Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity
Open accessAbstract
Background The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice.Methods Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses.Results The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in α- and β-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis.Conclusions Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.
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Both the obese phenotype and anxiodepressive behaviors are transmissible by transplanting gut microbiota of diet-induced obese mice to normal-weight, germ-free mice.
“Notably, both the obese phenotype [73] and anxiodepressive behaviors [74] are transmissible by transplanting gut microbiota of DIO to normal-weight, germ-free mice.”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [73]
Microbiota from diet-induced obese mice can weaken endothelial tight junctions and trigger inflammation in both intestine and brain and promote brain insulin resistance.
“Moreover, the microbiota from DIO mice can weaken endothelial tight junctions and trigger inflammation in both intestine and brain and promote brain insulin resistance [73,74].”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [73]
Mice colonized with GM from donors fed a high-fat diet show compositionally distinct microbiota, altered biochemical markers, and impairments in exploratory, cognitive, and stereotypical behaviors without significant body weight differences.
“Mice colonized with GM from donors fed a high-fat diet demonstrated compositionally distinct microbiota, altered biochemical markers, and developed impairments in exploratory, cognitive, and stereotypical behaviors, in the absence of significant differences in body weight (516).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [516]
Disrupted barrier function could facilitate translocation of bacterial metabolites and immune mediators from the gut into circulation, which could lead to activation of microglia as seen in an induced dysbiosis mouse model.
“disrupted barrier function could facilitate the translocation of bacterial metabolites and immune mediators from the gut into circulation (Fig. 1), which could lead to activation of microglia as seen in an induced dysbiosis mouse model [40].”
From The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders (2018) · cites this paper as [40]
Dysbiosis introduced in conventionally housed adult mice leads to abnormal behaviors, altered barrier functions, and activation of microglia.
“In addition, dysbiosis introduced in conventionally housed adult mice also leads to abnormal behaviors, altered barrier functions, and activation of the microglia, the resident immune cells of the brain [40].”
From The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders (2018) · cites this paper as [40]
Transferring microbiota from mice fed a high-fat diet to conventional mice resulted in altered behavior and increased neuroinflammation even when the recipient mice were fed a normal chow diet.
“Additionally, transferring microbiota from mice fed a high-fat diet to conventional mice resulted in altered behavior and increased neuroinflammation even when the recipient mice were fed a normal chow diet (518).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [518]
Various behavioral phenotypes can be transferred by FMT, including anxiety-like behavior and aspects of depressive symptomatology, suggesting that gut microbiota are key components of regulating anxiety and depression.
“Such studies have found that various behavioral phenotypes can be transferred by FMT, including anxiety-like behavior and aspects of depressive symptomatology, suggesting that gut microbiota are key components of regulating anxiety and depression”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Bruce-Keller et al., 2015
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- Authors
- Bruce-Keller, A. J., Salbaum, J. M., Luo, M., Blanchard, E., Taylor, C. M., Welsh, D. A., & Berthoud, H.-R.
- Affiliations
- Pennington Biomedical Research Center (US)
- Louisiana State University Health Sciences Center New Orleans (US)
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 77
- Issue
- 7
- Pages
- 607-615
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4297748
- OpenAlex
- W2087084954
- Cited by
- 563
- References
- 65
- Citations by year
- 2026: 25 · 2025: 33 · 2024: 65 · 2023: 41 · 2022: 60 · 2021: 60 · 2020: 70 · 2019: 50 · 2018: 43 · 2017: 42 · 2016: 46 · 2015: 25 · 2014: 3
- FWCI
- 15.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK047348, P20-RR021945, P30-DK072476, P60-AA009803)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- gut microbiota, obesity, neurobehavioral abnormalities, high-fat diet, microbiota transplantation, microbiota depletion, neuroinflammation, intestinal barrier function, endotoxin, Toll-like receptors, depression, dementia, gut-brain axis
- MeSH terms
- Animals, Body Weight, Brain, Exploratory Behavior, Male, Memory, Mice, Inbred C57BL, Motor Activity, Obesity, Stereotyped Behavior, Gastrointestinal Tract, Diet, High-Fat, Microbiota
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