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

In the paper

“These changes include increased hippocampal dopamine D1 receptor mRNA levels and decreased dopamine D1 receptor in the striatum and nucleus accumbens, as well as increased serotonin in the blood and hippocampus, with decreased serotonin receptor expression, respectively.”

What the sources say

• Disputed

  Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  cites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci sourceExperimental — accuracy not yet measured
• 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 [350] Clarke, 2013, The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner, Mol Psychiatry source
• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [378] Lukić, 2019, Role of tryptophan in microbiota-induced depressive-like behavior: evidence from tryptophan depletion study, Front Behav Neurosci sourceExperimental — accuracy not yet measured
• Not checked yetcites [379] Lyte, 2020, Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source
• Disputed

  Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  cites [380] Matsumoto, 2013, Cerebral low-molecular metabolites influenced by intestinal microbiota: a pilot study, Front Syst Neurosci sourceExperimental — accuracy not yet measured

In the paper

“Behavioral differences in germ-free mice include their anxiolytic-like manner when compared to SPF controls, although some studies report increased anxiety-like behavior in different species (124, 189, 351, 376).”

What the sources say

• Supported

  The Results report that germ-free mice showed reduced anxiety-like behavior compared with SPF controls, including more time in the light compartment and open maze arms. This paper supports the germ-free mouse comparison; the contrasting findings in other species are presented as findings from other studies in the multi-citation sentence. (LLM, conf=0.93)

  cites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci 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 [351] Crumeyrolle-Arias, 2014, Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats, Psychoneuroendocrinology source
• Not checked yetcites [376] Bercik, 2011, The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice, Gastroenterology source

In the paper

“In another study, B-GOS supplementation was compared to placebo in healthy participants and found to decrease waking salivary cortisol concentrations and increase the positive processing of information in a dot-probe task (485).”

What the sources say

• Supported

  The Discussion describes a study in healthy volunteers and reports decreased waking salivary cortisol reactivity after B-GOS compared with placebo. The Results (Cortisol; Emotional Test Battery) confirm a lower cortisol awakening response and increased vigilance to positive versus negative information in the unmasked dot-probe condition. (LLM, conf=0.94)

  cites [485] Schmidt, 2015, Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers, Psychopharmacology source

In the paper

“A study of chronic adrenal insufficiency patients highlighted that 30% of the participants suffered frequent and incapacitating gut symptoms, consistent with the Rome IV criteria for IBS, and that they had a decreased quality of life (530).”

What the sources say

• Partly supported

  The Results (Digestive assessment and quality of life; page unavailable) report that 35 CAI patients (30%) had symptoms consistent with Rome IV IBS criteria. The Abstract reports poorer quality of life among CAI patients than controls, but the Discussion says the study could not establish an association between digestive symptoms and quality of life. It therefore does not show that the 30% with IBS-like symptoms specifically had decreased quality of life. (LLM, conf=0.87)

  cites [530] Quénéhervé, 2021, Digestive symptoms in daily life of chronic adrenal insufficiency patients are similar to irritable bowel syndrome symptoms, Sci Rep sourceExperimental — accuracy not yet measured

In the paper

“Studies in animals have demonstrated the effect that the GM has on neural development and neurochemistry in the host, influencing the stress system, behavior, and cognition (42–47).”

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 [43] Moloney, 2014, The microbiome: stress, health and disease, Mamm Genome source
• Not checked yetcites [44] Salami, 2021, Interplay of good bacteria and central nervous system: cognitive aspects and mechanistic considerations, Front 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 [46] Vuong, 2017, The microbiome and host behavior, Annu Rev Neurosci source
• Not checked yetcites [47] Connell, 2022, Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia, Mol Neurodegener source

In the paper

“Alterations in the GM, whether due to diet, antibiotics, or other factors, can impact the stress response, HPA axis activity, and overall cognitive health.”

In the paper

“Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life.”

• Also stated in: § The HPA axis, glucocorticoids, and the stress response · plain

  “Glucocorticoids also play a vital role in central nervous system (CNS) development and are required for normal maturation (139).”

What the sources say

• Not checked yetcites [139] Strehl, 2019, Glucocorticoids–All-Rounders tackling the versatile players of the immune system, Front Immunol source

In the paper

“However, the acquisition of microbes occurs primarily at birth, with delivery through the birth canal exposing the infant to its mother’s microbiota, resulting in vertical transmission of an initial maternal signature (81).”

What the sources say

• Not checked yetcites [81] Frese, 2015, Birth of the infant gut microbiome: moms deliver twice, Cell Host Microbe source

In the paper

“Elevated cortisol levels have been associated with alterations in GM composition and increased gut permeability, which can lead to inflammation and contribute to brain dysfunction and various CNS disorders (56).”

What the sources say

• Not checked yetcites [56] Mangiola, 2016, Gut microbiota in autism and mood disorders, World J Gastroenterol source

In the paper

“Chronic or prolonged stress can lead to dysregulation of the HPA axis, which can have negative effects on various bodily systems, including the MGB axis (55).”

What the sources say

• Not checked yetcites [55] Kelly, 2016, Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat, J Psychiatr Res source

In the paper

“Cortisol receptors are expressed on various cells of the gut, including epithelial cells, immune cells, and enteroendocrine cells, indicating a direct effect of cortisol on gut function (21, 29, 48).”

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 [29] Tetel, 2018, Steroids, stress and the gut microbiome-brain axis, J Neuroendocrinol source
• Not checked yetcites [48] Mayer, 2000, The neurobiology of stress and gastrointestinal disease, Gut source

In the paper

“Cortisol can also affect the gut microbiota by altering gut transit time, intestinal permeability, and nutrient availability, which can in turn impact the composition and diversity of the GM (48).”

What the sources say

• Not checked yetcites [48] Mayer, 2000, The neurobiology of stress and gastrointestinal disease, Gut source

In the paper

“A more stable and complex, adult-like microbiota starts to emerge as early as one to three years of age, although this development may continue as late as pre-adolescence (85, 86).”

What the sources say

• Not checked yetcites [85] Yatsunenko, 2012, Human gut microbiome viewed across age and geography, Nature source
• Not checked yetcites [86] Hollister, 2015, Structure and function of the healthy pre-adolescent pediatric gut microbiome, Microbiome source

In the paper

“The HPA axis plays a central role in mediating the stress response and regulating the interaction between the GM, gut, and brain (42).”

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

In the paper

“In adulthood, the core GM is relatively stable, and the main factors influencing its composition are diet, exercise, stress, disease, and medications (88).”

What the sources say

• Not checked yetcites [88] Martino, 2022, Microbiota succession throughout life from the cradle to the grave, Nat Rev Microbiol source

In the paper

“Finally, germ-free animal studies demonstrate that the GM is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition (123).”

What the sources say

• Not checked yetcites [123] Luczynski, 2016, Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior, Int J Neuropsychopharmacol source

In the paper

“There is also evidence that the diversity levels of the GM differ with aging, with a reduction in the number of different bacterial species present and changes in the relative abundance of different bacterial phyla, with a decrease in beneficial bacteria such as Bifidobacteria and an increase in potentially harmful bacteria such as Proteobacteria (93–96).”

What the sources say

• Not checked yetcites [93] Claesson, 2011, Composition, variability, and temporal stability of the intestinal microbiota of the elderly, Proc Natl Acad Sci U.S.A. source
• Not checked yetcites [94] O’Toole, 2015, Gut microbiota and aging, Science source
• Not checked yetcites [95] Odamaki, 2016, Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study, BMC Microbiol source
• Not checked yetcites [96] Biagi, 2010, Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians, PloS One source

In the paper

“Human studies comparing the composition of the GM of elderly participants suffering from cognitive impairment with healthy individuals indicate significant changes in GM composition. Specifically, there is an increase in pro-inflammatory taxa and a reduction in anti-inflammatory taxa (104–109).”

What the sources say

• Not checked yetcites [104] Cattaneo, 2017, Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly, Neurobiol Aging source
• Not checked yetcites [105] Vogt, 2017, Gut microbiome alterations in alzheimer’s disease, Sci Rep source
• Not checked yetcites [106] Manderino, 2017, Preliminary evidence for an association between the composition of the gut microbiome and cognitive function in neurologically healthy older adults, J Int Neuropsychol Soc source
• Not checked yetcites [107] Zhuang, 2018, Gut microbiota is altered in patients with alzheimer’s disease, J Alzheimers Dis source
• Not checked yetcites [108] Saji, 2019, Analysis of the relationship between the gut microbiome and dementia: a cross-sectional study conducted in Japan, Sci Rep source
• Not checked yetcites [109] Sheng, 2021, Altered gut microbiota in adults with subjective cognitive decline: the SILCODE study, J Alzheimers Dis source

In the paper

“Similar to aging, dysbiosis has been associated with increased cortisol secretion, decreased negative feedback at the level of the hypothalamus, and changes in the circadian rhythm of cortisol release (113).”

What the sources say

• Not checked yetcites [113] Farzi, 2018, Gut microbiota and the neuroendocrine system, Neurotherapeutics source

In the paper

“Essentially, the HPA axis appears to become less responsive with aging, contributing to the dysregulation of stress responses and the resultant development of cognitive decline (111, 112).”

What the sources say

• Not checked yetcites [111] Lupien, 1998, Cortisol levels during human aging predict hippocampal atrophy and memory deficits, Nat Neurosci source
• Not checked yetcites [112] Hinkelmann, 2012, Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: a longitudinal study, Psychoneuroendocrinology source

In the paper

“These peptides stimulate the release of adrenocorticotropic hormone (ACTH) from corticotropic cells of the anterior pituitary gland, which in turn targets the zona fasciculata of the adrenal cortex to produce glucocorticoids, such as cortisol in humans and corticosterone in rodents (133–135).”

What the sources say

• Not checked yetcites [133] Rifai, 2018
• Not checked yetcites [134] Buckingham, 1996, The physiology of immunity, Progress in Brain Research
• Not checked yetcites [135] Buckingham, 2006, Glucocorticoids: exemplars of multi-tasking, Br J Pharmacol source

In the paper

“The HPA axis is a major stress response system in the body, with neurons in the hypothalamic paraventricular nucleus (PVN) synthesizing and secreting corticotropin-releasing hormone (CRH) and antidiuretic hormone (ADH) in response to stress (133).”

What the sources say

• Not checked yetcites [133] Rifai, 2018

In the paper

“Cortisol acts on the hypothalamus and pituitary in a negative feedback loop to regulate the response (133).”

What the sources say

• Not checked yetcites [133] Rifai, 2018

In the paper

“HPA axis dysfunction is linked to a decline in cognitive function, aging, immune system dysfunction, and systemic inflammation (135).”

What the sources say

• Not checked yetcites [135] Buckingham, 2006, Glucocorticoids: exemplars of multi-tasking, Br J Pharmacol source

In the paper

“Microbes influence CNS processes via modulation of the nervous system (52), endocrine system (51, 126), and immune system (120), together with their ability to synthesize neurotransmitters (127–129) and produce metabolites (127, 130–132) ( Figure 1 ).”

What the sources say

• Not checked yetcites [52] Forsythe, 2014
• 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 [126] Mudd, 2017, Serum cortisol mediates the relationship between fecal ruminococcus and brain n-acetylaspartate in the young pig, Gut Microbes source
• Not checked yetcites [120] Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat Neurosci source

In the paper

“male germ-free mice have increased hippocampal serotonin levels, which colonization immediately post-weaning does not reverse (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

“GABA does not cross the BBB and so microbial-derived GABA would need to act locally on the ENS or vagus nerve to influence the CNS.”

In the paper

“the development of the serotonergic system within the MGB axis depends on a low-stress environment and early life events may be critical.”

In the paper

“When administered to rats, B. infantis results in reduced 5-HIAA (serotonin metabolite) concentrations in the frontal cortex, and a marked increase in blood concentrations of tryptophan and kynurenic acid (224).”

What the sources say

• Not checked yetcites [224] Desbonnet, 2008, The probiotic bifidobacteria infantis: an assessment of potential antidepressant properties in the rat, J Psychiatr Res source

In the paper

“brainstem catecholaminergic centers play an important role in the regulation of the HPA axis (227) and noradrenergic neurons are required for normal activation in response to a variety of stressors.”

What the sources say

• Not checked yetcites [227] Herman, 2016, Regulation of the hypothalamic-Pituitary-Adrenocortical stress response, Compr Physiol source

In the paper

“in a study of healthy women, levels of Bacteroides, identified as the major microbial producers of GABA, were associated with increased grey matter in the cerebellum, hippocampus, and frontal regions of the brain, as well as reduced levels of anxiety, distress, and irritability (236).”

What the sources say

• Not checked yetcites [236] Tillisch, 2017, Brain structure and response to emotional stimuli as related to gut microbial profiles in healthy women, Psychosom Med source

In the paper

“The GM can further regulate serotonin availability by signaling enterochromaffin cells to produce serotonin via expression of tryptophan hydroxylase, and by altering levels of SCFAs and BAs which can influence serotonin production (46, 164, 221–223).”

What the sources say

• Not checked yetcites [46] Vuong, 2017, The microbiome and host behavior, Annu Rev Neurosci source
• Not checked yetcites [164] Yano, 2015, Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis, Cell source
• Not checked yetcites [221] Gershon, 2007, The serotonin signaling system: from basic understanding to drug development for functional GI disorders, Gastroenterology source
• Not checked yetcites [222] Reigstad, 2015, Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells, FASEB J Off Publ Fed Am Soc Exp Biol source
• Not checked yetcites [223] Wikoff, 2009, Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites, Proc Natl Acad Sci source

In the paper

“The GM can metabolize GABA and recent research has shown that certain microbes can produce GABA, required for their growth (235).”

What the sources say

• Not checked yetcites [235] Strandwitz, 2019, GABA-modulating bacteria of the human gut microbiota, Nat Microbiol source

In the paper

“the GM can indirectly influence the activity of the serotonergic system, which in turn can affect the HPA axis and stress response.”

In the paper

“SCFAs such as acetate can cross the BBB and be incorporated into the GABA metabolic cycle (237).”

What the sources say

• Not checked yetcites [237] Frost, 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nat Commun source

In the paper

“bacteria produce noradrenaline as a quorum sensing molecule, and noradrenaline and adrenaline can promote pathogenesis and growth (229, 230)”

What the sources say

• Not checked yetcites [229] Sperandio, 2003, Bacteria–host communication: the language of hormones, Proc Natl Acad Sci source
• Not checked yetcites [230] Lyte, 1992, Catecholamine induced growth of gram negative bacteria, Life Sci source

In the paper

“Activation of stress-responsive TDO or immune-responsive IDO can limit the availability of tryptophan for serotonin synthesis and increase the downstream production of neurotoxic or neuroprotective metabolites (31).”

What the sources say

• Not checked yetcites [31] O’Mahony, 2015, Serotonin, tryptophan metabolism and the brain-gut-microbiome axis, Behav Brain Res source

In the paper

“Glucocorticoids and tryptophan induce TDO, while cytokines induce IDO (200).”

What the sources say

• Not checked yetcites [200] Ruddick, 2006, Tryptophan metabolism in the central nervous system: medical implications, Expert Rev Mol Med source

In the paper

“The ECS modulates a multitude of physiological processes, including the HPA axis (241), cognition, learning and memory (242), intestinal-barrier function (243), inflammation (244), energy metabolism (245), among others (reviewed recently (239)).”

What the sources say

• Not checked yetcites [241] Micale, 2018, Endocannabinoid system, stress and HPA axis, Eur J Pharmacol source
• Not checked yetcites [242] Zanettini, 2011, Effects of endocannabinoid system modulation on cognitive and emotional behavior, Front Behav Neurosci source
• Not checked yetcites [243] Muccioli, 2010, The endocannabinoid system links gut microbiota to adipogenesis, Mol Syst Biol source
• Not checked yetcites [244] Donvito, 2018, The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain, Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol source
• Not checked yetcites [245] Wang, 2008, Role of the endocannabinoid system in metabolic control, Curr Opin Nephrol Hypertens source
• Not checked yetcites [239] Cristino, 2020, Cannabinoids and the expanded endocannabinoid system in neurological disorders, Nat Rev Neurol source

In the paper

“The HPA axis is also regulated by GABAergic signaling at the level of CRH, and nearly 50% of all synapses in the PVN are GABAergic (233).”

What the sources say

• Not checked yetcites [233] Miklós, 2002, GABAergic innervation of corticotropin-releasing hormone (CRH)-secreting parvocellular neurons and its plasticity as demonstrated by quantitative immunoelectron microscopy, Neuroscience source

In the paper

“Serotonergic neurons have a significant influence on neuroendocrine function, and there is a dynamic interplay and extensive crosstalk between the serotonergic system and HPA axis (215).”

What the sources say

• Not checked yetcites [215] Berger, 2009, The expanded biology of serotonin, Annu Rev Med source

In the paper

“Mounting evidence suggests that the GM modulates the tryptophan and kynurenine pathways and is a humoral route through which the GM may influence cognition at the level of the CNS (206–210).”

What the sources say

• Not checked yetcites [206] Bosi, 2020, Tryptophan metabolites along the microbiota-Gut-Brain axis: an interkingdom communication system influencing the gut in health and disease, Int J Tryptophan Res source
• Not checked yetcites [207] Kiser, 2012, The reciprocal interaction between serotonin and social behaviour, Neurosci Biobehav Rev source
• Not checked yetcites [208] Homberg, 2012, Serotonin and decision making processes, Neurosci Biobehav Rev source
• Not checked yetcites [209] Schwarcz, 2012, Kynurenines in the mammalian brain: when physiology meets pathology, Nat Rev Neurosci source
• Not checked yetcites [210] Szalardy, 2012, Manipulating kynurenic acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction, Curr Top Med Chem source

In the paper

“there is a growing body of evidence suggesting that the GM can ultimately influence the levels of neurotransmitters in the brain and alter brain function and cognition.”

In the paper

“Germ-free mice exhibit reduced colonic serotonin production and decreased levels in the blood, which normalize with microbial colonization (164, 223).”

What the sources say

• Not checked yetcites [164] Yano, 2015, Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis, Cell source
• Not checked yetcites [223] Wikoff, 2009, Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites, Proc Natl Acad Sci source

In the paper

“Healthy mice colonized with Candida albicans showed marked anxiety-like behavior and increased corticosterone concentrations that were inversely correlated with forebrain AEA, demonstrating disruption of the HPA axis through dysregulation of the ECS (253).”

What the sources say

• Not checked yetcites [253] Markey, 2020, Colonization with the commensal fungus candida albicans perturbs the gut-brain axis through dysregulation of endocannabinoid signaling, Psychoneuroendocrinology source

In the paper

“Microbes and microbial products then gain access to the circulation and may gain easier access to the CNS (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

“Dysbiosis affects eCB signaling, and vice versa (243).”

What the sources say

• Not checked yetcites [243] Muccioli, 2010, The endocannabinoid system links gut microbiota to adipogenesis, Mol Syst Biol source

In the paper

“SCFAs are necessary for the maintenance of CNS homeostasis, learning and cognition, and reward-associated behaviors (25).”

What the sources say

• Not checked yetcites [25] Cryan, 2019, The microbiota-gut-brain axis, Physiol Rev source

In the paper

“SCFAs can modulate the levels of neurotransmitters and neurotrophic factors and regulate the expression of tryptophan 5-hydroxylase, the enzyme involved in the synthesis of serotonin, and tyrosine hydroxylase, the enzyme involved in the rate-limiting step in dopamine, noradrenaline, and adrenaline synthesis (18, 132, 164, 222).”

What the sources say

• Not checked yetcites [18] Clarke, 2014, Minireview: gut microbiota: the neglected endocrine organ, Mol Endocrinol 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 [164] Yano, 2015, Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis, Cell source
• Not checked yetcites [222] Reigstad, 2015, Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells, FASEB J Off Publ Fed Am Soc Exp Biol source

In the paper

“microbial products, cytokines, and other immune molecules released under the influence of the GM may further influence the BBB’s integrity, alter BBB transport rates, and promote the release of neuroimmune molecules from the cells of the 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

“These factors may lead to neuroinflammation, which is an important process shaping brain function.”

In the paper

“Perturbations in microbial diversity, secondary to antimicrobials, have been shown to influence pro-inflammatory cytokine secretion in the CNS and alter microglial morphology (268–270).”

What the sources say

• Not checked yetcites [268] Minter, 2016, Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of alzheimer’s disease, Sci Rep source
• Not checked yetcites [269] Minter, 2017, Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP SWE /PS1 ΔE9 murine model of alzheimer’s disease OPEN, Sci Rep source
• Not checked yetcites [270] Jang, 2018, Evidence for interplay among antibacterial-induced gut microbiota disturbance, neuro-inflammation, and anxiety in mice, Mucosal Immunol source

In the paper

“The GM is therefore closely linked to the immune system, and they interact in several ways [reviewed recently (256, 257)].”

What the sources say

• Not checked yetcites [256] Zheng, 2020, Interaction between microbiota and immunity in health and disease, Cell Res source
• Not checked yetcites [257] Zhang, 2022, The complex link and disease between the gut microbiome and the immune system in infants, Front Cell Infect Microbiol source

In the paper

“In response to stress, eCB signaling modulates glucocorticoid and CRH signaling in the brain and is crucial in recovering homeostasis (241, 246, 247).”

What the sources say

• Not checked yetcites [241] Micale, 2018, Endocannabinoid system, stress and HPA axis, Eur J Pharmacol source
• Not checked yetcites [246] Srivastava, 2022, The microbiome and gut endocannabinoid system in the regulation of stress responses and metabolism, Front Cell Neurosci source
• Not checked yetcites [247] Hillard, 2016, Endocannabinoid signaling and the hypothalamic-Pituitary-Adrenal axis, Compr Physiol source

In the paper

“Some BAs serve as substrates for gut microbes, while others exhibit antimicrobial properties, actively shaping the GM at the highest taxonomic levels (318).”

What the sources say

• Not checked yetcites [318] Peter, 2006, Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria, J Bacteriol source

In the paper

“The GM influences BA metabolism, and BAs affect the GM’s composition (296).”

What the sources say

• Not checked yetcites [296] Ramírez-Pérez, 2017, The role of the gut microbiota in bile acid metabolism, Ann Hepatol source

In the paper

“These findings suggest that SCFAs regulate CNS processes through both direct and indirect mechanisms and may ultimately affect host cognition and response to stress.”

In the paper

“TGR5, expressed in brain and peripheral neurons, as well as glial and microglial cells, can be activated by several neurosteroids (305).”

What the sources say

• Not checked yetcites [305] Keitel, 2010, The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain, Glia source

In the paper

“Changes in the GM’s composition correspond to changes in blood and brain BA profiles, which are essential because specific BA ligands’ distinct physicochemical properties determine the potency of BA receptor activation (320–323).”

What the sources say

• Not checked yetcites [320] Grant, 2020, Bile acid signaling in neurodegenerative and neurological disorders, Int J Mol Sci source
• Not checked yetcites [321] Jia, 2020, Expert insights: the potential role of the gut microbiome-bile acid-brain axis in the development and progression of alzheimer’s disease and hepatic encephalopathy, Med Res Rev source
• Not checked yetcites [322] Makishima, 1999, Identification of a nuclear receptor for bile acids, Science source
• 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

“In stressed mice, SCFA administration reduced HPA axis hyperactivity and intestinal permeability (291).”

What the sources say

• Not checked yetcites [291] van de Wouw, 2018, Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations, J Physiol source

In the paper

“FXR knockout mice exhibit abnormal BA and neurotransmitter concentrations, resulting in impaired cognition and motor coordination (304).”

What the sources say

• Not checked yetcites [304] Huang, 2015, Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior, Front Behav Neurosci source

In the paper

“these metabolites have emerged as important modulators of the MGB axis, functioning directly via BA receptors in the ENS and brain or indirectly via GLP-1 or the FXR-FGF15/19 axis (297, 319).”

What the sources say

• Not checked yetcites [297] Mertens, 2017, Bile acid signaling pathways from the enterohepatic circulation to the central nervous system, Front Neurosci source
• Not checked yetcites [319] Katafuchi, 2022, Molecular basis of bile acid-FXR-FGF15/19 signaling axis, Int J Mol Sci source

In the paper

“BA receptors are present in the brain, and BAs can either be synthesized locally or actively transported across the BBB by BA transporters from circulation (297, 301, 302).”

What the sources say

• Not checked yetcites [297] Mertens, 2017, Bile acid signaling pathways from the enterohepatic circulation to the central nervous system, Front Neurosci source
• Not checked yetcites [301] Trauner, 2003, Bile salt transporters: molecular characterization, function, and regulation, Physiol Rev source
• Not checked yetcites [302] Baloni, 2020, Metabolic network analysis reveals altered bile acid synthesis and metabolism in alzheimer’s disease, Cell Rep Med source

In the paper

“Cholestasis, associated with suppression of the HPA axis, likely due to BA interactions with glucocorticoid receptors in the brain (299, 312).”

What the sources say

• Not checked yetcites [299] McMillin, 2015, Suppression of the HPA axis during cholestasis can be attributed to hypothalamic bile acid signaling, Mol Endocrinol source
• Not checked yetcites [312] Perry, 2015, FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis, Nat Commun source

In the paper

“FXR activation is known to regulate lipoprotein receptors and transporters, as well as enzymes in the steroidogenic pathway, and has been shown to increase corticosterone levels in mice (311).”

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

In the paper

“Mice supplemented with a BCAA-enriched cocktail exhibited improved physical endurance and an extended lifespan (335).”

What the sources say

• Not checked yetcites [335] D’Antona, 2010, Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice, Cell Metab source

In the paper

“Stress during pregnancy disrupts the vertical transmission of microbes from mother to offspring, leading to alterations in the maternal microbiota, which are then transferred to the offspring (342).”

What the sources say

• Not checked yetcites [342] Dinan, 2012, Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology, Psychoneuroendocrinology source

In the paper

“The microbiota and HPA axis develop rapidly and profoundly in the first years of life, and environmental stressors can affect both (146–148).”

What the sources say

• Not checked yetcites [146] Gur, 2019, Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring, Behav Brain Res source
• Not checked yetcites [147] Zijlmans, 2015, Maternal prenatal stress is associated with the infant intestinal microbiota, Psychoneuroendocrinology source
• Not checked yetcites [148] Jang, 2018, Immobilization stress-induced escherichia coli causes anxiety by inducing NF-κB activation through gut microbiota disturbance, Sci Rep source

In the paper

“In response to early life stress, younger rats had increased neurogenesis, decreased BDNF IV promoter histone methylation, with a complementary increase in hippocampal BDNF concentration, and associated improvements in spatial and non-spatial learning (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

“In contrast, middle-aged rats demonstrated opposing changes, concomitant with impairments in hippocampal-dependent cognitive tasks.”

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

“In the CNS, BCAAs play roles in protein synthesis, food intake regulation, and serve as nitrogen donors involved in intercellular shuttling and the synthesis of the neurotransmitters glutamate and GABA (both modulate the HPA axis) (336).”

What the sources say

• Not checked yetcites [336] Sperringer, 2017, Branched-chain amino acids and brain metabolism, Neurochem Res source

In the paper

“Early life stressors, and in utero stressors, can impact the development and function of the HPA axis (149).”

What the sources say

• Not checked yetcites [149] Maniam, 2014, Early-life stress, HPA axis adaptation, and mechanisms contributing to later health outcomes, Front Endocrinol source

In the paper

“Early life stress, such as maternal separation, activates the HPA axis with associated changes to the developing microbiota, ultimately leading to an imbalance in the GM and an inappropriate stress response (18).”

What the sources say

• Not checked yetcites [18] Clarke, 2014, Minireview: gut microbiota: the neglected endocrine organ, Mol Endocrinol source

In the paper

“The microbiota and HPA axis develop rapidly and profoundly in the first years of life, and environmental stressors can affect both (146–148).”

What the sources say

• Not checked yetcites [146] Gur, 2019, Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring, Behav Brain Res source
• Not checked yetcites [147] Zijlmans, 2015, Maternal prenatal stress is associated with the infant intestinal microbiota, Psychoneuroendocrinology source
• Not checked yetcites [148] Jang, 2018, Immobilization stress-induced escherichia coli causes anxiety by inducing NF-κB activation through gut microbiota disturbance, Sci Rep source

In the paper

“These discordant results illustrate the biphasic consequences of early life stress and indicate a role for epigenetic modification of BDNF expression.”

In the paper

“Jašarević et al. demonstrated changes in the microbiome of these offspring, as well as alterations in the metabolome of the gut and brain (343).”

What the sources say

• Not checked yetcites [343] Jašarević, 2015, Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain, Endocrinology source

In the paper

“In the CNS, BCAAs play roles in protein synthesis, food intake regulation, and serve as nitrogen donors involved in intercellular shuttling and the synthesis of the neurotransmitters glutamate and GABA (both modulate the HPA axis) (336).”

What the sources say

• Not checked yetcites [336] Sperringer, 2017, Branched-chain amino acids and brain metabolism, Neurochem Res source

In the paper

“Following chronic restraint stress, germ-free mice showed significantly greater HPA axis activity, whereas the SPF mice exhibited more anxiety-like behaviors under the same stress (349).”

What the sources say

• Not checked yetcites [349] Huo, 2017, Microbiota modulate anxiety-like behavior and endocrine abnormalities in hypothalamic-pituitary-adrenal axis, Front Cell Infect Microbiol source

In the paper

“A study by Allen et al. demonstrated that the GM is necessary for stress-induced immunomodulation, with enhancement of splenic macrophage reactivity occurring in colonized controls but not in germ-free mice, in response to social disruption stress (360).”

What the sources say

• Not checked yetcites [360] Allen, 2012, The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity, Brain Behav Immun source

In the paper

“Participants reported reductions in perceived stress, but these were not significantly different to controls, and markers of stress were unaffected.”

What the sources say

• Not checked yetcites [374] Berding, 2022, Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population, Mol Psychiatry source

In the paper

“In another RCT, a combination probiotic (L. helveticus (R0052) and B. longum (R0175)) administered to healthy volunteers was associated with beneficial psychological effects in participants and a decrease in 24-hour urinary cortisol, suggesting attenuation of the HPA axis in response to stressors (372).”

What the sources say

• Not checked yetcites [372] Messaoudi, 2011, Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and bifidobacterium longum R0175) in rats and human subjects, Br J Nutr source

In the paper

“The introduction of pathogenic bacteria reduced cognitive abilities and heightened anxiety-like behaviors (362, 363).”

What the sources say

• Not checked yetcites [362] Gareau, 2011, Bacterial infection causes stress-induced memory dysfunction in mice, Gut source
• Not checked yetcites [363] Jiang, 2013, The effect of maternal infection on cognitive development and hippocampus neuronal apoptosis, proliferation and differentiation in the neonatal rats, Neuroscience source

In the paper

“Similarly, pre-treatment with L. farciminis reduced HPA hyper-reactivity, intestinal permeability, and neuroinflammation resulting from restraint stress (367).”

What the sources say

• Not checked yetcites [367] Ait-Belgnaoui, 2012, Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats, Psychoneuroendocrinology source

In the paper

“Animal models of chronic stress demonstrate altered intestinal physiology and GM composition, with an increased secretory state and permeability (352–355).”

What the sources say

• Not checked yetcites [352] Söderholm, 2002, Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine, Gastroenterology source
• Not checked yetcites [353] Cameron, 2005, Stress impairs murine intestinal barrier function: improvement by glucagon-like peptide-2, J Pharmacol Exp Ther source
• Not checked yetcites [354] Sun, 2013, Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice, Gastroenterology source
• Not checked yetcites [355] Lutgendorff, 2008, The role of microbiota and probiotics in stress-induced gastro-intestinal damage, Curr Mol Med source

In the paper

“Alterations in cognition occurred both in the short- and long-term, confirming mechanisms for both the promotion and inhibition of cognitive performance during acute inflammatory stress.”

What the sources say

• Not checked yetcites [371] Grigoleit, 2011, Dose-dependent effects of endotoxin on neurobehavioral functions in humans, PloS One source

In the paper

“When challenged orally with the enteric murine pathogen C. rodentium, chronically stressed mice had an increased pathogen load and increased colonic TNF-α expression.”

What the sources say

• Not checked yetcites [359] Bailey, 2010, Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by citrobacter rodentium, Infect Immun source