troubling microbiome changes

A couple of recent studies have found very troubling microbial changes, one dealing with the effect of PPIs on the gut microbiome, the other with the evolution of a very serious development in antibiotic resistance.

1. I sent out a blog in December 2014 on use of PPIs (proton-pump inhibitors) and changes in the microbiome (see http://gmodestmedblogs.blogspot.com/2014/11/gastric-acid-suppression-and-microbiome_23.html  ), which noted that gastric acid suppression (mostly with PPIs) in kids led to pretty profound changes in both the lung and gut microbiomes. Another study just came out looking at the PPI-associated gut microbiome changes in adults, which could predispose people to C. difficile infections (see ppi microbiome gastro2015 in dropbox, or Gastroenterology 2015;149:883). details:

--background: C diff infections happen more often in those on PPIs. There are data showing that increases in gut Enterococcaceae and Streptococcaceae and decreases in Clostridiales taxa are associated with increased risk of subsequent C diff infections in hospitalized patients, with infections related to later use of NSAIDs and antibiotics, esp cephalosporins or fluoroquinolones (see J Infect Dis 2010; 202 (12): 1877). The relationship with NSAIDs is new to me, but there may be direct effects on the microbiome perhaps through decreased inflammatory response and increased proliferation of certain bad microbes including C diff.

--open-label cross-over study of 12 healthy volunteers, none of whom had taken antibiotics in the past year or had baseline C diff in their stool (small study, but the cross-over design adds more credibility, though no comment overall on the volunteers in terms of other meds, diet, exercise... all of which could affect the baseline microbiome)

--assessed 2 baseline stool samples, 4 weeks apart, then volunteers took omeprazole 40mg bid and collected stool sample at week 8. 6 subjects took the PPI for an additional 4 weeks and had another stool sample then checked at week 12.

--results:

    --no significant difference in the individual patients' gut microbiome diversity comparing baseline and on-medication samples

    --but: there were differences in the actual taxa in the gut, which are associated with C difficile infections (Enterococcaceae and Streptococcaceae were increased, Clostridiales decreased), as well as taxa associated with GI bacterial overgrowth (increased Micrococcaceae and Staphylococcaceae)

    --functional analysis showed not changes in bile acids when on PPIs, but there was an increase in genes involved in bacterial invasion (especially Staph aureus) and the renin-angiotensin system

    --not much difference in the microbiome at 12 weeks in those who continued the PPI vs those stopped at week 8.

so, as i mentioned in the 2014 blog, there are several infections that seem to be increased with PPI use:  C diff, but also community-acquired pneumonia, and likely campylobacter and salmonella (as well as other non-infectious problems, including malabsorption of magnesium, vit B12, iron, calcium-- and some studies finding decreased bone density and increased fracture risk; and also more atrophic gastritis, which may be a cancer precursor, esp in those with concurrent H Pylori infections). the important issue here is that our medical interventions typically have wide-spread collateral effects in the body, and for PPIs in particular, we should use them sparingly and step-down therapy to less potent agents as soon as we can do so clinically.  This small study, by finding a reasonable putative mechanism for C diff through adverse changes in the microbiome, further supports this approach.

for other blogs on the microbiome, see: http://blogs.bmj.com/ebm/category/microbiome/ 

2. another very, very concerning article hit the popular press regarding polymixin-resistance likely related to use of antibiotics in meat production in China. This resistance was transferred to humans through a plasmid (see antibiotic resistance colistin china lancetinfdis2015 in dropbox, or doi.org/10.1016/S1473-3099(15)00424-7). China is the world's largest producer of poulty and pig products and one of the largest veterinary users of colistin. details:

--background: prior polymixin resistance has involved chromosomal mutations. colistin (aka, polymixin E) is an old antibiotic, but has not been used much because of the advent of aminoglycosides which have fewer adverse effects. But, colistin is now being used for panresistant infections such as Pseudomonas, Acinetobacter spp. and in carbapenem-producing Enterobacteriaceae. Until this study, colistin was not known to spread from cell-to-cell (eg, as by a plasmid)

--on routine surveillance of animals, they found a pig with an E coli strain with colistin resistance which could be transferred to another strain through possible plasmid-mediated polymixin resistance

--polymixin resistance could be transferred in vivo to mice

--plasmids were then found in 78 of 523 samples of raw pig meat (15%) and 166 of 804 pigs (21%) during 2011-14

--AND, they found plasmid-induced colistin resistance in 16 of 1322 samples from inpatients with infections!! (4 from urine, 3 from sputum, 3 from drainage fluid, 3 from ascitic fluid, 2 from bile and 1 from a wound)

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so, this is rather profound. we have lived in a prolonged era of of effective antibiotics, with the ability to treat almost all bacterial infections and to keep up with the emergence of resistant strains. Much of the issue of antibiotic resistance is attributable to the wanton and extensive veterinary use of antibiotics. it seems that the little microbes are pretty adept at keeping ahead of us, but unless we can stop both the excessive routine veterinary use of antibiotics as well as our overprescribing them (and their easy availability without prescription in many countries), it is unclear that we will be able to continue to catch up with the increasing resistance. in this Chinese case, the prior mechanism of polymixin resistance (chromosomal changes) has evolved into a spreadable, plasmid-mediated one, and this is happening in an antibiotic of last resort for some infections.

see http://gmodestmedblogs.blogspot.com/search/label/antibiotic%20resistance for a large number of blogs on this, incluing the WHO report and a US White House report.  (ie, there are lots of concerns around the world on this. at this point the issue is not one of knowledge but one of action.)