Table 2.
Afferent and efferent signaling along the microbiome-gut-brain axis, clinical studies
| Reference | Direction | Dep. Induction/Dx | Treatment | Measurement | Relevant Effects | |
|---|---|---|---|---|---|---|
| 1 | (Rajca et al., 2014) | Efferent (host system to microbiota) | Mood symptoms not reported | None | None | Immune System (IS): Individuals who relapsed with Crohn’s disease symptoms after discontinuing infliximab treatment had decreased fecal microbiota relative abundance (↑phylum Firmicutes). |
| Endocrine System (ES): None Reported | ||||||
| Central Nervous System (CNS): None Reported | ||||||
| 2 | (Maes, et al., 2012) | Afferent (microbiota to host system) | DSM-IV-R diagnosis of major depression with or without melancholia | None | Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF), Hamilton Depression Rating Scale (HDRS) | IS: Depressed individuals had ↑ circulating IgM and ↑ IgA antibodies against LPS, indicating increased bacterial translocation. IgA concentration correlated with severity of gastrointestinal symptoms. |
| ES: None Reported | ||||||
| CNS: None Reported | ||||||
| 3 | (Stevens et al., 2018) | Afferent (microbiota to host system) | DSM-5 criteria for a depressive or anxiety disorder | None | None | IS: Individuals with depressive and/or anxiety disorders had altered plasma levels of: ↑ LPS, ↑ zonulin, and ↑ fatty acid-binding protein 2, as well as an overrepresentation of LPS biosynthesis genes in the fecal microbiome. |
| ES: None Reported | ||||||
| CNS: None Reported | ||||||
| 4 | (Kiecolt-Glaser et al., 2018) | Afferent (microbiota to host system) | No diagnostic inclusion criteria | None | Couples Satisfaction Index (CSI), Behavioral coding of exchanges via the Rapid Marital Interaction Coding System (RMICS), Structured Clinical Interview for the DSM-IV, nonpatient version (SCID-IV-NP) | IS: Couples with hostile marital interactions had altered circulating: ↑ LPS binding protein (LBP), and ↑ CRP, and individuals with a history of mood disorders had altered circulating levels: ↑ ratio LBP/sCD14 and ↑ CRP |
| ES: None Reported | ||||||
| CNS: None Reported | ||||||
| 5 | (Akkasheh et al., 2016) | Afferent (microbiota to host system) | DSM-IV diagnosis of major depressive disorder | Three-strain probiotic blend (L. acidophilus, L. casei, and B. bifidum) | Beck Depression Inventory (BDI) | IS: Depressed individuals receiving the probiotic had ↓ circulating CRP. |
| None Reported | ||||||
| CNS: Probiotic treatment decreased depression symptoms | ||||||
| 6 | (Nishihira et al., 2014) | Afferent (microbiota to host system) | Healthy subjects | Probiotic yogurt containing L. gasseri SBT2055 and B. longum SBT2928 | General Health Questionnaire-28 (GHQ-28) | IS: Probiotic treatment resulted in ↑ activity of circulating NK cells. |
| ES: Probiotic treatment ↓ circulating ACTH | ||||||
| CNS: Probiotic treatment decreased anxiety, but not depression, symptoms | ||||||
| 7 | (Marcos et al., 2004) | Afferent (microbiota to host system) | Healthy subjects | Probiotic milk beverage containing L. casei DN-11400 | None | IS: Twice daily probiotic consumption resulted in ↑ blood lymphocytes and rescued ↓ CD56+ cells in response to stress. |
| ES: Probiotic treatment prevented the ↑ in morning cortisol due to exam stress. | ||||||
| CNS: Probiotic treatment had no effect on anxiety symptoms | ||||||
| 8 | (Shinkai et al., 2013) | Afferent (microbiota to host system) | Healthy subjects over 65 years of age | L. pentosus b240 | Profile of Mood States Questionnaire (POMS), 36-Item Short Form Survey (SF-36) | IS: Probiotic treatment ↓ incidence of the common cold. |
| ES: None Reported | ||||||
| CNS: Probiotic treatment had no effect on depression or anxiety symptoms, but did improve general health perception | ||||||
| 9 | (Romijn, et al., 2017) | Afferent (microbiota to host system) | Self-reported depression | L. helveticus R0052 and B. longum R0175 | Depression, Anxiety and Stress Scales (DASS-42), Global Assessment of Functioning (GAF), Improved Clinical Global Impressions scale (iCGI), Montgomery–Åsberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology-Self-Report-16 (QIDS-SR-16) | IS: Probiotic treatment resulted in no change to measured circulating immune markers. |
| ES: None Reported | ||||||
| CNS: Probiotic treatment had no effect on depression or anxiety symptoms | ||||||
| 10 | (Rudzki et al., 2019) | Afferent (microbiota to host system) | DSM-IV-R diagnosis of major depression | L. plantarum 299v | Attention and Perceptivity Test (APT), California Verbal Learning Test (CVLT), HAMD, Symptom Checklist-90 (SC-90), Perceived Stress Scale (PSS) | IS: Probiotic treatment resulted in no change to measured circulating immune markers. |
| ES: None Reported | ||||||
| CNS: Probiotic treatment had no effect on depression or anxiety symptoms, however it did increase cognitive functioning on the APT and CVLT, as well as decrease circulating kynurenine and increased the 3-HK:kynurenine ratio. | ||||||
| 16 | (Vanuytsel et al., 2014) | Efferent (system to microbiota) | Healthy subjects | Intravenous bolus injection of CRH | State Trait Anxiety Inventory (STAI) | IS: None Reported |
| ES: Both the public speech condition and the CRH injection resulted in elevated intestinal permeability as measured by a lactulose-mannitol urinary excretion test. | ||||||
| CNS: The public speech condition increased anxiety scores, while the injection of CRH did not. | ||||||
| 22 | (Szczesniak, et al., 2016) | Afferent (microbiota to system) | ICD-10 diagnosis of depression | None | MADRS | IS: None Reported |
| ES: Fecal levels of isovaleric acid positively correlated with an average of morning and mid-day salivary cortisol measurements. | ||||||
| CNS: Depression symptoms positively correlated with fecal levels of isovaleric acid | ||||||
| 23 | (Messaoudi, Lalonde, et al., 2011) | Afferent (microbiota to system) | Healthy subjects | L. helveticus R0052 and B. longum R0175 | 90-item Hopkins Symptom Checklist (HSCL-90), Coping Checklist (CCL), HADS | IS: None Reported |
| ES: Probiotic treatment reduced 24-hour urinary free cortisol | ||||||
| CNS: Probiotic treatment decreased psychological distress, including depression symptoms | ||||||
| 11 | (Gorard, et al., 1996) | Efferent (host system to microbiota) | DSM-III-R criteria for major depression and or generalized anxiety disorder | None | BDI, HADS | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Individuals with GAD had the shortest whole-gut transit time when compared to individuals with MDD or controls. Whole gut transit time positively correlated with the BDI and HADS | ||||||
| 12 | (Emmanuel, et al., 2001) | Efferent (host system to microbiota) | Women with idiopathic constipation | None | GHQ-28 | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Mucosal blood flow correlated negatively with scores of depression and anxiety | ||||||
| 13 | (Christian et al., 2015) | Efferent (host system to microbiota) | Healthy children | None | Early Childhood Behavior Questionnaire | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Lower scores on Surgency/Extraversion were associated with decreased phylogenetic diversity in the gut | ||||||
| 14 | (Peter et al., 2018) | Afferent (microbiota to host system) | Subjects with IBD | None | HADS | IS: None Reported |
| ES: None Reported | ||||||
| CNS: 65% of individuals with IBD exhibited elevated psychological distress and 21% exhibited symptoms of depression | ||||||
| 15 | (Murphy, et al., 2018) | Afferent (microbiota to host system) | Women exposed to antibiotics peripartum | None | Edinburgh Postnatal Depression Scale (EPDS), PSS | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Antibiotic exposure predicted depressive symptoms at 1 month, but not at 3 or 6 months, postpartum | ||||||
| 16 | (Kazemi et al., 2018) | Afferent (microbiota to host system) | Mild to moderate major depression | L. helveticus R0052 and B. longum R0175 or galacto-oligosaccharide | BDI, HADS | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment, but not prebiotic treatment, decreased depressive symptoms. Probiotic treatment resulted in ↓ circulating kynurenine/tryptophan ratio, when adjusting for isoleucine | ||||||
| 17 | (Miki et al., 2016) | Afferent (microbiota to host system) | Healthy subjects | None | Center for Epidemiologic Studies Depression scale (CES-D) | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Dietary fiber intake negatively correlated with symptoms of depression | ||||||
| 18 | (Pinto-Sanchez et al., 2017) | Afferent (microbiota to host system) | Mild to moderate anxiety and/or depression scores on the HADS | B. longum NCC3001 | HADS | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment showed sustained reduction in depression symptoms, but not anxiety symptoms | ||||||
| 19 | (Mohammadi et al., 2016) | Afferent (microbiota to host system) | Healthy subjects | Probiotic capsule, probiotic yogurt, or conventional yogurt | GHQ-28 | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Both probiotic treatment conditions decreased depression symptoms | ||||||
| 20 | (Messaoudi, Violle, et al., 2011) | Afferent (microbiota to host system) | Healthy subjects | L. helveticus R0052 and B. longum R0175 | HSCL-90 | IS: None Reported |
| ES: Individuals who are low in urinary free cortisol still benefit from probiotic treatment | ||||||
| CNS: Probiotic treatment decreased psychological distress, including depression symptoms | ||||||
| 21 | (Slykerman et al., 2017) | Afferent (microbiota to host system) | Pregnant woman (due to risk for postpartum depression) | L. rhamnosus HN001 | EPDS, STAI | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment decreased depression and anxiety symptoms | ||||||
| 22 | (Benton et al., 2007) | Afferent (microbiota to host system) | Healthy subjects | Milk drink containing L. casei Shirota | POMS | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment decreased depression symptoms for subjects who initially began the study in the bottom third of the depressed/elated POMS dimension | ||||||
| 23 | (Steenbergen et al., 2015) | Afferent (microbiota to host system) | Healthy subjects | Multi-strain probiotic | Leiden Index of Depression Sensitivity Scale | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment decreased cognitive reactivity to sad mood | ||||||
| 24 | (Rao et al., 2009) | Afferent (microbiota to host system) | Subjects with chronic fatigue syndrome | L. casei Shirota | Beck Anxiety Inventory (BAI), BDI | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment decreased anxiety, but not depression, symptoms | ||||||
| 25 | (Chung et al., 2014) | Afferent (microbiota to host system) | Healthy subjects between 60 and 75 years of age | Fermented milk containing L. helveticus IDCC3801 | Geriatric Depression Scale Short Form, PSS, Neuropsychological test battery | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment had no effect on depression or anxiety symptoms, but did↑ cognitive functioning on a battery of neuropsychological tests | ||||||
| 26 | (Östlund-Lagerström et al., 2015) | Afferent (microbiota to host system) | Healthy subjects over 65 years of age | L. reuteri DSM17938 | HADS, EuroQuol, PSS | IS: None Reported |
| ES: None Reported | ||||||
| CNS: Probiotic treatment had no effect on symptoms of depression, anxiety, or well-being |