Examining the Influence of the Human Gut Microbiota on Cognition and Stress: A Systematic Review of the Literature.

The gut microbiota is seen as an emerging biotechnology that can be manipulated to enhance or preserve cognition and physiological outputs of anxiety and depression in clinical conditions. However, the existence of such interactions in healthy young individuals in both non-stressful and stressful environments is unclear. The aim of this systematic review was to examine the relationship between the human gut microbiota, including modulators of the microbiota on cognition, brain function and/or stress, anxiety and depression. A total of n = 25 eligible research articles from a possible 3853 published between October 2018 and August 2021 were identified and included. Two study design methods for synthesis were identified: cross-sectional or pre/post intervention. Few cross-sectional design studies that linked microbiota to cognition, brain activity/structure or mental wellbeing endpoints existed (n = 6); however, correlations between microbiota diversity and composition and areas of the brain related to cognitive functions (memory and visual processing) were observed. Intervention studies targeting the gut microbiota to improve cognition, brain structure/function or emotional well-being (n = 19) generally resulted in improved brain activity and/or cognition (6/8), and improvements in depression and anxiety scores (5/8). Despite inherit limitations in studies reviewed, available evidence suggests that gut microbiota is linked to brain connectivity and cognitive performance and that modulation of gut microbiota could be a promising strategy for enhancing cognition and emotional well-being in stressed and non-stressed situations.

A Systematic Review of the Effect of Dietary Supplements on Cognitive Performance in Healthy Young Adults and Military Personnel.

Intake of dietary supplements has increased, despite evidence that some of these have adverse side effects and uncertainty about their effectiveness. This systematic review examined the evidence for the cognitive benefits of a wide range of dietary supplements in healthy young adult samples; the aim was to identify if any might be useful for optimising cognitive performance during deployment in military personnel. Searches were conducted in 9 databases and 13 grey literature repositories for relevant studies published between January 2000 and June 2017. Eligible studies recruited healthy young adults (18-35 years), administered a legal dietary supplement, included a comparison control group, and assessed cognitive outcome(s). Thirty-seven of 394 identified studies met inclusion criteria and were included for synthesis. Most research was deemed of low quality (72.97%; SIGN50 guidelines), highlighting the need for sound empirical research in this area. Nonetheless, we suggest that tyrosine or caffeine could be used in healthy young adults in a military context to enhance cognitive performance when personnel are sleep-deprived. Caffeine also has the potential benefit of improving vigilance and attention during sustained operations offering little opportunity for sleep. Inconsistent findings and methodological limitations preclude firm recommendations about the use of other specific dietary supplements.

Sphingosine 1-phosphate is a ligand for peroxisome proliferator-activated receptor-γ that regulates neoangiogenesis.

Sphingosine 1-phosphate (S1P) is a bioactive lipid that can function both extracellularly and intracellularly to mediate a variety of cellular processes. Using lipid affinity matrices and a radiolabeled lipid binding assay, we reveal that S1P directly interacts with the transcription factor peroxisome proliferator-activated receptor (PPAR)γ. Herein, we show that S1P treatment of human endothelial cells (ECs) activated a luciferase-tagged PPARγ-specific gene reporter by ∼12-fold, independent of the S1P receptors. More specifically, in silico docking, gene reporter, and binding assays revealed that His323 of the PPARγ ligand binding domain is important for binding to S1P. PPARγ functions when associated with coregulatory proteins, and herein we identify that peroxisome proliferator-activated receptor-γ coactivator 1 (PGC1)ß binds to PPARγ in ECs and their progenitors (nonadherent endothelial forming cells) and that the formation of this PPARγ:PGC1ß complex is increased in response to S1P. ECs treated with S1P selectively regulated known PPARγ target genes with PGC1ß and plasminogen-activated inhibitor-1 being increased, no change to adipocyte fatty acid binding protein 2 and suppression of CD36. S1P-induced in vitro tube formation was significantly attenuated in the presence of the PPARγ antagonist GW9662, and in vivo application of GW9662 also reduced vascular development in Matrigel plugs. Interestingly, activation of PPARγ by the synthetic ligand troglitazone also reduced tube formation in vitro and in vivo. To support this, Sphk1(-/-)Sphk2(+/-) mice, with low circulating S1P levels, demonstrated a similar reduction in vascular development. Taken together, our data reveal that the transcription factor, PPARγ, is a bona fide intracellular target for S1P and thus suggest that the S1P:PPARγ:PGC1ß complex may be a useful target to manipulate neovascularization.

Oral ingestion of Streptococcus thermophilus does not affect mucositis severity or tumor progression in the tumor-bearing rat.

Preventative or adjunctive agents for the amelioration of small intestinal chemotherapy-induced mucositis are not currently available for clinical use. We have previously demonstrated that oral ingestion of Streptococcus thermophilus (TH-4) partially attenuated chemotherapy-induced mucositis in the rat. Here we assess the effects of TH-4 on small intestinal damage and tumor progression in tumor-bearing rats with experimentally-induced mucositis. Female Dark Agouti tumor-bearing (mammary adenocarcinoma) rats (n = 36; 139 ± 1 g) had small intestinal damage induced via the administration of methotrexate (MTX). Rats were administered MTX; (1.5 mg/kg intramuscular) or saline at 0 and 24 h; with daily gavage administration of TH-4 (109 cfu/mL) or skim milk from -48 to +96 h post-MTX. Rats were allocated to groups (n=9): saline control, TH-4 control, MTX control or TH-4+MTX. The non-invasive ( 13) C-sucrose breath test (SBT) was conducted prior to tumor inoculation, pre-MTX (-24 h) and prior to sacrifice (96 h) to monitor gut function. At sacrifice small intestinal segments were excised and assessed for sucrase and myeloperoxidase activity as well as histological damage. Irrespective of TH-4 treatment, MTX-treated rats had a significant decrease in bodyweight, SBT levels, sucrase and myeloperoxidase activity, and histological damage score (p < 0.05) compared to saline and TH-4 control rats. TH-4 treatment did not result in tumor progression (p > 0.05) but failed to alleviate mucositis indices. Although TH-4, at a dose of 109 cfu/mL, yielded neither protection nor amelioration of chemotherapy-induced mucositis, progression of mammary adenocarcinoma was unaffected.

Maternal milk, but not formula, regulates the immune response to beta-lactoglobulin in allergy-prone rat pups.

Controversy exists regarding the timing of the introduction of allergic foods into the diet. We investigated the immune response of rat pups exposed to beta-lactoglobulin (BLG), one of the main allergenic proteins in cow milk. Brown Norway allergy-prone rats were allocated into groups: dam-reared and unchallenged (DR), DR challenged with BLG via gavage (11 mg/d), or rats fed via gastric cannula a formula containing BLG (11 mg/d). BLG was given from d 4 of life. Rats were killed at d 10, 14, or 21. Sera were assayed for total IgE, BLG-specific IgG1, and rat mucosal mast cell protease II (RMCPII; indicator of mucosal mast cell degranulation). Ileum was assessed for cytokine mRNA. Mesenteric lymph nodes (MLN) were assessed for forkhead boxP3 (Foxp3) and chemokine (C-C motif) receptor 7 (CCR7) expression by real-time PCR and immunostained for Foxp3(+) CD4(+) regulatory cells. Formula feeding compared with dam-rearing with or without oral BLG challenge resulted in significantly greater serum IgE, BLG-specific IgG1, RMCPII, and intestinal mast cells but reduced MLN Foxp3(+) cells, Foxp3, and CCR7 expression and ileal cytokines, interleukin (IL)-4, IL-10, and interferon-gamma (P < 0.05). Importantly, giving BLG in the presence of maternal milk resulted in an immune response profile similar to that of unchallenged DR rats but with greater Foxp3 and CCR7 mRNA expression and CD4(+) Foxp3(+) cells (P < 0.05). We conclude that introducing an allergenic food with breast milk reduces immunological indicators of an allergic response, whereas introduction during formula feeding generates an allergic response.

Mucositis and non-invasive markers of small intestinal function.

Mucositis is a common and debilitating side effect of chemotherapy that manifests due to the inability of chemotherapy agents to discriminate between normal and neoplastic cells. This results in ulcerating lesions lining the gastrointestinal tract. Moreover, the development of efficacious treatments for small intestinal mucositis has been hindered as the pathobiology of mucositis is still not fully understood. The small intestine is an extensive organ which is largely inaccessible by conventional means. Non-invasive biomarkers such as small intestinal permeability, H(2) breath tests, serum citrulline tests and the (13)C-sucrose breath test (SBT) have emerged as potential markers of small intestinal function. The SBT is emerging as the more appropriate biomarker to assess chemotherapy-induced mucositis in cancer patients and animal models, where it measures the decrease in sucrase activity associated with villus blunting and crypt disruption. The SBT has been successfully applied to detect mucositis induced by different classes of chemotherapy agents and has been used successfully to monitor small intestinal function with a range of candidate anti-mucositis treatments. We propose the SBT a superior biomarker of small intestinal function that could be successfully applied in clinical practice for monitoring the development of mucositis in cancer patients undergoing chemotherapy.

Lyprinol only partially improves indicators of small intestinal integrity in a rat model of 5-fluorouracil-induced mucositis.

BACKGROUND: Intestinal mucositis is a common and debilitating side-effect of chemotherapy, associated with severe small intestinal inflammation. Marine oils, such as Lyprinol, a lipid extract derived from New Zealand Green-lipped Mussels, rich in long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA), have demonstrated therapeutic potential for the treatment of inflammatory conditions. We assessed the effects of Lyprinol on the severity of 5-fluorouracil (5-FU)-induced mucositis in female Dark Agouti rats. RESULTS: Small intestinal weight was significantly greater in rats treated with 5-FU+HDL, 5-FU+LDL and 5-FU+FO compared to 5-FU-treated controls (p < 0.05). Myeloperoxidase activity in the proximal and mid small intestine were significantly lower in 5-FU+OO-treated rats compared to 5-FU+vehicle-treated controls (p < 0.05). Histological damage severity was elevated in 5-FU+vehicle, 5-FU+OO and 5-FU+FO-treated rats compared to saline-treated controls, but not in rats treated with 5-FU+HDL or 5-FU+LDL. SBT results and biochemically-assessed sucrase activity were lower in all 5-FU-treated rats compared to saline-treated controls. 5-FU+HDL treated animals had significantly longer crypts and increased proliferation in the mid small intestine compared to 5-FU+vehicle rats (p < 0.05). CONCLUSION: Lyprinol treatment in rats with 5-FU-induced mucositis only minimally decreased indicators of intestinal integrity. Further studies of marine oils high in omega-3 PUFA content are warranted for the potential prophylactic treatment of intestinal mucositis. METHODS: Rats were allocated to six groups (n = 8/group); Saline+vehicle, 5-FU+vehicle, 5-FU+high-dose Lyprinol (5-FU+HDL), 5-FU+low-dose Lyprinol (5-FU+LDL), 5-FU+olive oil (5-FU+OO), and 5-FU+fish oil (5-FU+FO). Treatments were administered via oro-gastric gavage from days 0-7. Mucositis was induced on day 5 by 5-FU injection (150mg/kg i.p.). (13)C-sucrose breath tests (SBT) were conducted on days 0, 5 and 8 to assess small intestinal function. Rats were sacrificed on day 8 and small intestinal tissues collected for histological and biochemical analysis.

Probiotic effects on 5-fluorouracil-induced mucositis assessed by the sucrose breath test in rats.

The sucrose breath test (SBT) was employed to noninvasively assess the efficacy of probiotics in 5-fluorouracil (5-FU)-induced intestinal mucositis. Dark Agouti rats were allocated to 5 groups (n = 10): 5-FU + L. fermentum BR 11, 5-FU + L. rhamnosus GG, 5-FU + B. lactis BB 12, 5-FU + skim milk (SM), and saline + SM. Probiotics were administered by oral gavage for 10 days. Mucositis was induced on day 7 by intraperitoneal injection of 5-FU (150 mg/kg) or vehicle (saline). Rats were sacrificed 72 h after 5-FU injection. The SBT measured breath 13CO2 (expressed as percentage cumulative dose at 90 min; %CD90) on days 0, 7, and 10. %CD90 was significantly lower in 5-FU-treated controls compared with that in saline-treated controls on day 10. 5-FU caused an 83% reduction in sucrase and a 510% increase in MPO activity. The SBT detected damage induced by 5-FU and is a simple, noninvasive indicator of small bowel injury. The probiotics assessed offered no protection from mucositis at the dose tested.

A novel non-invasive biomarker for assessment of small intestinal mucositis in children with cancer undergoing chemotherapy.

BACKGROUND: Small intestinal mucositis is a common side-effect following high-dose chemotherapy, causing patients to experience pain and abdominal complications often leading to extended stays in hospital. A biomarker to detect these small intestinal changes does not exist in clinical practice. This study aimed to assess the noninvasive 13C-Sucrose breath test (SBT) to detect small intestinal damage associated with mucositis in pediatric cancer patients having chemotherapy. PATIENTS AND METHODS: Small intestinal function was assessed in 15 pediatric cancer patients and 26 healthy children. Subjects were studied for small intestinal permeability (SIP; lactulose/rhamnose), digestive and absorptive capacity (SBT; sucrose), and oro-cecal transit time (OCTT; lactulose), by ingesting two sugar drinks containing the respective sugars. Combined tests were carried out at baseline, day 1, day 3-5 and day 6-9, and in healthy individuals on two separate occasions. A total of 25 cycles of chemotherapy were assessed. Breath samples for the SBT were collected every 15 min for 3 h (expressed as % cumulative dose at 90 min (CD)), a 5 h urine collection for SIP and breath hydrogen determined every 30 min for three hours for OCTT. RESULTS: Clinical mucositis occurred in seven of the 25 cycles of chemotherapy (28%). No significant difference was observed for SIP and OCTT. The SBT %CD at 90 min was significantly lower in the mucositis group compared to the unaffected group and controls at baseline (p<0.05). Patients who developed mucositis maintained a significantly lower %CD, for all test points (p<0.05) compared to the unaffected patients. In patients who developed mucositis the SBT was below the reference range of the controls at all time points. CONCLUSION: The findings show for the first time that it is possible to noninvasively detect and monitor gut damage associated with chemotherapy-induced mucositis in pediatric cancer patients.

A non-invasive method for detection of intestinal mucositis induced by different classes of chemotherapy drugs in the rat.

BACKGROUND: The Sucrose Breath Test (SBT) is a simple noninvasive technique for the detection of small intestinal mucositis. AIM: We utilised rat models of intestinal mucositis induced by different classes of chemotherapeutic agents to broaden application of the SBT. METHODS: Mucositis was induced in rats by injection of Doxorubicin (Dox), Etoposide (Etop), Irinotecan (Irin), or Cyclophosphamide (Cy) and Etop in combination (Cy+Etop). The SBT was carried out following sucrose gavage, 72 h after chemotherapy. At kill, intestinal tissues were collected for mucositis assessments. RESULTS: SBT for controls was 16.0 +/- 0.6% (mean +/- SEM) cumulative dose at 90 min. Irin, Doxo, Etop, and Cy+Etop significantly decreased the SBT to 53%, 43%, 32% and 30% of saline control values, respectively (p < 0.01) whilst sucrase activity was correspondingly decreased to 60%, 36%, 14% and 2%. There was good concordance with histological mucositis severity in the jejunum, with median scores of 11, 19, 28 and 27. Correlations between SBT, sucrase activity, and histological severity score yielded r(2) values of 0.82. CONCLUSIONS: The SBT detected mucositis induced by the alkylating agent, anthracycline and DNA-topoisomerase inhibitor classes, facilitating the detection of small intestinal dysfunction, providing a further means to screen newly-developed drugs for intestinal side-effects.

Oral ingestion of streptococcus thermophilus diminishes severity of small intestinal mucositis in methotrexate treated rats.

BACKGROUND: Currently, there are no available effective preventative or adjunctive agents to alleviate symptoms of chemotherapy-induced mucositis. This is compounded by the absence of a recognized and validated noninvasive biomarker to assess gut function. This study investigated the effects of orally ingested Streptococcus thermophilus (TH-4) on chemotherapy-induced small intestinal damage in rats using the noninvasive (13)C-sucrose breath test (SBT). METHODS: Gastrointestinal damage was induced in 27 female dark agouti rats (148 +/- 1g) with MTX (1.5 mg/kg; i.m.). Rats received MTX or saline at 0 h; with daily treatment of: TH-4 at doses of 10(9) (high), 10(8) (low) cfu/mL, or skim milk (vehicle), 48 h pre and 96 h post-MTX. The noninvasive (13)C-sucrose breath test (SBT) was conducted at -24, 24 and 96 h post-MTX to monitor gut function. At sacrifice, small intestinal tissues were collected for determinations of sucrase activity, myeloperoxidase (MPO) activity and histological assessment. RESULTS: MTX + vehicle and MTX + low TH-4-treated rats produced significantly lower SBT and sucrase activity results compared to saline controls (p < 0.001). In contrast, MTX + high TH-4 treatment showed no significant differences in the SBT compared to saline controls, and the SBT results were significantly higher compared to MTX + vehicle and MTX + low TH-4 (p < 0.05). MPO levels were significantly elevated (p < 0.05) in MTX + vehicle and MTX + low TH-4, but not following MTX + high TH-4 treatment, compared to saline controls. This was further confirmed by histological analyses. CONCLUSION: Oral ingestion of TH-4 at 10(9) cfu/mL is capable of partially attenuating small bowel damage in rats. The noninvasive SBT is a useful technique to longitudinally assess the efficacy of treatments or interventions for small bowel disease.