Non-nutritive food additives and C difficile infection

A recent study highlighted in an article in the 4/6/18 NY Times noted that the artificial sugar trehalose is associated with more virulent strains of C difficile (see file:///C:/Users/geoff/Downloads/The%20Germs%20That%20Love%20Diet%20Soda%20%20.pdf , as well as the article itself at cdiff virulence trehalose nature2018 in dropbox, or doi:10.1038/nature25178). thanks to paul susman for bringing this to my attention.

Details:

--C diff is an increasingly severe illness, now affecting about 1/2 million people/yr in the US, with 15,000 attributable deaths, >80% in those >65yo. 20% or patients experience a recurrent infection and 9% of those >65yo die. excess health care costs of $4.8 billion (see https://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html​ ). Deaths from C diff have increased 5-fold between 1999 and 2007

--2 C diff variants have been associated with highly virulent epidemic C diff infections: RT027 and RT078, as compared to less virulent strains (such as RT053)

--trehalose, also called mycose or tremalose, is a disaccharide composed to 2 molecules of glucose occurring naturally in mushrooms (esp shiitake, oyster, golden needle), yeast, and shellfish. it is broken down to glucose by trehalase in the brush border of the small intestine, but leads to lower increases in blood glucose levels than glucose itself. trehalose is used in ice cream/frozen foods to lower their freezing point. it is a non-reducing and extremely stable sugar, which is resistant to high temperatures and acid hydrolysis, and considered an "ideal sugar for use in the food industry"​:  it is added to processed foods to stabilize them, keep them moist on the shelf and improve texture. it is also used in fruit juices, cream cakes, and jams, as well as artificial tears.

--its use was delayed until a novel production process mitigated the high cost from prior production methods. ultimately it was approved by the FDA in 2000, as "generally recognized as safe"; also approved in Europe in 2001. Used in concentrations of 2%-11.25% for pasta, ground beef, ice cream.

--the development of outbreaks of both RT027 and RT078 strains of C diff coincided with the widespread use of trehalose.  it is also likely that fluoroquinolone resistance played a part in the spread of the RT027 strain (which is resistant to fluoroquinolones, so taking these antibiotics will give selection advantage to RT027 and RT078, the latter now becoming more important as a community-acquired CDI… more in the next blog)

--though there is a localized brush border trehalase enzyme, human studies have confirmed that eating lots of trehalose does lead to significant amounts reaching the distal ileum and colon. in mice, these levels of trehalose do induce the RT027, though not the less virulent RT053 strains of C diff. The first epidemic outbreaks were in 2003, non-epidemic outbreaks had occurred earlier.

--the RT027 strains have a single point mutation which increases its sensitivity to trehalose >500-fold

--lines of evidence supporting the role of trehalose in these more aggressive forms of C diff:

    --the ability of the RT027 and RT078 strains to metabolize trehalose was evident prior to the outbreaks

    ​--though the RT027 and RT078 strains converged in their ability to metabolize low levels of trehalose, these lineages are evolutionarily/phylogenetically distinct from each other (ie, these are 2 very different strains that evolved in distinct, separate ways, supporting the idea that it is these strains and not some common variation in these strains leading to increased C. diff virulence)

    --mouse models have documented the increased virulence of the RT027 and RT078 strains

    --there is a documented growth advantage of these strains in the presence of trehalose

    --humans ingesting normal diets have sufficiently high trehalose levels in ileostomy fluid to stimulate the RT027 strains.

--as the NY Times points out, there may well be an unfortunate convergence: hospitals, the highest reservoir for C diff, are probably regularly and repeatedly serving patients foods that contain trehalose (as well as lots of non-nutritive food additives, see below, which may not directly lead to short-term harm, but may be misinterpreted by patients as being "healthy" since they got them in the hospital).

Commentary:

so, this article brings up some really broad and difficult issues: there may be significant harm in many of the non-nutritive food ingredients, especially in processed foods. and these additives overall do not have much federal regulation, either for short-termor especially for long-term potential adverse effects.

--other blogs have looked at the adverse microbiome effects of non-nutritive sweeteners, which in fact may exacerbate obesity/diabetes, perhaps largely through microbiome changes. see http://gmodestmedblogs.blogspot.com/2017/01/artificial-sweeteners-microbiome1.html 

--Dietary emulsifiers, as used in mayonnaise or ice cream to preserve their homogeneous nature, may be another example of unexpected longterm detriment: one of the reasons that the bacteria in the gut do not penetrate the intestinal barrier and lead to disease is because of a protective mucous layer, which could be disrupted by emulsifiers (ie, detergents, such as carboxymethylcellulose and polysorbate-80). A trial in mice showed that these emulsifiers lead to low-grade inflammation, impaired glycemic control, obesity/metabolic syndrome, and colitis (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910713/ . On the other hand, diets rich in soluble fiber enhance the protective mucous layer.

--The polysaccharide maltodextrin, a highly processed​ highly digestible artificial sugar added to lots of foods as a thickener or preservative to extend shelf life, can lead to increased E coli adhesion, which has been hypothesized as a reason and mechanism for the heightened incidence of Crohn's disease (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520894/ )

--and, this study points out that it seems to be pretty common that we clinicians (and patients) jump on plausible mechanism (eg that these virulent C diff strains arise because of selective pressure by fluoroquinolones), though the story is often more complex: for decades it really did seem that we should avoid eating butter since it made sense that eating lots of saturated fats might exacerbate atherosclerotic heart disease.  it just turns out that trans fats (as in butter substitutes such as margarine) are the most potent atherogens in foods that we know... of that artificial sweeteners were okay for diabetics or overweight people

one issue here is that we may be missing the boat in simply targeting diet/exercise as ways to impact the increasing incidence of obesity/metabolic syndrome/etc. Perhaps the actual content of the added non-nutritional substances may be more the issue​, whether used as preservatives (eg trehalose, maltodextrin) or as ways to emulsify foods to make them more homogeneous with longer shelf-lives.  As Michael Pollan (Omnivore's Dilemma and other notable books) has commented "don't eat anything your great-great-great grandmother wouldn’t recognize as food".  i would add that some of these additives are unavoidable in the intensity of our lives, and fortunately, the microbiome is pretty forgiving: it does improve with increased vegetarian diet and exercise (and avoiding antibiotics). so, at this point the lifestyle goal, i think, is to reinforce how important it is to maximize these positive lifestyle changes of diet and exercise, while minimizing processed foods and artificial ingredients, in particular.