Fructose malabsorption induces dysbiosis and increases anxiety in male human and animal models
Brain, Behavior, and Immunity. 2025-12-01; : 106221
DOI: 10.1016/j.bbi.2025.106221
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https://www.bordeaux-neurocampus.fr/12412
1. Brain Behav Immun. 2025 Dec 17:106221. doi: 10.1016/j.bbi.2025.106221. Online
ahead of print.
Fructose malabsorption induces dysbiosis and increases anxiety in male human and
animal models.
Coursan A(1), Polve D(2), Leroi AM(3), Monnoye M(4), Roussin L(4), Benatar C(4),
Tavolacci MP(5), Muraine MQ(6), Maccarone M(7), Guérin O(8), Houivet E(8),
Guérin C(9), Brunel V(10), Bellenger J(11), de Barros JP(12), Gourcerol G(3),
Naudon L(4), Layé S(1), Madore C(1), Fioramonti X(13), Melchior C(14), Douard
V(15).
Author information:
(1)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux,
France.
(2)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux,
France; Université Paris-Saclay, INRAE, AgroParisTech, MICALIS Institute,
Jouy-en-Josas, France.
(3)Univ Rouen Normandie, INSERM, ADEN UMR1073, Nutrition, Inflammation and
microbiota-gut-brain axis, France; CHU Rouen, CIC-CRB 1404, F-76000 Rouen,
France; CHU Rouen, Physiology Department, F-76000 Rouen, France.
(4)Université Paris-Saclay, INRAE, AgroParisTech, MICALIS Institute,
Jouy-en-Josas, France.
(5)Univ Rouen Normandie, INSERM, ADEN UMR1073, Nutrition, Inflammation and
microbiota-gut-brain axis, France; CHU Rouen, CIC-CRB 1404, F-76000 Rouen,
France.
(6)Univ Rouen Normandie, INSERM, ADEN UMR1073, Nutrition, Inflammation and
microbiota-gut-brain axis, France; CHU Rouen, CIC-CRB 1404, F-76000 Rouen,
France; CHU Rouen, department of General Biochemistry, F-76000 Rouen, France.
(7)CHU Rouen, Department of Gastroenterology, F-76000 Rouen, France.
(8)CHU Rouen department of Biostatistics, F-76000 Rouen, France.
(9)Univ Rouen Normandie, INSERM, ADEN UMR1073, Nutrition, Inflammation and
microbiota-gut-brain axis, France.
(10)CHU Rouen, department of General Biochemistry, F-76000 Rouen, France.
(11)LipSTIC LabEx, FCS Bourgogne-Franche Comté, Dijon, France.
(12)LipSTIC LabEx, FCS Bourgogne-Franche Comté, Dijon, France; Plateforme
DiviOmics, UMS BioSanD 58, Université de Bourgogne, F-21000 Dijon, France.
(13)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux,
France. Electronic address: .
(14)Univ Rouen Normandie, INSERM, ADEN UMR1073, Nutrition, Inflammation and
microbiota-gut-brain axis, France; CHU Rouen, CIC-CRB 1404, F-76000 Rouen,
France; CHU Rouen, Department of Gastroenterology, F-76000 Rouen, France.
(15)Université Paris-Saclay, INRAE, AgroParisTech, MICALIS Institute,
Jouy-en-Josas, France. Electronic address: .
Excessive fructose intake is a growing public health concern, yet many
individuals have a limited capacity to absorb typical dietary levels, leading to
chronic fructose malabsorption and intestinal spillover. In animal models, this
spillover disrupts the gut microbiota, but its impact in humans remains
unexplored. We hypothesized that fructose malabsorption-induced dysbiosis
contributes to peripheral inflammation, which, together with neuroinflammation,
plays a role in mood disorders. This study investigates the link between
fructose malabsorption, gut microbiota, and mood disorders in a human cohort,
and explores their association with neuroinflammation in a GLUT5 knockout mouse
model of fructose-malabsorption. In a human cohort of male healthy volunteers,
fructose malabsorption was assessed using a breath hydrogen test, while plasma
lipopolysaccharide (LPS), IL8 and TNFα levels and anxiety traits (measured using
the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota
composition was characterized through 16S rRNA sequencing, and dietary fructose
intake was recorded. In the preclinical study, Glut5-KO male mice, which lack
intestinal fructose transport, were fed a 5% fructose diet for four weeks.
Behavioral assays assessed anxiety- and depressive-like behaviors, while gut
microbiota composition and microglia-associated gene expression were analyzed.
Sixty % of volunteers exhibited fructose malabsorption, along with elevated
plasma LPS, IL8 and TNFα levels, increased anxiety traits on the STAI, and
distinct gut microbiota alterations, partially linked to fructose intake
patterns. The average daily fructose intake was 30 g per individual, with
significant variability in dietary sources. In the preclinical model, Glut5-KO
mice on a 5% fructose diet displayed increased anxiety- and depressive-like
behaviors, pronounced gut microbiota shifts, and altered expression of
microglia-associated genes. These findings highlight the complex interplay
between dietary fructose, gut microbiota, low grade inflammation and
neuroinflammation in shaping mental health. Chronic fructose malabsorption may
contribute to mood disorders through gut dysbiosis and microglia-dependent
neuroinflammation, warranting further investigation into dietary interventions.
Copyright © 2025. Published by Elsevier Inc.
DOI: 10.1016/j.bbi.2025.106221
PMID: 41418890
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.