Jen Pluznick Dept Physiology Johns Hopkins Univ School of Medicine Novel Sensory Receptors in Non Sensory tissues Taste receptors and olfactory receptors play important roles in ID: 175327
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Slide1
Can your gut microbiota affect your blood pressure?
Jen Pluznick
Dept. Physiology, Johns
Hopkins
Univ. School of MedicineSlide2
Novel
Sensory Receptors in ‘Non-
Sensory’ tissues
Taste receptors and olfactory receptors play important roles in:
Airway smooth muscleBladderSpinal columnSkeletal muscleGI tract Sperm (Nature Medicine 2010; J Urology 2011, Nature Letters 2006, Developmental Cell 2009; J Cell Science 2004, Science 2003; Gastroenterology 2007)
What about the kidney?Slide3
Novel
Sensory Receptors in ‘Non-
Sensory’ tissues
Olfactory Receptor 78 (Olfr78) in the kidney and
blood pressure regulationSlide4
Spoiler Alert: Olfr78, Blood Pressure…and the Microbiome
The Economist,
Microbes
M
aketh Man, Aug. 2012Olfactory Receptor 78 (Olfr78) in the kidney and blood pressure regulationSlide5
Viruses, Fungi, and Bacteria…oh, my!
Marsland
and
Gollwitzer
, Nature Reviews 2014Slide6
Microbiota and Host Physiology: an emerging field
1051 articles thus far in 2015Slide7
Microbiota and Host Physiology:
what we do know vs. what we don’t knowMicrobial cells outnumber human cells by 10:1.
Microbial genes outnumber human genes by 100:1.
Gut microbiota have been implicated in pathophysiological processes as varied as: immune disorders, atherosclerosis, irritable bowel syndrome,
coilitis, obesity, type II diabetes, susceptibility to type I diabetes, metabolic syndrome, susceptibility to HIV infection, chronic kidney disease… (references: too many to cite!)We are just beginning to understand the implications of the microbiota, let alone the mechanisms underlying these interactions.Slide8
One olfactory receptor expressed in the kidney is Olfr78 (PNAS 2009).
What is the physiological role of Olfr78?
Where is Olfactory Receptor 78 localized? What is Olfactory Receptor 78 “smelling”? Olfr78 in the KidneySlide9
Olfr78
localizes to cell types important in blood pressure regulation.
Olfr78: localization
renal afferent arteriole (100X)
vSMCs in resistance beds (diaphragm, 4X)Slide10
What is the physiological role of Olfr78?
Where
is Olfactory Receptor 78
localized? Cells which play important roles in blood pressure regulation. What is Olfactory Receptor 78 “smelling”? Olfr78 is an “orphan receptor” – no known ligand! Olfr78 in the KidneySlide11
Olfr78: a receptor for short chain fatty acids (SCFAs)
Are SCFAs in plasma? What is their source?
Identified
acetate
and propionate as ligands for Olfr78
and its human ortholog (hOR51E2) Slide12
Short Chain Fatty Acids (SCFAs)
come from the
gut microbiota!
SCFAs
Activates Olfactory Receptor 78Slide13
SCFAs modulate blood pressure via Olfr78Slide14
….and via another receptor called Gpr41
Gut Microbiota
SCFAs
↓Blood Pressure
Gpr41Peripheral VasculatureSlide15
↑Renin
Angiotensin I
Angiotensin II
Angiotensinogen
ACE
Gut Microbiota
SCFAs
~Blood Pressure
Gpr41
Olfr78
Olfr78
JGA
Peripheral Vasculature
Together, Olfr78 and Gpr41 modulate blood pressure controlSlide16
Blood Pressure and Hypertension
Incidence: 29% of American Adults have high blood pressure or ‘hypertension’ (CDC)
Hypertension costs the US $46 billion/year in health services, medication, and missed work. (CDC)
Another 1/3 of American adults are “
prehypertensive’ (CDC)~95% of hypertension patients have “essential hypertension” – hypertension with no known causeGenes? Salt intake? Vitamin D? Stress? Obesity? Alcohol? Combination of different factors?There is a need to better understand causes and contributing factors: perhaps there is a role for gut microbiota?Slide17
Is there evidence that microbial SCFAs affect BP regulation?
Dysbiosis (changes in the gut microbiota) has been noted in two rat models of hypertension, and in a small cohort of human patients (Hot off the press! published March 31, 2015 and April 13, 2015)
In humans:
An increase in dietary fiber intake (which leads to elevated SCFA production) decreases BP
A meta-analysis of randomized controlled trials found that probiotic use (which elevates SCFA production) was associated with lowered blood pressureIn a population of >4,000 humans from Asia and Europe, lower urinary levels of formate (an SCFA produced by gut microbiota) are correlated with higher BPFuture studies needed!Slide18
Blood Pressure Control is Complex!!
AC Guyton 1972Slide19
Conclusion
SCFA activation of Olfr78 and Gpr41 represents a novel crosstalk pathway through which colonic bacteria can modulate blood pressure control.
The Economist,
Microbes
Maketh Man, Aug. 2012Slide20
Acknowledgements
Johns Hopkins
Niranjana
Natarajan
Blythe ShepardVictoria HalperinPrem Rajkumar Will AisenbergOmar AcresRyan ProtzkoDan BerkowitzNick FlavahanCindy SearsDan PetersonThank you!
YaleMichael
Caplan
Tong
Wang
Anne Eichmann
Jinah
Han
USC
(78 mice)
Janos
Peti-Peterdi
Arnold
Sipos
Haykanush
Gevorgyan
Columbia
(
OR
Signaling)
Stuart Firestein
Zita
Peterlin
Wash U.
(41 mice, microbiota)
Jeffrey Gordon
Federico Rey
UT-Southwestern
(41 mice)
Masashi
Yanagisawa
Funding
: NIH-NIDDK,
ASN Gottschalk,
AHA (to NN), JHU GI Core Center