Yes We C(r)an(berry)!

That title is awful I know but I'm tired. Cut me some slack :)

 

I ran into a something that I have heard about before but assumed was rubbish and never really looked into it properly. A friend of mine insisted it was the case so I looked it up and I have to say, I was a little surprised.

So this is what cranberries look like. I never knew.

Cranberry juice is apparently very good at prevent urinary tract infection, particularly in women. There have been a few studies approaching it from different angles but, disappointingly, the studies all use different types of cranberry product, different doses and dosing techniques but despite all this the message seems to be pretty clear. Cranberries prevent urinary tract infections kicking in.

Before we can consider how this occurs its important to define what we are talking about. Urinary tract infections or UTIs are generally caused by a strain of Escherichia coli called Uropathogenic E. coli (UPEC) and it gets there by moving from the colon…ew. For this reason men rarely have to worry about them while they can be a chronic problem for women around the world, however the insertion of urinary catheters is a major risk factor for both genders. Clinical symptoms include burning sensation during urination and cloudy urine but these are only really evident once the bacteria have ascended the urethra into the bladder causing urethritis and cystitis respectively. If you want to feel real pain however let the little bastards work their way into your kidneys where kidney infection (or pyelonephritis) results in the above symptoms plus back pain and fever and the possibility of systemic spread.

So the first step in the infective process is generally stable colonisation of the colon. This step is often overlooked but without a source of UPEC it’s hard to get a proper infection going. The next step is invasion of the vaginal microbiota. Not an insignificant task since the vaginal niche is normally fully occupied by lactobacilli and other innocuous strains. Only once this has occurred can the UPEC ascend the urethra.

Having ascended the urethra the UPEC are not in the free and clear because the bladder and urethra have a formidable barrier to infection, the waterfall of flushing, cleansing urine that washes away all in its path. To overcome this UPEC have developed powerful adhesins, proteins used adherence of the bacterium to a surface and in this case specifically to the urinary epithelial tissue.

Adhesins are found in most pathogenic bacterial species but the array and strength of the UPEC adhesins is staggering. Among the most important adhesins produced by the UPEC are the pili. Pili are hair-like structures on the bacterial surface that are often capped with sticky (in the molecular sense) ends that facilitate adhesion. Importantly for UPEC possessing three different sticky caps (S, P and Type 1 pili) increases the chances of binding.

The S pili tend to be more important for adhesion outside of the gentio-urinary tract and so may play a part in systemic spread. In the urine however these pili bind the mannose filled protein uromodulin. Because of this S pili are called mannose sensitive pili and its thought that the ability to bind uromodulin, the most abundant protein in urine, possibly results in bacterial clumping and this allows a better opportunity for the P and Type 1 pili to do their thing. These two pili are responsible for the binding in the urethra and bladder.

Initially the Type 1 pili bind mannose sugars on the surface of the bladder cells allowing the bacteria to get some traction on the bladder/urethra walls before the P pili bind to a different sugar group to cement the interaction. The ability of P pili to bind non-mannose sugars has earned them the alternative title mannose resistant pili whereas type 1 pili are grouped with the mannose sensitive S pili.

The pili are the hairy bits on the picture of E. coli. The paper this pic is from is referenced at the bottom.

Once adhered to the host surface the UPEC can invade the epithelial cells but the bladder’s defence against this is to kick those invaded cells into the urine. A good defence strategy but it may contribute to tissue damage in the urinary tract when infections are recurrent. Also it seems some bacteria can prevent this expulsion of the cell they have invaded and in doing so remain as a reservoir of infection out of the way of the immune system and most antibiotic treatments.

Invasion does not always occur and instead some UPEC strains are able to release toxins directly onto the host epithelial surface due to the close interaction between bacterium and host. These toxins, as well as one of my boss’s favourite little molecules lipopolysaccharide (LPS) cause the inflammation that goes with the UTI.

So that’s the UTI side of things but where does Cranberry juice come into this story?

Cranberries (Vaccinium macrocarpon if you don’t mind) together with blueberries and Concord grapes constitute the only native fruit species to the US and Canada. Bet you didn’t know that, or maybe you did but I didn’t. In any case often the best way to work out what the native flora is capable of you have to look back to the indigenous peoples and, surprise surprise, Native Americans have known about and utilised the medicinal properties of cranberries for many years. Commonly used in different preparations to treat blood disorders, stomach issues, liver trouble and fevers.

By the 1880’s people were trying to work out what was doing what with cranberries and some German researchers found benzoic acid in cranberries. Then as now it was known to be a potent antiseptic and was included in a number of medicines and topical anti-bacteria treatments. This observation set researchers down the wrong path from the get go as the real power of cranberries lies in other activities of other compounds.

Continuing research into the antibacterial properties of cranberries found the benzoic acid was converted to hippuric acid, another antibacterial agent that also has a role in acidifying the urine. Everyone thought they were onto a winner. A powerful antibacterial compound excreted in the urine because you ate some cranberries. This is open and closed right? Well…

Could I be any clearer?

Some very smart research burst the bubble. Bodel et al. showed that even the consumption of a litre of cranberry juice mix (side note – straight cranberry juice tastes horrible, most ‘juices’ only contain 20 - 30% juice and the rest is water and sugar) barely acidified the urine at the detected hippuric acid concentrations were too low to be relevant. In fact it was subsequently shown that, as benzoic acid constitutes <0.1% of the weight of a cranberry in excess of 4 L/day every day of a strong cranberry juice mix would have to be consumed to have any antibacterial effect There had to be something else going on.

Sobota et al. suggested an alternative in 1984. In order to prevent a UTI you don’t have to kill all incoming bacteria, simply preventing them from attaching would also prevent UTIs developing. Using clinical E. coli isolates they were able to show cranberry juice impaired adherence in the majority of strains. Once on the right track research moved quickly. It could be shown that it was the mannose sensitive and mannose resistant pili that were being inhibited, preventing adherence and therefore UTIs. Cranberry juice contains at least two compounds capable of inhibiting adhesion. Being high in fructose allows for inhibition of the mannose sensitive type 1 and S pili and another product, apparently unique to Vaccinium sp. berries is proanthocyanidin, which inhibits the mannose resistant adhesins.

Some really interesting work has shown that the consumption of ‘normal’ amounts of cranberry juice has an anti-adherent effect as soon as 2 hours post consumption and will last approx 10 hours!

Unfortunately from this point onwards it gets a little cloudy. A consensus on mode of dose (pills or juice) and size of dose has not been established which makes it very hard to determine what the best course of action is. What is becoming clearer is that consuming as strong a cranberry juice as you can tolerate on a regular basis will help to prevent UTIs. It seems to be particularly useful in helping those that suffer recurrent UTIs and the literature seems to suggest it could be heavily utilised in women 10 – 35 years old as a background passive type defence against UTI.

I don’t know if it still works when made up like this but does anyone else feel like a vodka cranberry?

References
Raz, R., Chazan, B., & Dan, M. (2004). Cranberry Juice and Urinary Tract Infection Clinical Infectious Diseases, 38 (10), 1413-1419 DOI: 10.1086/386328

Gross, L. (2006). Bacterial Fimbriae Designed to Stay with the Flow PLoS Biology, 4 (9) DOI: 10.1371/journal.pbio.0040314

BODEL PT, COTRAN R, & KASS EH (1959). Cranberry juice and the antibacterial action of hippuric acid. The Journal of laboratory and clinical medicine, 54, 881-8 PMID: 13801916

Sobota AE (1984). Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. The Journal of urology, 131 (5), 1013-6 PMID: 6368872