Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis

In the paper

“There is also evidence for signaling between the GM and CNS, since microbes residing in the gut can activate stress circuits in the CNS through the vagus nerve and sensory neurons of the ENS (21, 49–54).”

What the sources say

• Not checked yetcites [21] Carabotti, 2015, The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems, Ann Gastroenterol
• Not checked yetcites [49] Lyte, 2006, Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia citrobacter rodentium, Physiol Behav source
• Partly supported

  The Introduction reports that gastrointestinal C. jejuni infection activates vagal sensory neurons and brain regions involved in visceral and stress-related processing; it describes the vagal pathway as a likely conduit. The Discussion and conclusion also link infection to activation of stress-related brain circuits. The paper does not establish the additional route through sensory neurons of the enteric nervous system (ENS). (LLM, conf=0.87)

  cites [50] Goehler, 2008, Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior, Brain Behav Immun sourceExperimental — accuracy not yet measured
• Not checked yetcites [51] Sudo, 2004, Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice, J Physiol source
• Not checked yetcites [52] Forsythe, 2014
• Partly supported

  The Introduction (page not supplied) says gut microbes influence the ENS and that sensory vagal fibers relay information from the ENS to the CNS. The Neurodegenerative Diseases in the CNS section also says gut microbes affect the ENS–vagus pathway. Neither passage establishes the more specific claim that microbes activate CNS stress circuits through those neurons. (LLM, conf=0.84)

  cites [53] Geng, 2022, Enteric nervous system: the bridge between the gut microbiota and neurological disorders, Front Aging Neurosci sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction describes vagal communication between the ENS and CNS, and Section 4 reports that gut microbes can alter enteric sensory-neuron activity, potentially connecting the microbiota–ENS–brain axis. Section 5.3 also describes a possible route for microbial signals to reach sensory enteric neurons. These passages do not establish that gut microbes activate stress circuits in the CNS through those pathways; the paper describes the proposed connection more cautiously. (LLM, conf=0.85)

  cites [54] Hyland, 2016, Microbe-host interactions: influence of the gut microbiota on the enteric nervous system, Dev Biol sourceExperimental — accuracy not yet measured

In the paper

“The ECS and GM interact to regulate intestinal homeostasis resulting in relevant functional effects in the gut and CNS (238, 246, 248, 250).”

What the sources say

• Not checked yetcites [238] Cani, 2016, Endocannabinoids–at the crossroads between the gut microbiota and host metabolism, Nat Rev Endocrinol source
• Supported

  The section “Potential Interventions Targeting the Endocannabinoid System in Stress-Related Disorders” describes a mutual interaction between gut endocannabinoid signaling and the microbiome that can affect stress responses through the gut–brain axis, including via intestinal barrier regulation. The “Gut Microbiota” section also says the microbiota control intestinal endocannabinoid tone, affecting gut motility and permeability. Page numbers are not available in our copy. (LLM, conf=0.90)

  cites [246] Srivastava, 2022, The microbiome and gut endocannabinoid system in the regulation of stress responses and metabolism, Front Cell Neurosci source
• Supported

  The section ‘Reciprocal Regulation of the Endocannabinoid System and the Gut Microbiome’ describes interactions in both directions and links them to intestinal homeostasis. It also reports gut effects, including changes in intestinal endocannabinoid signaling, and brain-related effects, including anxiety-like behavior and altered hippocampal neurogenesis. The indexed passages provide no page numbers. (LLM, conf=0.92)

  cites [248] Cuddihey, 2022, Role of the endocannabinoid system in the regulation of intestinal homeostasis, Cell Mol Gastroenterol Hepatol source
• Partly supported

  The Bioactive lipids section (page unavailable) describes bidirectional crosstalk between the endocannabinoid system and gut microbiota, including effects on gut barrier function. It also reports hypothalamic neuron changes in a mouse model involving intestinal endocannabinoids and altered microbiota. The paper does not establish the broader claim that their interaction regulates intestinal homeostasis and thereby produces functional effects in both the gut and CNS. (LLM, conf=0.82)

  cites [250] de Vos, 2022, Gut microbiome and health: mechanistic insights, Gut sourceExperimental — accuracy not yet measured

In the paper

“SCFA-induced activation of receptors on enteroendocrine cells can promote gut-brain signaling by inducing hormones such as glucagon-like peptide 1 (GLP1) and peptide YY (PYY), as well as neurotransmitters like GABA and serotonin (276).”

What the sources say

• Partly supported

  The Discussion (page unavailable) says SCFAs can act on intestinal L cells to enhance release of GLP-1 and PYY, and the Results demonstrate SCFA-stimulated GLP-1 secretion. The cited paper does not report SCFA-induced GABA or serotonin release, so it does not support those parts of the sentence. (LLM, conf=0.88)

  cites [276] Tolhurst, 2012, Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-Protein–coupled receptor FFAR2, Diabetes sourceExperimental — accuracy not yet measured

In the paper

“Bile duct ligation alters the GM composition, and increases the permeability of the BBB (328, 329).”

What the sources say

• ?Could not verify

  The Animal Treatment section describes bile duct ligation in rats, and the Abstract Results report increased blood–brain barrier permeability. Neither addresses gut microbiota composition; searches for gut microbiota, microbial flora, and dysbiosis found no supporting passage in our copy. (LLM, conf=0.76)

  cites [328] Quinn, 2014, Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms, Dig Liver Dis sourceExperimental — accuracy not yet measured
• Supported

  The Discussion states that bile duct ligation promotes changes in microbiome composition. The Results also report significant differences between control mice and mice examined 3 and 7 days after ligation. These passages support the attributed gut-microbiota claim; they do not address the separate BBB statement. (LLM, conf=0.94)

  cites [329] Cabrera-Rubio, 2019, Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice, Sci Rep source

In the paper

“Furthermore, glucocorticoids may modulate the brain indirectly through their effects on the immune system, metabolism, sleep, other hormones, and the GM (432, 433).”

What the sources say

• Partly supported

  The Introduction links excess glucocorticoids in Cushing’s disease to effects on the brain, and the Discussion identifies immune-signaling genes and microglia as possible contributors to persistent brain changes. This supports the immune-related possibility, but the paper does not address indirect effects through metabolism, sleep, other hormones, or the gut microbiota. (LLM, conf=0.86)

  cites [432] Bauduin, 2021, Potential associations between immune signaling genes, deactivated microglia, and oligodendrocytes and cortical gray matter loss in patients with long-term remitted cushing’s disease, Psychoneuroendocrinology sourceExperimental — accuracy not yet measured
• Partly supported

  The section on variations in cortisol and cognition proposes sleep as an indirect pathway, and the Addison’s disease section says disrupted cortisol patterns may cause sleep disturbances that impair memory. Our copy does not support the additional attributed pathways through the immune system, metabolism, other hormones, or gut microbiota. (LLM, conf=0.86)

  cites [433] Henry, 2021, Sleep, cognition and cortisol in addison’s disease: a mechanistic relationship, Front Endocrinol sourceExperimental — accuracy not yet measured

In the paper

“C. difficile infection is an important example demonstrating these adverse health consequences, beyond acute intestinal dysbiosis (454).”

What the sources say

• Supported

  The Discussion states that CDI may have consequences beyond acute intestinal infection, citing its association with cognitive impairment, functional decline, and delayed mortality in older patients. This supports using CDI as an example of adverse consequences beyond the acute intestinal illness; the paper does not use the term “dysbiosis.” (LLM, conf=0.91)

  cites [454] Fernandez-Cotarelo, 2019, Functional and cognitive status in clostridium difficile infection in the hospitalized elderly: a retrospective study of two sites, J Gen Intern Med source

In the paper

“In the gut, the GM and its metabolites have been shown to modulate gastrointestinal functions via their effects on intestinal permeability (32–35), mucosal immune function (36–38), intestinal motility and sensitivity (39, 40), and the enteric nervous system (ENS) (21, 24, 25, 41).”

What the sources say

• Not checked yetcites [32] Cani, 2012, Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity, Gut Microbes source
• Not checked yetcites [33] Rutsch, 2020, The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology, Front Immunol source
• Not checked yetcites [34] Frazier, 2011, Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury, JPEN J Parenter Enteral Nutr source
• Not checked yetcites [35] Fasano, 2017, Gut permeability, obesity, and metabolic disorders: who is the chicken and who is the egg, Am J Clin Nutr source
• Not checked yetcites [36] Round, 2009, The gut microbiota shapes intestinal immune responses during health and disease, Nat Rev Immunol source
• Not checked yetcites [37] Allaire, 2018, The intestinal epithelium: central coordinator of mucosal immunity, Trends Immunol source
• Not checked yetcites [38] Wlodarska, 2015, An integrative view of microbiome-host interactions in inflammatory bowel diseases, Cell Host Microbe source
• Not checked yetcites [39] Cani, 2013, Gut microbiota, enteroendocrine functions and metabolism, Curr Opin Pharmacol source
• Not checked yetcites [40] Valdez-Morales, 2013, Sensitization of peripheral sensory nerves by mediators from colonic biopsies of diarrhea-predominant irritable bowel syndrome patients: a role for PAR2, Am J Gastroenterol source

In the paper

“Emerging evidence suggests that the GM, the hypothalamic-pituitary-adrenal (HPA) axis, and cognitive processes are linked bidirectionally via multiple pathways, including the vagus nerve, neurotransmitter and metabolite production, immune system and blood-brain barrier regulation, and hormone metabolism.”

In the paper

“Stress can significantly impact the MGB axis via the HPA axis and other pathways.”

In the paper

“As a key regulator, the GM can modulate host physiological processes through several proposed mechanisms (25, 26).”

What the sources say

• Not checked yetcites [25] Cryan, 2019, The microbiota-gut-brain axis, Physiol Rev source
• Not checked yetcites [26] Dinan, 2017, The microbiome-Gut-Brain axis in health and disease, Gastroenterol Clin North Am source

In the paper

“Confirming the role of the GM in cognitive function in midlife, Meyer et al. explored the relationship between gut microbial community composition and cognitive function in 597 middle-aged adults, and found a significant positive association between β-diversity and all higher cognitive functions tested (89).”

What the sources say

• Not checked yetcites [89] Meyer, 2022, Association of the gut microbiota with cognitive function in midlife, JAMA Netw Open source

In the paper

“The GM can stimulate the release of peptides and hormones from enteroendocrine cells, which can have direct or indirect central effects (22, 39).”

What the sources say

• Not checked yetcites [22] Burokas, 2015, Microbiota regulation of the mammalian gut-brain axis source
• Not checked yetcites [39] Cani, 2013, Gut microbiota, enteroendocrine functions and metabolism, Curr Opin Pharmacol source

In the paper

“The first year of life encompasses a critical “window period” of development in which the GM may be more susceptible to environmental influences and highly influential with regards to the overall health of the host.”

In the paper

“Furthermore, recent studies have shown dramatic changes in the GM of patients with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and schizophrenia (73–77).”

What the sources say

• Not checked yetcites [73] Haran, 2019, Alzheimer’s disease microbiome is associated with dysregulation of the anti-inflammatory p-glycoprotein pathway, MBio source
• Not checked yetcites [74] Romano, 2021, Meta-analysis of the parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation, NPJ Park Dis source
• Not checked yetcites [75] Sampson, 2016, Gut microbiota regulate motor deficits and neuroinflammation in a model of parkinson’s disease, Cell source
• Not checked yetcites [76] Correale, 2022, The role of the gut microbiota in multiple sclerosis, Nat Rev Neurol source
• Not checked yetcites [77] Zheng, 2019, The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice, Sci Adv source

In the paper

“Preclinical evidence suggests that GM-mediated mechanisms are likely involved in modulating brain processes, including brain biochemistry, response to stress, pain interpretation, feeding, emotional behaviors, and cognition (57–64).”

What the sources say

• Not checked yetcites [57] Stilling, 2014, Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis, Genes Brain Behav source
• Not checked yetcites [58] Foster, 2017, Stress & the gut-brain axis: regulation by the microbiome, Neurobiol Stress source
• Not checked yetcites [59] Cryan, 2012, Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour, Nat Rev Neurosci source
• Not checked yetcites [60] Bercik, 2012, Microbes and the gut-brain axis, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source
• Not checked yetcites [61] Alcock, 2014, Is eating behavior manipulated by the gastrointestinal microbiota? evolutionary pressures and potential mechanisms, Bioessays source
• Not checked yetcites [62] Lam, 2017, Are the gut bacteria telling us to eat or not to eat? reviewing the role of gut microbiota in the etiology, disease progression and treatment of eating disorders, Nutrients source
• Not checked yetcites [63] Foster, 2013, Gut-brain axis: how the microbiome influences anxiety and depression, Trends Neurosci source
• Not checked yetcites [64] Humann, 2016, Bacterial peptidoglycan traverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior, Cell Host Microbe source

In the paper

“Initial clinical evidence of MGB interactions primarily stems from associations between dysbiosis and CNS disorders, such as autism, anxiety-depressive behaviors, and functional gastrointestinal disorders (63, 65–72).”

What the sources say

• Not checked yetcites [63] Foster, 2013, Gut-brain axis: how the microbiome influences anxiety and depression, Trends Neurosci source
• Not checked yetcites [65] Mayer, 2014, Altered brain-gut axis in autism: comorbidity or causative mechanisms, Bioessays source
• Not checked yetcites [66] Song, 2004, Real-time PCR quantitation of clostridia in feces of autistic children, Appl Environ Microbiol source
• Not checked yetcites [67] Hsiao, 2013, Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell source
• Not checked yetcites [68] Naseribafrouei, 2014, Correlation between the human fecal microbiota and depression, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source
• Not checked yetcites [69] Du, 2020, Crosstalk between the microbiota-gut-brain axis and depression, Heliyon source
• Not checked yetcites [70] Mayer, 2011, The brain-gut axis in abdominal pain syndromes, Annu Rev Med source
• Not checked yetcites [71] Berrill, 2013, An observational study of cognitive function in patients with irritable bowel syndrome and inflammatory bowel disease, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source
• Not checked yetcites [72] Simrén, 2013, Intestinal microbiota in functional bowel disorders: a Rome foundation report, Gut source

In the paper

“Caesarean section delivery alters the initial microbial composition (82).”

What the sources say

• Not checked yetcites [82] Zeng, 2022, The road not taken: host genetics in shaping intergenerational microbiomes, Trends Genet source

In the paper

“Conversely, the brain can affect intestinal function and the GM, for example, by HPA axis-mediated glucocorticoid modification of immunity in response to stress (29).”

What the sources say

• Not checked yetcites [29] Tetel, 2018, Steroids, stress and the gut microbiome-brain axis, J Neuroendocrinol source

In the paper

“After birth, several factors influence GM composition in early life, including breastfeeding, nutrition, infection and antibiotic use, environmental stressors, and host genetics (83).”

What the sources say

• Not checked yetcites [83] Tamburini, 2016, The microbiome in early life: implications for health outcomes, Nat Med source

In the paper

“Fecal microbiota transplant (FMT) studies have added evidence for causality by inducing many of the symptoms of these diseases in germ-free animals (78).”

What the sources say

• Not checked yetcites [78] Fülling, 2019, Gut microbe to brain signaling: what happens in vagus, Neuron source

In the paper

“There is growing evidence that age-related changes in the microbiota may contribute to cognitive decline and other neurodegenerative disorders (102, 103).”

What the sources say

• Not checked yetcites [102] Liu, 2020, Gut microbiota and dysbiosis in alzheimer’s disease: implications for pathogenesis and treatment, Mol Neurobiol source
• Not checked yetcites [103] Gorecki, 2019, Altered gut microbiome in parkinson’s disease and the influence of lipopolysaccharide in a human α-synuclein over-expressing mouse model, Front Neurosci source

In the paper

“antibiotic administration to deplete the GM can change the levels of neurotransmitters in the gut and blood (195, 196).”

What the sources say

• Not checked yetcites [195] Gao, 2018, Antibiotics-induced modulation of large intestinal microbiota altered aromatic amino acid profile and expression of neurotransmitters in the hypothalamus of piglets, J Neurochem source
• Not checked yetcites [196] Fujisaka, 2018, Diet, genetics, and the gut microbiome drive dynamic changes in plasma metabolites, Cell Rep source

In the paper

“In a study that used metagenomic profiles from over 4,000 healthy people aged 18–90, the authors were able to construct an algorithm that predicted individuals’ ages within approximately six years of their actual age (98).”

What the sources say

• Not checked yetcites [98] Galkin, 2020, Human gut microbiome aging clock based on taxonomic profiling and deep learning, iScience source

In the paper

“Germ-free mice studies have shown significant alterations in multiple neurotransmitter systems and their receptors in several brain regions (124).”

What the sources say

• Not checked yetcites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci source

In the paper

“The GM appears to influence microglial development and maturation (120, 121), and animal models have demonstrated downstream effects on various aspects of neurocognitive function (19, 45, 60, 114, 115).”

What the sources say

• Not checked yetcites [120] Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat Neurosci source
• Not checked yetcites [121] Abdel-Haq, 2019, Microbiome-microglia connections via the gut-brain axis, J Exp Med source

In the paper

“Microbial composition can predict human chronological age relatively accurately (97).”

What the sources say

• Not checked yetcites [97] Chen, 2022, Human gut microbiome aging clocks based on taxonomic and functional signatures through multi-view learning, Gut Microbes source

In the paper

“In contrast, early-life disruptions of gut colonization have been linked to CNS alterations (122).”

What the sources say

• Not checked yetcites [122] Borre, 2014, Microbiota and neurodevelopmental windows: implications for brain disorders, Trends Mol Med source

In the paper

“The aging process of the host parallels a continuous aging progression of the GM (90).”

What the sources say

• Not checked yetcites [90] Xu, 2019, Aging progression of human gut microbiota, BMC Microbiol source

In the paper

“Stability begins to decline as we age, and studies suggest that there is greater inter-individual variation in older adults than younger adults (<65 years old) (91, 92)”

What the sources say

• Not checked yetcites [91] Jeffery, 2016, Composition and temporal stability of the gut microbiota in older persons, ISME J source
• Not checked yetcites [92] Claesson, 2012, Gut microbiota composition correlates with diet and health in the elderly, Nature source

In the paper

“Animal studies suggest that the GM plays a crucial role in regulating early brain development (19, 45, 60, 114–117).”

What the sources say

• Not checked yetcites [19] Mayer, 2014, Gut microbes and the brain: paradigm shift in neuroscience, J Neurosci source
• Not checked yetcites [45] Sampson, 2015, Control of brain development, function, and behavior by the microbiome, Cell Host Microbe source
• Not checked yetcites [60] Bercik, 2012, Microbes and the gut-brain axis, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source
• Not checked yetcites [114] Collins, 2014, Intestinal microbiota influence the early postnatal development of the enteric nervous system, Neurogastroenterol Motil source
• Not checked yetcites [115] Borre, 2014, The impact of microbiota on brain and behavior: mechanisms & therapeutic potential, Adv Exp Med Biol source
• Not checked yetcites [116] Sharon, 2016, The central nervous system and the gut microbiome, Cell source
• Not checked yetcites [117] Sarkar, 2020, The role of the microbiome in the neurobiology of social behaviour, Biol Rev source

In the paper

“HPA axis dysfunction is also associated with many major psychopathologies, including autism, anxiety disorders, depression, and schizophrenia, as well as other cognitive disorders (145).”

What the sources say

• Not checked yetcites [145] Misiak, 2020, The HPA axis dysregulation in severe mental illness: can we shift the blame to gut microbiota, Prog Neuropsychopharmacol Biol Psychiatry source

In the paper

“preliminary human studies demonstrate that microbiota-based interventions can alter neurotransmitter concentrations (28).”

What the sources say

• Not checked yetcites [28] Strandwitz, 2018, Neurotransmitter modulation by the gut microbiota, Brain Res source

In the paper

“Animal studies provide evidence that microbial modulation of these neurotransmitters may impact host physiology”

What the sources say

• Not checked yetcites [28] Strandwitz, 2018, Neurotransmitter modulation by the gut microbiota, Brain Res source

In the paper

“microbial abundance has been shown to alter the expression of neurotransmitter receptors in the brain (51, 189, 191).”

What the sources say

• Not checked yetcites [51] Sudo, 2004, Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice, J Physiol source
• Not checked yetcites [189] Neufeld, 2011, Reduced anxiety-like behavior and central neurochemical change in germ-free mice, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source
• Not checked yetcites [191] Bravo, 2011, Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve, Proc Natl Acad Sci source

In the paper

“the importance of the GM’s ability to metabolize tryptophan into aryl hydrocarbon receptor ligands and, therefore, modulate gut inflammation, was demonstrated in patients with celiac disease (202).”

What the sources say

• Not checked yetcites [202] Lamas, 2020, Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation, Sci Transl Med source

In the paper

“Pre-gestational and early-life stress, with activation of the HPA axis, have been linked with an altered serotonergic system, leading to interruptions in brain development and cognition (218–220).”

What the sources say

• Not checked yetcites [218] Ohta, 2014, Prolonged maternal separation disturbs the serotonergic system during early brain development, Int J Dev Neurosci Off J Int Soc Dev Neurosci source
• Not checked yetcites [219] Sood, 2018, Early emergence of altered 5-HT(2A) receptor-evoked behavior, neural activation and gene expression following maternal separation, Int J Dev Neurosci Off J Int Soc Dev Neurosci source
• Not checked yetcites [220] Huang, 2012, Pre-gestational stress reduces the ratio of 5-HIAA to 5-HT and the expression of 5-HT1A receptor and serotonin transporter in the brain of foetal rat, BMC Neurosci source

In the paper

“Several bacterial taxa can also affect tryptophan levels by direct utilization for growth or via tryptophanase expression (28, 203, 204)”

What the sources say

• Not checked yetcites [28] Strandwitz, 2018, Neurotransmitter modulation by the gut microbiota, Brain Res source
• Not checked yetcites [203] Lee, 2010, Indole as an intercellular signal in microbial communities, FEMS Microbiol Rev source
• Not checked yetcites [204] Li, 2013, Indole production by the tryptophanase TnaA in escherichia coli is determined by the amount of exogenous tryptophan, Microbiology source

In the paper

“the activity of CRH neurons is ultimately regulated by GABAergic inhibition, mediated by GABAA receptors (234).”

What the sources say

• Not checked yetcites [234] Camille Melón, 2016, GABAergic regulation of the HPA and HPG axes and the impact of stress on reproductive function, J Steroid Biochem Mol Biol source

In the paper

“they have increased turnover rates of dopamine, noradrenaline, and serotonin in the brain (124).”

What the sources say

• Not checked yetcites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci source

In the paper

“these bacteria have been associated with the development of neuropsychiatric disorders, including autism spectrum disorders (205).”

What the sources say

• Not checked yetcites [205] Roth, 2021, Tryptophan metabolism and gut-brain homeostasis, Int J Mol Sci source

In the paper

“Germ-free mice show decreased noradrenaline in the cecal lumen and tissue, which is restored with colonization (231).”

What the sources say

• Not checked yetcites [231] Asano, 2012, Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice, Am J Physiol Gastrointest Liver Physiol source

In the paper

“Serotonin regulates upstream CRH signaling systems via the activation of serotonin 2C receptors of the hypothalamic PVN (217).”

What the sources say

• Not checked yetcites [217] Heisler, 2007, Serotonin activates the hypothalamic–Pituitary–Adrenal axis via serotonin 2C receptor stimulation, J Neurosci source

In the paper

“Its synthesis by microbes has been well described (197).”

What the sources say

• Not checked yetcites [197] Agus, 2018, Gut microbiota regulation of tryptophan metabolism in health and disease, Cell Host Microbe source

In the paper

“changes in GM composition have been associated with alterations in GABA receptor expression and GABA levels in the brain (191).”

What the sources say

• Not checked yetcites [191] Bravo, 2011, Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve, Proc Natl Acad Sci source

In the paper

“In the gut, it may be further metabolized under direct or indirect control by the GM, giving rise to several compounds, such as serotonin, kynurenines, tryptamine, and indolic compounds, which participate in MGB communication (197, 198).”

What the sources say

• Not checked yetcites [197] Agus, 2018, Gut microbiota regulation of tryptophan metabolism in health and disease, Cell Host Microbe source
• Not checked yetcites [198] Kennedy, 2017, Kynurenine pathway metabolism and the microbiota-gut-brain axis, Neuropharmacology source

In the paper

“Both animal and human studies have shown that the ECS and GM play a role in cognitive decline (254).”

What the sources say

• Not checked yetcites [254] Bisogno, 2021, The endocannabinoid system: a bridge between alzheimer’s disease and gut microbiota, Life source

In the paper

“Although microbes secrete eCBs, their role in host physiology remains unclear (255).”

What the sources say

• Not checked yetcites [255] Cohen, 2017, Commensal bacteria make GPCR ligands that mimic human signalling molecules, Nature source

In the paper

“SCFAs appear to play a significant role in MGB communication (286).”

What the sources say

• Not checked yetcites [286] Silva, 2020, The role of short-chain fatty acids from gut microbiota in gut-brain communication, Front Endocrinol source

In the paper

“Changes in eCBs correlated with increased butyrate levels, and decreased TNF, IL-6 and IL-10.”

What the sources say

• Not checked yetcites [252] Vijay, 2021, The anti-inflammatory effect of bacterial short chain fatty acids is partially mediated by endocannabinoids, Gut Microbes source

In the paper

“Injury, infections and autoimmune diseases can influence the permeability of the gut and BBB (262).”

What the sources say

• Not checked yetcites [262] Logsdon, 2018, Gut reactions: how the blood-brain barrier connects the microbiome and the brain, Exp Biol Med (Maywood) source

In the paper

“Antibiotic-treated and germ-free mice have pro-inflammatory systemic and CNS immune system responses (120, 267).”

What the sources say

• Not checked yetcites [120] Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat Neurosci source
• Not checked yetcites [267] Stanisavljević, 2019, Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in dark agouti rats, Sci Rep source

In the paper

“SCFAs can modify neuroinflammation by affecting the morphology and function of glial cells (120, 286, 289, 290).”

What the sources say

• Not checked yetcites [120] Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat Neurosci source
• Not checked yetcites [286] Silva, 2020, The role of short-chain fatty acids from gut microbiota in gut-brain communication, Front Endocrinol source
• Not checked yetcites [289] Patnala, 2017, HDAC inhibitor sodium butyrate-mediated epigenetic regulation enhances neuroprotective function of microglia during ischemic stroke, Mol Neurobiol source
• Not checked yetcites [290] Wang, 2018, Sodium butyrate triggers a functional elongation of microglial process via akt-small RhoGTPase activation and HDACs inhibition, Neurobiol Dis source

In the paper

“One critical interaction involves the activation of pattern recognition receptors (PRRs), including TLRs, by microbial associated molecular patterns (MAMPs) (54).”

What the sources say

• Not checked yetcites [54] Hyland, 2016, Microbe-host interactions: influence of the gut microbiota on the enteric nervous system, Dev Biol source

In the paper

“SCFAs can cross the BBB, which is supported by the presence of SCFAs in human cerebrospinal fluid (CSF) and in brain uptake studies (286).”

What the sources say

• Not checked yetcites [286] Silva, 2020, The role of short-chain fatty acids from gut microbiota in gut-brain communication, Front Endocrinol source

In the paper

“Cytokines and chemokines are another mechanism by which the immune system, GM, and CNS (including HPA axis) interact (259).”

What the sources say

• Not checked yetcites [259] Mou, 2022, Gut microbiota interact with the brain through systemic chronic inflammation: implications on neuroinflammation, neurodegeneration, and aging, Front Immunol source

In the paper

“SCFAs may also improve neuronal homeostasis and function by influencing neurotrophic factors such as nerve growth factor, glial cell line-derived neurotrophic factor, and BDNF (119–122).”

What the sources say

• Not checked yetcites [119] Wilton, 2019, Neuron-glia signaling in synapse elimination, Annu Rev Neurosci source
• Not checked yetcites [120] Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat Neurosci source
• Not checked yetcites [121] Abdel-Haq, 2019, Microbiome-microglia connections via the gut-brain axis, J Exp Med source
• Not checked yetcites [122] Borre, 2014, Microbiota and neurodevelopmental windows: implications for brain disorders, Trends Mol Med source

In the paper

“chronic systemic inflammation, mainly in the form of infections, has long been associated with behavioral alterations and cognitive dysfunction (264–266).”

What the sources say

• Not checked yetcites [264] Perry, 2007, Systemic infections and inflammation affect chronic neurodegeneration, Nat Rev Immunol source
• Not checked yetcites [265] Perry, 2003, The impact of systemic infection on the progression of neurodegenerative disease, Nat Rev Neurosci source
• Not checked yetcites [266] Sankowski, 2015, Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration, Front Cell Neurosci source

In the paper

“The GM can also alter BBB permeability by changing the expression of occludin and claudin 5 (263).”

What the sources say

• Not checked yetcites [263] Braniste, 2014, The gut microbiota influences blood-brain barrier permeability in mice, Sci Transl Med source

In the paper

“SCFAs can indirectly modulate the PNS through expression of FFA3 in the enteric neural plexus, portal nerve, and autonomic and sensory ganglia (131).”

What the sources say

• Not checked yetcites [131] Stilling, 2016, The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis, Neurochem Int source

In the paper

“Activation of FFA3 receptors on vagus nerve cells can result in the activation of various neurons in the CNS, including dynamic regulation of hypothalamic neuronal circuitry (287).”

What the sources say

• Not checked yetcites [287] Li, 2018, Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit, Gut source

In the paper

“Crosstalk between the GM and CNS is also essential for normal development and homeostatic functioning of the immune system, both innate and adaptive (256).”

What the sources say

• Not checked yetcites [256] Zheng, 2020, Interaction between microbiota and immunity in health and disease, Cell Res source

In the paper

“the anti-inflammatory effects of SCFAs may be partly mediated by the ECS.”

In the paper

“Germ-free animals demonstrate significant changes in the expression of CB1 and CB2, and synthetic and degradative enzymes throughout the gut (251).”

What the sources say

• Not checked yetcites [251] Manca, 2020, Germ-free mice exhibit profound gut microbiota-dependent alterations of intestinal endocannabinoidome signaling, J Lipid Res source

In the paper

“SCFAs also influence the integrity of the BBB by upregulating the expression of tight junction proteins (263).”

What the sources say

• Not checked yetcites [263] Braniste, 2014, The gut microbiota influences blood-brain barrier permeability in mice, Sci Transl Med source

In the paper

“BA disorders are also associated with neural symptoms (300).”

What the sources say

• Not checked yetcites [300] Monteiro-Cardoso, 2021, Bile acids: a communication channel in the gut-brain axis, NeuroMolecular Med source

In the paper

“The BA-microbiota axis modulates the immunoregulatory environment along the gut (303).”

What the sources say

• Not checked yetcites [303] Mulak, 2021, Bile acids as key modulators of the brain-Gut-Microbiota axis in alzheimer’s disease, J Alzheimer’s Dis source

In the paper

“BAs might act via TGR5 in a cAMP/protein kinase A (PKA)-dependent fashion phosphorylating and thus activating steroidogenic acute regulatory protein (StAR) and hormone sensitive lipase (HSL) (316).”

What the sources say

• Not checked yetcites [316] Stocco, 1996, Regulation of the acute production of steroids in steroidogenic cells, Endocr Rev source

In the paper

“Specific BAs demonstrate neuroprotective effects in cellular and animal models, with human clinical trials underway (306–308).”

What the sources say

• Not checked yetcites [306] Yanovsky, 2012, Waking action of ursodeoxycholic acid (UDCA) involves histamine and GABAA receptor block, PloS One source
• Not checked yetcites [307] Huang, 2022, From dried bear bile to molecular investigation: a systematic review of the effect of bile acids on cell apoptosis, oxidative stress and inflammation in the brain, across pre-clinical models of neurological, neurodegenerative and neuropsychiatric disorde, Brain Behav Immun source
• Not checked yetcites [308] Yanguas-Casás, 2017, TUDCA: an agonist of the bile acid receptor GPBAR1/TGR5 with anti-inflammatory effects in microglial cells, J Cell Physiol source

In the paper

“BAs modulate HPA axis activity by inhibiting CRH release through FXR activation, expressed in the hypothalamus (309).”

What the sources say

• Not checked yetcites [309] McMillin, 2016, Effects of bile acids on neurological function and disease, FASEB J source

In the paper

“Specific microbes directly contribute to BA transformation, impacting the BA pool’s composition and size (317).”

What the sources say

• Not checked yetcites [317] Schoeler, 2019, Dietary lipids, gut microbiota and lipid metabolism, Rev Endocr Metab Disord source

In the paper

“SCFA supplementation was shown to downregulate the HPA axis by significantly attenuating the cortisol response.”

What the sources say

• Not checked yetcites [292] Dalile, 2020, Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: a randomized, placebo-controlled trial, Neuropsychopharmacology source

In the paper

“Altered SCFA production has also been demonstrated in a variety of neuropathologies (42, 116, 127, 130, 132, 292–295).”

What the sources say

• Not checked yetcites [42] Dinan, 2017, Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration, J Physiol source
• Not checked yetcites [116] Sharon, 2016, The central nervous system and the gut microbiome, Cell source
• Not checked yetcites [127] Fung, 2017, Interactions between the microbiota, immune and nervous systems in health and disease, Nat Neurosci source
• Not checked yetcites [130] Tan, 2014, The role of short-chain fatty acids in health and disease, Adv Immunol source
• Not checked yetcites [132] Dalile, 2019, The role of short-chain fatty acids in microbiota–gut–brain communication, Nat Rev Gastroenterol Hepatol source
• Not checked yetcites [292] Dalile, 2020, Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: a randomized, placebo-controlled trial, Neuropsychopharmacology source
• Not checked yetcites [293] Wang, 2012, Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder, Dig Dis Sci source
• Not checked yetcites [294] Ho, 2018, Protective roles of intestinal microbiota derived short chain fatty acids in alzheimer’s disease-type beta-amyloid neuropathological mechanisms, Expert Rev Neurother source
• Not checked yetcites [295] Skonieczna-Żydecka, 2018, Faecal short chain fatty acids profile is changed in polish depressive women, Nutrients source

In the paper

“recent studies have also revealed their function as hormones via receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), with significant regulatory and signaling activities (298).”

What the sources say

• Not checked yetcites [298] Perino, 2020, Molecular physiology of bile acid signaling in health, disease, and aging, Physiol Rev source

In the paper

“Germ-free mice excrete less fecal BAs, have a larger BA pool, and have different gene expression profiles involved in BA metabolism, than wild-type mice (323).”

What the sources say

• Not checked yetcites [323] Sayin, 2013, Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist, Cell Metab source

In the paper

“By administering SCFAs to germ-free mice, Erny et al. were able to rescue deficits in microglial immaturity and morphology (120).”

What the sources say

• Not checked yetcites [120] Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat Neurosci source

In the paper

“The discovery of FXR and TGR5 receptors in the adrenal gland further connects BAs with glucocorticoid metabolism (311, 313–315).”

What the sources say

• Not checked yetcites [311] Theiler-Schwetz, 2019, Bile acids and glucocorticoid metabolism in health and disease, Biochim Biophys Acta - Mol Basis Dis source
• Not checked yetcites [313] Forman, 1995, Identification of a nuclear receptor that is activated by farnesol metabolites, Cell source
• Not checked yetcites [314] Kawamata, 2003, A G protein-coupled receptor responsive to bile acids*, J Biol Chem source
• Not checked yetcites [315] Baptissart, 2013, Farnesoid X receptor alpha: a molecular link between bile acids and steroid signaling, Cell Mol Life Sci source

In the paper

“Germ-free mice excrete less fecal BAs, have a larger BA pool, and have different gene expression profiles involved in BA metabolism, than wild-type mice (323).”

What the sources say

• Not checked yetcites [323] Sayin, 2013, Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist, Cell Metab source

In the paper

“BAs may substantially affect cognitive function by their affinity to muscarinic receptors, as well as GABA and NMDA receptors (325).”

What the sources say

• Not checked yetcites [325] Schubring, 2012, The bile steroid chenodeoxycholate is a potent antagonist at NMDA and GABA(A) receptors, Neurosci Lett source

In the paper

“Altered BA profiles have been observed in several neuropathologies associated with cognitive decline, such as Alzheimer’s disease (302, 324).”

What the sources say

• Not checked yetcites [302] Baloni, 2020, Metabolic network analysis reveals altered bile acid synthesis and metabolism in alzheimer’s disease, Cell Rep Med source
• Not checked yetcites [324] Bin, 2022, A review of bile acid metabolism and signaling in cognitive dysfunction-related diseases, Oxid Med Cell Longev source

In the paper

“circulating BA levels significantly influence the CNS’s BA profile (303).”

What the sources say

• Not checked yetcites [303] Mulak, 2021, Bile acids as key modulators of the brain-Gut-Microbiota axis in alzheimer’s disease, J Alzheimer’s Dis source

In the paper

“BAs can interact with TGR5, expressed in the hypothalamic PVN, stimulating the HPA axis by increasing CRH (310, 311).”

What the sources say

• Not checked yetcites [310] Duboc, 2014, The bile acid TGR5 membrane receptor: from basic research to clinical application, Dig Liver Dis source
• Not checked yetcites [311] Theiler-Schwetz, 2019, Bile acids and glucocorticoid metabolism in health and disease, Biochim Biophys Acta - Mol Basis Dis source

In the paper

“Excessive BCAA concentrations are considered toxic and can cause tissue damage, particularly in the CNS (338).”

What the sources say

• Not checked yetcites [338] O’Reilly, 2021, Maple syrup urine disease: clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the republic of Ireland, J Inherit Metab Dis source

In the paper

“Germ-free mice excrete less fecal BAs, have a larger BA pool, and have different gene expression profiles involved in BA metabolism, than wild-type mice (323).”

What the sources say

• Not checked yetcites [323] Sayin, 2013, Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist, Cell Metab source

In the paper

“The GM produces higher proportions of specific BCAAs (valerate, isobutyrate, and isovalerate) relative to other amino acids, which have been shown to influence epithelial and mucosal homeostasis (332).”

What the sources say

• Not checked yetcites [332] Blachier, 2007, Effects of amino acid-derived luminal metabolites on the colonic epithelium and physiopathological consequences, Amino Acids source

In the paper

“The GM produces higher proportions of specific BCAAs (valerate, isobutyrate, and isovalerate) relative to other amino acids, which have been shown to influence epithelial and mucosal homeostasis (332).”

What the sources say

• Not checked yetcites [332] Blachier, 2007, Effects of amino acid-derived luminal metabolites on the colonic epithelium and physiopathological consequences, Amino Acids source

In the paper

“Furthermore, chronic antidepressant treatment post-exposure was able to rescue the neurological decline observed in the middle-aged rats (348).”

What the sources say

• Not checked yetcites [348] Suri, 2013, Early stress evokes age-dependent biphasic changes in hippocampal neurogenesis, BDNF expression, and cognition, Biol Psychiatry source

In the paper

“Mice deprived of leucine had increased HPA axis activation via CRH expression (337).”

What the sources say

• Not checked yetcites [337] Cheng, 2011, Leucine deprivation stimulates fat loss via increasing CRH expression in the hypothalamus and activating the sympathetic nervous system, Mol Endocrinol source

In the paper

“Interestingly, these consequences appear to be age-dependent.”

In the paper

“In a study of patients with depression and anxiety, BA profiles associated with altered GM composition were significantly different in those with more severe symptoms, and specific BA parameters were able to distinguish treatment failures from remitters (330).”

What the sources say

• Not checked yetcites [330] MahmoudianDehkordi, 2022, Gut microbiome-linked metabolites in the pathobiology of major depression with or without anxiety-a role for bile acids, Front Neurosci source

In the paper

“A landmark paper by Sudo et al. provided evidence for the essential role of the GM in programming the stress response by illustrating the differences in HPA axis hormones and receptors in germ-free mice when compared to specific pathogen free (SPF) mice (51).”

What the sources say

• Not checked yetcites [51] Sudo, 2004, Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice, J Physiol source

In the paper

“Postnatal maturation of the GM in newborn mice was shown to be dependent on BAs and neonatal cholestasis is associated with dysbiosis in infants (326, 327).”

What the sources say

• Not checked yetcites [326] van Best, 2020, Bile acids drive the newborn’s gut microbiota maturation, Nat Commun source
• Not checked yetcites [327] Li, 2020, Gut microbiota dysbiosis associated with bile acid metabolism in neonatal cholestasis disease, Sci Rep source

In the paper

“BCAAs regulate key signaling pathways, most notably the activation of mechanistic target of rapamycin (mTOR), which serves as the master regulator of cell growth and proliferation (331).”

What the sources say

• Not checked yetcites [331] Zhang, 2017, Novel metabolic and physiological functions of branched chain amino acids: a review, J Anim Sci Biotechnol source

In the paper

“Additionally, BCAAs can be utilized by microbes, potentially regulating intestinal microbial species, diversity, and metabolism (333, 334).”

What the sources say

• Not checked yetcites [333] Dai, 2010, Utilization of amino acids by bacteria from the pig small intestine, Amino Acids source
• Not checked yetcites [334] Yang, 2016, Metabolic shifts and structural changes in the gut microbiota upon branched-chain amino acid supplementation in middle-aged mice, Amino Acids source

In the paper

“Bile duct ligation alters the GM composition, and increases the permeability of the BBB (328, 329).”

What the sources say

• Not checked yetcites [328] Quinn, 2014, Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms, Dig Liver Dis source
• Not checked yetcites [329] Cabrera-Rubio, 2019, Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice, Sci Rep source

In the paper

“In a subsequent study, it was shown that FMT from stressed dams into stress-naïve germ-free mice was sufficient to instill the phenotype observed in stress-exposed offspring (344).”

What the sources say

• Not checked yetcites [344] Jašarević, 2018, The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus, Nat Neurosci source

In the paper

“Germ-free mice had increased acetylcholine, ACTH, and corticosterone responses following acute stress, indicative of enhanced HPA axis activity.”

What the sources say

• Not checked yetcites [51] Sudo, 2004, Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice, J Physiol source