Long chain acyl CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates preabsorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid preabsorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs preabsorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat fed rodents restores Lactobacillus gasseri levels and fatty acid sensing via increased ACSL3 expression, while Lactobacillus gasseri probiotic administration to non-transplanted high-fat fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing.

In summary, we unveil a glucoregulatory role of upper small intestinal Lactobacillus gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid sensing pathway.


P.V. Bauer: None. F. Duca: None. T. Waise: None. H.J. Dranse: None. B.A. Rasmussen-Small: None. A. Puri: None. M. Rasti: None. T.K.T. Lam: None.

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