Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates.
The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Madhu S
MS
Malo
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Omeed
O
Moaven
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Nur
N
Muhammad
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Brishti
B
Biswas
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Sayeda N
SN
Alam
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Konstantinos P
KP
Economopoulos
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Sarah Shireen
SS
Gul
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Sulaiman R
SR
Hamarneh
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Nondita S
NS
Malo
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Abeba
A
Teshager
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Mussa M Rafat
MM
Mohamed
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
Qingsong
Q
Tao
Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California;
Sonoko
S
Narisawa
Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California;
José Luis
JL
Millán
Infectious Disease Unit, Departments of Pediatrics and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
Elizabeth L
EL
Hohmann
Infectious Disease Unit, Departments of Pediatrics and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
H Shaw
HS
Warren
Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Simon C
SC
Robson
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; rhodin@mgh.harvard.edu.
Richard A
RA
Hodin
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D003854:Deoxyribonucleotides / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D005243:Feces / Q000382:microbiology; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020613:Morganella morganii / Q000187:drug effects; D010649:Phenylalanine / Q000494:pharmacology; D013217:Starvation / Q000503:physiopathology; D013307:Streptomycin / Q000494:pharmacology
D003854:Deoxyribonucleotides; D010649:Phenylalanine; D000667:Ampicillin; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase; D013307:Streptomycin
CpG DNA; dysbiosis; flagellin; gut flora; intestinal loop model; lipopolysaccharides; microbiotal homeostasis