TY - JOUR
T1 - Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth
AU - Gillis, Caroline C.
AU - Hughes, Elizabeth R.
AU - Spiga, Luisella
AU - Winter, Maria G.
AU - Zhu, Wenhan
AU - Furtado de Carvalho, Tatiane
AU - Chanin, Rachael B.
AU - Behrendt, Cassie L.
AU - Hooper, Lora V.
AU - Santos, Renato L.
AU - Winter, Sebastian E.
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/1/10
Y1 - 2018/1/10
N2 - During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARγ agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection. Intestinal infection with Salmonella Typhimurium results in inflammation-induced dysbiosis. Gillis et al. demonstrate that depletion of commensal Clostridia reduces butyrate availability and subsequently alters host metabolism to produce lactate. Lactate oxidation by Salmonella enhances fitness in the gut and allows the pathogen to outcompete the microbiota.
AB - During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARγ agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection. Intestinal infection with Salmonella Typhimurium results in inflammation-induced dysbiosis. Gillis et al. demonstrate that depletion of commensal Clostridia reduces butyrate availability and subsequently alters host metabolism to produce lactate. Lactate oxidation by Salmonella enhances fitness in the gut and allows the pathogen to outcompete the microbiota.
KW - Salmonella
KW - gut microbiota
KW - host metabolism during infection
KW - host-microbe interaction
KW - microbial metabolism
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U2 - 10.1016/j.chom.2017.11.006
DO - 10.1016/j.chom.2017.11.006
M3 - Article
C2 - 29276172
AN - SCOPUS:85038815699
SN - 1931-3128
VL - 23
SP - 54-64.e6
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -