Cited by 573Gut microbiota and healthGastrointestinal motility and disordersNeuropeptides and Animal Physiology

The DOI matches its Crossref record; 414 of the 421 references it cites were found in a registry or an index; none of the 237 sources its claims cite is checked for support yet.

Anxiety, Depression, and the Microbiome: A Role for Gut Peptides

Open access
Lach, Gilliard, Schellekens, Harriet, Dinan, Timothy G., Cryan, John F.·2018·Neurotherapeutics

Abstract

The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review proposes that gut-derived peptides are key mediators of microbiota–gut–brain signaling in anxiety and depression. It synthesizes evidence that microbiota composition and microbial metabolites alter peptides such as NPY, PYY, PP, GLP-1, CCK, ghrelin, CRF, and oxytocin, with psychobiotics suggested as a future therapeutic route.

Key findings

  • The gastrointestinal tract is described as the largest endocrine organ in mammals, with enteroendocrine cells representing no more than 1% of the total gut epithelium cell population and releasing more than 20 signaling molecules. The review argues these gut peptides can signal to the brain via immune cells, vagus nerve terminals, and the bloodstream.
  • Microbiota manipulations are reported to alter gut peptides: germ-free mice, antibiotic-treated mice, and animals given probiotics or prebiotics show increases in NPY and PYY and increases in GLP-1; germ-free mice show decreased CCK and ghrelin; fasted germ-free mice show increased ghrelin; antibiotic treatment from adolescence decreases oxytocin without changing CRF; and *Lactobacillus reuteri* increases oxytocin.
  • GLP-1 is reported to be rapidly degraded, with <10% of secreted GLP-1 reaching systemic circulation. The review notes that GLP-1 receptor agonists blunt anxiety-like behavior in diabetic mice, promote antidepressant-like effects in rodents, and a 4-week GLP-1 agonist treatment reverted cognitive deficits in patients with mood disorders without affecting metabolic parameters.
  • PP is about 100 times more potent than NPY in activating Y4 receptors, and the review suggests PP/Y4 signaling may be an important gut–brain route in anxiety and depression. CCK levels are positively correlated with increased anxiety-like behavior in human and rodent studies, while ghrelin and CRF are discussed as modulators of stress, fear, and depressive-like phenotypes.

Methods

  • Design: narrative review of the microbiota–gut–brain axis, focusing on gut peptides as signaling molecules in anxiety and depression.
  • Data/sample: synthesis of preclinical animal studies, germ-free and antibiotic-treated rodent models, probiotic/prebiotic interventions, human cohort data, and human clinical trials cited in the reference list.
  • Main analysis: thematic discussion of peptide families and systems—NPY/PYY/PP, GLP-1, CCK, ghrelin, CRF, and oxytocin—and their interactions with gut microbiota, immune signaling, vagal pathways, and psychobiotic strategies.

Limitations

  • The paper states that mechanisms underlying enteroendocrine cell–microbiota interactions have yet to be fully resolved, that a direct link between the gut microbiota and ghrelin modulation remains absent, that more studies linking PYY changes and the gut microbiota are needed, and that additional studies are needed to demonstrate a functional role of the gut microbiota in the host oxytocin system.
  • The paper states we are at very early stages of understanding microbiota–gut–brain communication.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis; many findings are from animal models or correlative human data, and the review notes interspecies variability and contrasting results between humans and animals, so causal direction is often not established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s13311-017-0585-0

Cites

414 of 414 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

147 Not checked yet · 33 Own interpretation · 2 No basis given

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Show all 95 claims

  • Probably not a substantial claim. 22
  • It may state two separate claims as one. 73
87 of 87
  • The paper relies on this without support.

    Some patients are resistant to the therapeutic effects of conventional pharmacological therapies.

    “Conversely, some patients are resistant to the therapeutic effects of conventional pharmacological therapies.”
  • The paper relies on this without support.

    Alterations in gut microbiota cause changes in gut peptide release that are sufficient to affect brain function and behavior.

    “Evidence of direct involvement interaction between the NPY system and the gut microbiota modulating behavior is lacking.”
  • The paper relies on this without support.

    The gut microbiota strongly affects the immune system.

    “Since the gut microbiota strongly affects the immune system”
  • The paper relies on this without support.

    Stress can alter the gut microbiota composition.

    “Since stress can alter the gut microbiota composition”
  • The paper relies on this without support.

    The nature of bacteria that occupy overlapping niches is to compete for the same nutrients.

    “Since the nature of bacteria that occupy overlapping niches is to compete for the same nutrients”
5 of 5

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Metadata

Authors
Lach, G., Schellekens, H., Dinan, T. G., & Cryan, J. F.
Affiliations
University College Cork (IE)
Corresponding author
Cryan, John F.
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2018-01
Volume
15
Issue
1
Pages
36-59
ISSN
1878-7479 (ISSN-L)
OpenAlex
W2769787189
Cited by
573
References
421
Citations by year
2026: 34 · 2025: 59 · 2024: 74 · 2023: 97 · 2022: 82 · 2021: 91 · 2020: 76 · 2019: 38 · 2018: 19
FWCI
3.43
Type
journal article
Language
en
Open access
Locations
  • Neurotherapeutics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Science Foundation Ireland (SFI/12/RC/, 12/RC/2273, 12/RC/, SFI/12/RC/2273.)
  • APC Microbiome Institute (SFI/12/RC/2273)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
gut microbiota, gut-brain axis, anxiety, depression, gut peptides, gastrointestinal hormones, neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, ghrelin, vagus nerve, stress-related psychiatric disorders
MeSH terms
Gastrointestinal Microbiome, Anxiety, Brain, Cholecystokinin, Corticotropin-Releasing Hormone, Depression, Endocrine System, Humans, Neuropeptide Y, Oxytocin, Peptide Hormones, Glucagon-Like Peptide 1, Ghrelin

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