. One of his colleagues drew the following picture to show how it works:

In Zafriri's picture the bacteria are the happy ovals hanging on to the green sugar molecules and the unhappy ovals not hanging on. When an appropriate sugar is put into this environment the bacteria hold onto it and can't hang on to the sugar on the cell wall. In the original the bacteria were pictured as being unhappy (like the one at the top) if they were holding on to the sugar in solution rather than that on the bladder wall. If we can attribute emotions to bacteria I think that they are just happy holding on to sugar, wherever it is and edited the picture to make them so.

Sharon's search for means of interfering with bacterial adherence has been joined by many others, but has not been too well known. 

• Part of the reason for this lack of notoriety is that most of the sugars shown to have this effect are foods that cannot easily be classified as drugs. 

• If there was a way for the pharmaceutical industry to make money from these foods we would all know about it, but because they are foods they can't do that.  

• People would just buy the food sugar that would be less expensive, but accomplish the same thing as the "drug" sugar.

•  Some of these other, less well known, sugars are the subject of Dr. Emil Mondoa's recent book, Sugars that Heal. 

The bacterial lectin that we know the most about is that for mannose  on Escherichia coli. 

• This bacteria causes most urinary infections, in large part because the numerous mannose molecules on the wall of the bladder provide a place for these bacteria to hold on.

•  We should be able to block many of these infections just by putting mannose into this environment. 

• But anyone can buy mannose; it is not a drug, so no one is going to pay for clinical studies and without clinical studies few people know about the science. 

• Cranberry juice has been found to have similar effects and studies have been funded by  manufacturers such as "Ocean Spray", but mannose should be more effective because cranberry juice doesn't have much mannose. 

• It does have lots of fructose, which works the same way, but is only about a tenth as effective as mannose.

One researcher tried to get funding for such studies and finally got her department to fund a study using mannose to prevent infections in mares undergoing artificial insemination. 

• Because of the nature of this process there are a lot of infections in the mares. 

• Based on Sharon's work she felt this would be a good use of a benign sugar. 

• When she put mannose on cells from the lining of the mare's uteri the bacteria, both E. coli and another bacteria, Pseudomonas aeruginosa, were blocked from attaching to these cells. 

    She also found a side effect as she took the next step. This worked so well in the laboratory she mixed some mannose with the semen used to inseminate the mares. It worked here too because none of the mares got infected, but neither did any of them get pregnant. She found out what most fertility experts already knew: that the acrosome, the point at the head of the sperm that attaches to the egg in fertilizing it, is a mannose lectin. When she looked at this under her microscope she saw all of the sperm hanging on to the mannose that the bacteria were holding on to. They appeared to be sharing the mannose. This is something that we apparently share with horse because the human acrosome is also a mannose lectin. So if any of you young women are tired of pumping hormones into your bodies to prevent pregnancy you might try using some mannose in a small capsule prior to intercourse. This recommendation has not been tested on any other than Dr. King's horses because, of course, it won't make any money for anyone.

• Mannose works in people the same way it does in horses. We also have these mannose molecules on our cells, especially in the bladder, which is why these bacteria are the major cause of bladder infections.  

• Putting a specific sugars into the environment fills up the binding sites on the bacteria so that they cannot bind to the human cell.   

• Dr. Jonathan Wright is already recommending, as do I, that people who have chronic problems with urinary tract infections eat a teaspoon of mannose at least twice a day. 

• This sugar is not absorbed as well as glucose in the intestine, but both absorbed and non-absorbed mannose is effective. 

  • Of the absorbed mannose about a fifth is excreted in the kidneys. This mannose fills up the receptor sites on E. Coli so that these bacteria cannot bind to cells in the bladder.

  •   Mannose that is not absorbed can bind with strains of this bacteria in the GI tract

    • Since these infections all come from bacteria in the GI tract this gets them at their source.

    • Regular use of mannose changes the flora in the GI tract to bacteria that cannot cause UTI's

    • Other strains of E. coli, the good bacteria that help with digestion of our food, are not effected. 

• This effect was shown for cranberry and blueberry juice and Zafriri showed that this was due to the fructose that is in the cranberry juice. 

The fructose binds less strongly than does the mannose to these receptor sites, but it still reduced the adherence of the bacteria. The cranberry juice industry does not mention this decreased adherence as a reason for its use in preventing urinary infections. They credit the benefits to acidifying the urine which makes it less hospitable to bacteria and to substances in it that kill bacteria. These factors, however, cannot explain the results of the following study. 

The same Finnish researchers that looked at xylitol and ear infections looked at using cranberry lingonberry (similar to our blueberries) extract regularly in women with recurrent urinary infections.

•  It resulted in long term benefits that extended beyond the treatment period which can only be explained on the basis of bacterial change.  

  • This study was supposed to last for a year, but the company providing the extract went out of business after six months. 

  • The graph below is from the original article modified to show when the extract treatment ended.           

The only way to explain the presence of long-term benefits seen in a number of people is that the treatment led to changes in either the nature or the type of bacteria. And there is laboratory evidence that both happen. 

• When the adherence of bacteria is competitively blocked by local sugars fewer of the effected bacteria remain. So it is easy to see why the type of bacteria can change. 

• But the nature of bacteria can change as well. There are strains of E. coli that don't have these mannose lectins. When people eat mannose regularly these strains multiply, and they don't cause bladder infections.       

Xylitol has a similar effect on the bacteria causing tooth decay.

• Decay, as we saw in the section on xylitol, is caused by the acids made by bacteria on the teeth like S. mutans. 

• Luc Trahan showed that over a few generations, a day or so in the life of bacteria, this bacteria learned not to eat the xylitol in its environment; they became what he called xylitol resistant.

•  At the same time, however, something else changed, because the bacteria no longer caused tooth decay. 

I believe that xylitol acts in this way when we use it in the mouth and the nose. Oral use leads to fewer bacteria caused cavities and nasal use results in fewer upper respiratory problems. 

This is too good of a time not to insert an editorial comment.  Our grandmother 20 to 50 thousand generations ago, according to the reasonable conjecture of Rudyard Kipling, fed the wolf that was threatening her children cooked meat. The wolf liked the cooked meat and grandmother kept feeding it. But she had to feed it every day for a long, long time before the wolf became dog and man's best friend. As a society and culture we have concentrated on killing our enemies. We did it with the Indians, the Germans did it with the Jews, we did it with the Germans, as well as with our current al-Qaida enemies—just like we do with bacteria. What grandmother and these studies point out is that there is another way. Feeding our enemies has the potential to change them into friends.  Today we want to use bacteria to carry modified DNA into human cells so that we can try to cure genetic diseases like cystic fibrosis and diabetes. Bacteria, having transferred genetic material among themselves for over a billion years, are the undeniable experts. But attempts so far have resulted in the patients dying from the infection we introduced with the bacteria. Maybe we ought to make friends first.

Why do not people know about such sugars and their use to prevent infections? 

• One reason, specific for xylitol, is that it is not one of the sugars found on our cell surfaces, nor has there ever been found a lectin specific for xylitol.

• Xylitol has the advantage, however, of being very flexible so it is able to look like a part of many of the other sugars. 

  • The other sugars are all in a ring form and fixed. 

  • Xylitol is an open molecule and can bend and rotate so that it looks like parts of many other sugars. 

  • Just as Zafriri showed that fructose in cranberry juice could mimic mannose and impede the adherence of urinary bacteria, xylitol is able to mime many other sugars. 

  • We have already seen how it impairs the adherence of oral and nasal bacteria. It also blocks the adherence of the bowel pathogen Clostridium dificile. The chart below, from a study by Paul Naaber, shows how effectively it does this.   
    
     

The question of why these leads are not pursued more also has an economic angle. It's not profitable since the sugars are not patentable. 

Summary.

The faster people know about and use these alternatives the more successful we will be at preventing the spread of antibiotic resistance and reducing the overuse of antibiotics that is the primary cause of the problem. Antibiotics help individuals, but they don't help wars. As Lt. Gen. Yaalon said in our opening statement, "Our tactical decisions are hostile to our strategic interests." In countries such as Norway, where more attention is paid to strategic interests, both the use of antibiotics and bacterial resistance are lower. Bacteria learn resistance when they are challenged by the antibiotic and they do tend to forget when they are not. The best way to prevent antibiotic resistance is to use antibiotics much more judiciously. And one of the best ways to do that is to use these sugars to wash bacteria out so they don't cause problems in the first place.

Return to HOME            Read more about sugars and Intelligent bacteria

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References:

Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells.

Zafriri D, Ofek I, Adar R, Pocino M, Sharon N.

Department of Human Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Inhibition of bacterial adherence to bladder cells has been assumed to account for the beneficial action ascribed to cranberry juice and cranberry juice cocktail in the prevention of urinary tract infections (A. E. Sobota, J. Urol. 131:1013-1016, 1984). We have examined the effect of the cocktail and juice on the adherence of Escherichia coli expressing surface lectins of defined sugar specificity to yeasts, tissue culture cells, erythrocytes, and mouse peritoneal macrophages. Cranberry juice cocktail inhibited the adherence of urinary isolates expressing type 1 fimbriae (mannose specific) and P fimbriae [specific for alpha-D-Gal(1----4)-beta-D-Gal] but had no effect on a diarrheal isolate expressing a CFA/I adhesin. The cocktail also inhibited yeast agglutination by purified type 1 fimbriae. The inhibitory activity for type 1 fimbriated E. coli was dialyzable and could be ascribed to the fructose present in the cocktail; this sugar was about 1/10 as active as methyl alpha-D-mannoside in inhibiting the adherence of type 1 fimbriated bacteria. The inhibitory activity for the P fimbriated bacteria was nondialyzable and was detected only after preincubation of the bacteria with the cocktail. Cranberry juice, orange juice, and pineapple juice also inhibited adherence of type 1 fimbriated E. coli, most likely because of their fructose content. However, the two latter juices did not inhibit the P fimbriated bacteria. We conclude that cranberry juice contains at least two inhibitors of lectin-mediated adherence of uropathogens to eucaryotic cells. Further studies are required to establish whether these inhibitors play a role in vivo.

[Anti-bacterial defense mechanism of the urinary bladder. Role of mannose in urine].

[Article in Japanese]

Toyota S, Fukushi Y, Katoh S, Orikasa S, Suzuki Y

Bacterial adherence to mucosa is thought to be an initial and important stage to cause urinary tract infection. Among some mechanisms of bacterial adherence, the role of fimbriae and its receptor is worthy of notice. In particular, type 1 fimbriae, for which mannose is assumed as a receptor, is reported as the most common type and called "common fimbriae". Therefore if a certain amount of mannose is present in urine, it will cover the fimbriae of bacteria and competitively block the bacterial adherence to bladder mucosa. As the first step, we tried to detect mannose in urine by high performance liquid chromatography (HPLC). Sugar can be measured by detecting the fluorescence which is produced by a sugar separated by ion exchange, reacting with arginine at high temperature. The results using standard sugar samples should have highly stable retention time and concentration curve with the minimum detectable mannose concentration of 0.02 microgram. We investigated mannose in urine from 186 cases. Since the mannose peak was often masked by near unidentified peaks, the peak of mannose could be detected only in 80 cases and its concentration could be measured only in 24 cases. Mannose concentration in the urine of the 24 cases was between 2.6 and 108.7 micrograms/ml and in most of cases it was lower than 20 micrograms/ml. Secondary, we examined the possibility of a mannose in urine to prevent bacterial adherence to mucosa by the hemagglutination test using guinea pig erythrocytes and type 1 fimbriated E. coli.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 2576290, UI: 90172805             [See also Dr. Jonathan Wright's article on mannose and urinary tract infections online at http://www.tahoma-clinic.com/mannose.shtml  ]  

Use of specific sugars to inhibit bacterial adherence to equine endometrium in vitro.

King SS, Young DA, Nequin LG, Carnevale EM

Department of Animal Science, Food, and Nutrition, College of Agriculture and Science, Southern Illinois University, Carbondale 62901, USA.

OBJECTIVE: To determine whether specific sugars inhibit adhesion of Streptococcus zooepidemicus, Pseudomonas aeruginosa, and Escherichia coli to equine endometrial epithelial cells in vitro. SAMPLE POPULATION: Endometrial biopsy specimens collected during estrus from 7 healthy mares. PROCEDURE: Endometrial specimens on glass slides were incubated for 30 minutes at 4 C with suspensions of S. zooepidemicus, P. aeruginosa, or E. coli in phosphate-buffered saline solution (PBSS) alone or with various concentrations of D-(+)-mannose, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-(+)-glucose, galactose, or N-acetyl-neuraminic acid. Inhibition of bacterial adherence was determined by comparing adhesion of bacteria (i.e., percentage of glandular epithelial cells with adherent bacteria) suspended in each sugar solution with that of bacteria suspended in PBSS. RESULTS: Mannose and N-acetyl-D-galactosamine inhibited adhesion of E. coli and P. aeruginosa to epithelial cells, whereas only mannose inhibited adhesion of S. zooepidemicus. The other sugars did not affect bacterial adherence. CONCLUSIONS AND CLINICAL RELEVANCE: Mannose and N-acetyl-D-galactosamine appear to play a role in adhesion of S. zooepidemicus, P. aeruginosa, and E. coli to equine endometrium. In horses with uterine infections, use of sugars to competitively displace bacteria from attachment sites on cells may provide an adjunct to antibiotic treatment.

PMID: 10772112

J Exp Med 1988 Jul 1;168(1):267-77

Receptor analogs and monoclonal antibodies that inhibit adherence of Bordetella pertussis to human ciliated respiratory epithelial cells.

Tuomanen E, Towbin H, Rosenfelder G, Braun D, Larson G, Hansson GC, Hill R

Laboratory of Microbiology, Rockefeller University, New York, New York 10021.

The adherence of Bordetella pertussis to human respiratory cilia is critical to the pathogenesis of whooping cough. To explore the development of agents that could interrupt adherence, the structure of the receptor on the ciliary surface was investigated. Using an in vitro adherence assay to human ciliated epithelial cells, galactose, lactose, and complex carbohydrates containing lactose eliminated adherence when preincubated with the bacteria. 10(-2) M galactose eluted adherent bacteria from cilia. B. pertussis and its two purified adhesins bound specifically to natural lactose-containing glycolipids in a TLC assay. mAbs to eukaryotic glycoconjugates with specificity for substituted galactose-glucose moieties blocked adherence when preincubated with ciliated cells. The carbohydrates that serve as receptors for B. pertussis on human cilia are galactose-glucose-containing glycolipids. Receptor analogs and anti-receptor antibodies effectively block adherence of B. pertussis to cilia and thus should be considered candidates for therapeutic intervention against disease.