Proton Pump Inhibitors are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. These findings describe a significant impact of PPI on the gut microbiome and should caution overuse of PPI.

1. Proton Pump Inhibitors,
Microbiota and Bones
Fabio Piccini MD PhD
CoCo

2. From bacteriology to prokaryotology
• 1684. Van Leeuwenhoek discovers bacteria
• 1864. Pasteur resolves the issue of spontaneous generation
of diseases
• 1884. Kock postulates 4 criteria designed to establish a
causative relationship between a microbe and a disease
• 1958. Freeman wins a Nobel Prize in Human Physiology for
his discoveries concerning genetic recombination and the
organization of the genetic material of bacteria
• 1963. Watanabe demonstrates the links between bacterial
plasmids and antibiotic resistance
• 1977. Woese classifies Archea as a separate domain of life
within the phylogenetic tree of life
• 2007. NIH launches the Human Microbiome Project

3. Things you must know about
prokaryotes
• Prokariotes are ancient but not primitive highly specialized
and standardized cells which show an amazing capacity and
tendency to collaborate among themselves
• Most of them live in close association with each other in
mutualistic mixed groups practicing an effective division of
labour
• When advantageous or necessary these communities can
easily modify the mixture of their cells replacing some strains
with others drawn from the prokayotic giant reserve of cells
• Extreme adaptability allows prokaryotes to react and adjust
quickly and opportunistically to the changes around them
• The prokaryotic world behaves as a superorganism of
elements capable of solidarity

4. New concepts and hypoteses
• We are not alone
• The prokaryotic super
organism as a unique type of
clonal entity (there are no
prokaryotic species)
• Bacteria-host coevolution
• Human gut as an evolutionary
accelerator
• Microbiome as a second
human genome
• Gut microbiome as a human
(transplantable) organ
• Gut microbiome as a
therapeutic target

5. Glossary
• Microbiota: the ecological
community of commensal,
symbiotic and pathogenic
microorganisms that share
our body space
• Microbiome: the totality of
microorganisms and their
collective genetic material

6. Main functions of bacteria in the gut
• Bacteria play an important role in the
development and training of the
immune system
• Bacteria provide pathogens
colonization resistance
• Bacteria protect against epithelial
injury
• Bacteria promote angio-genesis
• Bacteria break down food
compounds and sythesize vitamins
and amino acids
• Bacteria modulate bone mass density
• Bacteria control fat storage
• Bacteria modify the CNS
• Bacteria metabolize therapeutics into
active compounds
Debby Laukens, Brigitta M. Brinkman, Jeroen Raes, Martine De Vos,
Peter Vandenabeele, Birgitta Henriques Normark; Heterogeneity of
the gut microbiome in mice: guidelines for optimizing experimental
design. FEMS Microbiol Rev 2015; 40 (1): 117-132. doi:
10.1093/femsre/fuv036

7. What affects gut microbiome?
• Mode of delivery
• Age
• Gender
• Diet
• Environment
• Pets
• Alchool consumption
• Workout routines
• Drugs
Arrieta M-C, Stiemsma LT, Amenyogbe N, Brown EM and Finlay B
(2014) The intestinal microbiome in early life: health and disease.
Front. Immunol. 5:427. doi: 10.3389/fimmu.2014.00427

8. About PPIs
• PPIs have established clinical efficacy for many health
conditions including gastroesophageal reflux, eosinophilic
esophagitis and acid hypersecretory conditions
• Since they are effective and are believed to be benign PPIs
have gained widespread use
• PPIs are among the 3 drug classes by sales in the world
• Esomeprazole was the 4th most prescribed drug by sales in
the USA in 2012
• Over half of all inpatients who receive PPIs do not have an
appropriate indication for the drugs and among these
patients over one third are discharged on PPIs
• Among outpatients 80% of PPIs prescriptions are repeats
and 40 to 50% are for non specific abdominal pain

9. Can there ever be too much of a good
thing?

10. Impact of PPIs on the gut microbiome
• Potent gastric acid suppression using PPIs is
common in clinical practice
• PPIs have important effects on human health
that are mediated through changes in the
gastrointestinal microbiome
• Acting through pH-dependent or pH-
independent mechanisms PPIs alter the
normal mcrobiota throughout the
gastrointestinal lumen

11. Bacteria affected by PPIs
Freedberg DE, Lebwohl B, Abrams JA. The impact of proton pump inhibitors on the
human gastrointestinal microbiome. Clinics in laboratory medicine. 2014;34(4):771-
785. doi:10.1016/j.cll.2014.08.008.

12. How the gut microbiome affects
distant organs
Hernandez, C. J., Guss, J. D., Luna, M. and Goldring, S. R. (2016), Links Between the Microbiome and
Bone. J Bone Miner Res, 31: 1638–1646. doi:10.1002/jbmr.2887

13. PPIs microbiome and bone
• The human microbiome has been shown to influence a number of
chronic conditions associated with impaired bone mass and bone
quality including obesity, diabetes, and inflammatory bowel disease
• The few studies available demonstrate that the microbiome can
have a large effect on bone remodeling and bone mass
• How the microbiome can affect organs distant from the gut is not
well understood but is believed to occur through regulation of
nutrition, regulation of the immune system, and/or translocation of
bacterial products across the gut endothelial barrier
• Since we know that lower limb metaphyseal bone is lost in men
with celiac disease and that PPIs may be a risk factor for celiac
disease this could be a possible mechanism for increased risk of
fracture associated with treatment

14. PPIs indications reviewed in Cochrane meta-
analysis
Mössner J. The Indications, Applications, and Risks of Proton Pump Inhibitors: A Review After 25 Years. Deutsches Ärzteblatt
International. 2016;113(27-28):477-483. doi:10.3238/arztebl.2016.0477.

15. Current indications to long term use of
PPIs
• Refractory gastroesophageal reflux disease
• Barrett’s esophagus disease
• Zollinger-Ellison syndrome
• Idiopathic chronic ulcer
• Bleeding prevention in selected patients

16. Summary
• PPIs are highly effective treatment for acid-related disorders but are widely
overused
• PPIs alter the human microbiome throughout the gastrointestinal tract with
important consequences on human health
• The ability of PPIs to heal erosive esophagitis and slow progression of Barrett’s
esophagus may be partly mediated by PPI-related decreases in gram-neg bacteria
• In the stomach PPIs have a chemopreventive effect if used for eradication of H.
Pylori, yet contribute to gastric dysbiosis if given after the H. Pylori is eradicated
• In the small bowel PPIs may cause diarrhea through bacterial overgrowth and may
be a risk factor for celiac disease
• In the large bowel PPIs have been associated with C. Difficile infection although
the mechanism remains unclear
• Literature analysis of PPI use and bone fractures revealed conflicting results but
the reported increased risk for hip fracture linked to long term PPIs use may also
be related to microbiome alterations
• As a matter of fact further research is needed to determine the effect of PPIs on
gastrointestinal microbiome and on human health

17. Thank you for attention
f.piccini@univpm.it