The Microbiota-Inflammasome Hypothesis of Major Depression
Open accessAbstract
We propose the “microbiota‐inflammasome” hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long‐lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro‐inflammatory pathways mediated by the Nod‐like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress‐induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive‐like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co‐morbid conditions. A number of testable predictions surface from this microbiota‐gut‐inflammasome‐brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change.
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Many psychobiotics are being tested to identify possible therapeutic benefits.
“At the moment, many psychobiotics, being them prebiotics, probiotics, postbiotics, and even single molecules involved in the gut microbial signaling, are being tested to identify any possible therapeutic benefits [116,120].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [116]
People suffering from depression frequently display an altered gut microbiota, with decreased richness and diversity of species; Bacteroidales are increased and Lachnospiraceae family decreased.
“Moreover, it was reported that people suffering from depression frequently displayed an altered gut microbiota, with a decreased richness and diversity of species that Bacteroidales are increased in depressed patients who have a decreased level of the Lachnospiraceae family (a more exhaustive list can be found in a recent review [116]).”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [116]
A recent hypothesis suggests that shifts in the gut microbial composition upregulate proinflammatory pathways leading to worsening of depressive symptoms, implicating the immune system.
“A recent hypothesis suggests that shifts in the gut microbial composition upregulate proinflammatory pathways leading to the worsening of depressive symptoms, a theory that implicates also the immune system in this complex balance [116].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [116]
A relevant contribution of gut microbiota is not restricted to neuroinflammatory and psychiatric disorders but also extends to brain development.
“Moreover, a relevant contribution of gut microbiota is not only restricted to neuroinflammatory and psychiatric disorders (23–32) but also to brain development (13).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [26]
Functional immune cells can enter the CNS through the blood-brain barrier, choroid plexus, and lymphatic vessels and have been described beyond neuropathological conditions.
“However, the idea that the CNS is an immune privileged organ has been reconsidered, as the functional immune cells can enter the CNS through the BBB, the choroid plexus, and the lymphatic vessels and have been described beyond neuropathological conditions (26, 35–47).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [26]
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References 122 · Cited by 134
Research works printed but not linked: 7
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- Authors
- Inserra, A., Rogers, G. B., Licinio, J., & Wong, M.
- Affiliations
- Flinders University (AU)
- Mind and Brain Theme South Australian Health and Medical Research Institute Adelaide 5001 SA Australia
- Corresponding author
- Wong, Ma‐Li
- Venue
- BioEssays
- Publisher
- Wiley
- Published
- 2018-07-13
- Volume
- 40
- Issue
- 9
- Pages
- e1800027-e1800027
- ISSN
- 0265-9247 (ISSN-L)
- 1521-1878
- PMC
- PMC12180310
- OpenAlex
- W2884443283
- Cited by
- 134
- References
- 122
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 22 · 2023: 20 · 2022: 19 · 2021: 18 · 2020: 16 · 2019: 16 · 2018: 3
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- BioEssays (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- National Center for Research Resources (M01RR000865, K24RR016996)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- major depressive disorder, gut microbiota, NLRP3 inflammasome, gut dysbiosis, chronic stress, neuroinflammation, microbiota-gut-brain axis, depression-like behavior, fecal microbiota transplantation, psychobiotics, dietary intervention, metabolic pathways
- MeSH terms
- Gastrointestinal Microbiome, Animals, Depressive Disorder, Major, Major Depressive Disorder, Humans, Inflammation, Signal Transduction, Metabolic Networks and Pathways, Inflammasomes
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