Faye Chleilat

All Publications

• Short-chain fatty acids propionate and butyrate control growth and differentiation linked to cellular metabolism. Research square Nshanian, M., Geller, B. S., Gruber, J. J., Chleilat, F., Camarillo, J. M., Kelleher, N. L., Zhao, Y., Snyder, M. P. 2024

  Abstract

  The short-chain fatty acids (SCFA) propionate and butyrate are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. In order to better understand the function of these modifications we used ChIP-seq to map the genome-wide location of four short-chain acyl histone marks H3K18pr/bu and H4K12pr/bu in treated and untreated colorectal cancer (CRC) and normal cells, as well as in mouse intestines in vivo. We correlate these marks with open chromatin regions along with gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate act as promoters of growth, differentiation as well as ion transport. We propose a mechanism involving direct modification of specific genomic regions, resulting in increased chromatin accessibility, and in case of butyrate, opposing effects on the proliferation of normal versus CRC cells.

  View details for DOI 10.21203/rs.3.rs-3935562/v1

  View details for PubMedID 38410440

  View details for PubMedCentralID PMC10896393

• The Chemo-Gut Pilot Study: Associations between Gut Microbiota, Gastrointestinal Symptoms, and Psychosocial Health Outcomes in a Cross-Sectional Sample of Young Adult Cancer Survivors. Current oncology (Toronto, Ont.) Deleemans, J. M., Chleilat, F., Reimer, R. A., Baydoun, M., Piedalue, K., Lowry, D. E., Henning, J., Carlson, L. E. 2022; 29 (5): 2973-2994

  Abstract

  Chemotherapy adversely affects the gut microbiota, inducing dysbiosis, and negatively impacts gastrointestinal (GI) and psychosocial health during treatment, but little is known about the long-term effects or how these factors are related.METHODS: This cross-sectional pilot study investigated the effects of chemotherapy on the gut microbiota, GI symptoms, and psychosocial outcomes in cancer survivors aged 18-39 years old, compared to healthy controls. Gut microbial diversity and composition were assessed from stool samples using 16S rRNA gene sequencing.RESULTS: Survivors (n = 17) and healthy controls (n = 18) participated. Mean age at diagnosis was 31 years (±5.3). Mean time off treatment was 16.9 months (±16.4). Survivors had more severe GI symptoms, poorer psychosocial health, and increased relative abundance of Selenomondales, Veilloneliaceae, and Intestinibacter. In survivors, Lachnospiraceae, Ruminococcaceae and Intestinibacter correlated with psychosocial symptoms, while diarrhea correlated positively with Lachnospiraceae. Results are statistically significant. Survivors ≤6 months post-treatment had lower alpha diversity than survivors >6 months post-treatment (p = 0.04) and controls (p = 0.19).CONCLUSION: This small exploratory study demonstrates potential long-term gut microbial dysbiosis in cancer survivors, which may be associated with psychosocial symptoms. Larger trials concurrently and longitudinally examining gut microbiota, GI symptoms, and psychosocial outcomes are needed.

  View details for DOI 10.3390/curroncol29050243

  View details for PubMedID 35621633

• Effect of supplementation with select human milk oligosaccharides on artificially reared newborn rats BRITISH JOURNAL OF NUTRITION Wang, W., Mu, C., Cho, N. A., Tuplin, E., Lowry, D. E., Chleilat, F., Sales, K. M., Sampsell, K., Shearer, J., Reimer, R. A. 2021

  View details for DOI 10.1017/S0007114521005146

  View details for Web of Science ID 000742208700001

• The Effects of Human Milk Oligosaccharide Supplementation During Critical Periods of Development on the Mesolimbic Dopamine System NEUROSCIENCE Tuplin, E., Chleilat, F., Alukic, E., Reimer, R. A. 2021; 459: 166-178

  Abstract

  Human milk oligosaccharides (HMO)s are a key component in human milk and represent an important dietary modulator of infant gut microbiota composition and associated gut-brain axis development and homeostasis. The brain reward system, specifically the mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc) is involved in the motivation and preference for food. The objective of the present study was to determine if HMO fortified diets given during the critical period of reward system development (p21) could affect the structure of the reward system. At weaning (p21), Sprague-Dawley rats were randomized to one of four fortified diet groups: Control, 3'sialyllactose (3'FL), 2'-fucosyllactose (2'FL), or a combination of 3'SL and 2'FL (3'SL + 2'FL). Messenger RNA (mRNA) expression was quantified for DA and appetite associated markers in the VTA and NAc and western blots measured the immediate early gene FosB and its isoform ΔFosB. Females fed the 3'SL + 2'FL fortified diet displayed a decrease in DAT expression in the VTA and an increase in leptin expression in the NAc. Females displayed an overall lower expression of NAc D2, VTA ghrelinR, and VTA leptin. In males, VTA DAT and FosB were negatively correlated with body weight and systemic leptin. Sex differences in the expression of DA markers underscore the need to investigate this phenomenon and understand the functional significance in preventing or treating obesity. This study highlights sex differences in response to HMO supplementation and the need for further investigations into the functional significance of nutritional interventions during DA system development.

  View details for DOI 10.1016/j.neuroscience.2021.02.006

  View details for Web of Science ID 000632036200013

  View details for PubMedID 33588004

• Microbiota Changes in Fathers Consuming a High Prebiotic Fiber Diet Have Minimal Effects on Male and Female Offspring in Rats NUTRIENTS Chleilat, F., Schick, A., Reimer, R. A. 2021; 13 (3)

  Abstract

  Consuming a diet high in prebiotic fiber has been associated with improved metabolic and gut microbial parameters intergenerationally, although studies have been limited to maternal intake with no studies examining this effect in a paternal model.Male Sprague Dawley rats were allocated to either (1) control or (2) oligofructose-supplemented diet for nine weeks and then mated. Offspring consumed control diet until 16 weeks of age. Bodyweight, body composition, glycemia, hepatic triglycerides, gastrointestinal hormones, and gut microbiota composition were measured in fathers and offspring.Paternal energy intake was reduced, while satiety inducing peptide tyrosine tyrosine (PYY) gut hormone was increased in prebiotic versus control fathers. Increased serum PYY persisted in female prebiotic adult offspring. Hepatic triglycerides were decreased in prebiotic fathers with a similar trend (p = 0.07) seen in female offspring. Gut microbial composition showed significantly reduced alpha diversity in prebiotic fathers at 9 and 12 weeks of age (p < 0.001), as well as concurrent differences in beta diversity (p < 0.001), characterized by differences in Bifidobacteriaceae, Lactobacillaceae and Erysipelotrichaceae, and particularly Bifidobacterium animalis. Female prebiotic offspring had higher alpha diversity at 3 and 9 weeks of age (p < 0.002) and differences in beta diversity at 15 weeks of age (p = 0.04). Increases in Bacteroidetes in female offspring and Christensenellaceae in male offspring were seen at nine weeks of age.Although paternal prebiotic intake before conception improves metabolic and microbiota outcomes in fathers, effects on offspring were limited with increased serum satiety hormone levels and changes to only select gut bacteria.

  View details for DOI 10.3390/nu13030820

  View details for Web of Science ID 000633999400001

  View details for PubMedID 33801321

  View details for PubMedCentralID PMC8001975

• Paternal Methyl Donor Supplementation in Rats Improves Fertility, Physiological Outcomes, Gut Microbial Signatures and Epigenetic Markers Altered by High Fat/High Sucrose Diet INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Chleilat, F., Schick, A., Deleemans, J. M., Reimer, R. A. 2021; 22 (2)

  Abstract

  Increased consumption of high fat/sucrose (HF/S) diets has contributed to rising rates of obesity and its co-morbidities globally, while also negatively impacting male reproductive health. Our objective was to examine whether adding a methyl donor cocktail to paternal HF/S diet (HF/S+M) improves health status in fathers and offspring. From 3-12 weeks of age, male Sprague Dawley rats consumed a HF/S or HF/S+M diet. Offspring were followed until 16 weeks of age. Body composition, metabolic markers, gut microbiota, DNA methyltransferase (DNMT) and microRNA expression were measured in fathers and offspring. Compared to HF/S, paternal HF/S+M diet reduced fat mass in offspring (p < 0.005). HF/S+M fathers consumed 16% fewer kcal/day, which persisted in HF/S+M female offspring and was explained in part by changes in serum glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels. Compared to HF/S, HF/S+M fathers had a 33% improvement in days until conception and 300% fewer stillbirths. In fathers, adipose tissue DNMT3a and hepatic miR-34a expression were reduced with HF/S+M. Adult male offspring showed upregulated miR-24, -33, -122a and -143 expression while females exhibited downregulated miR-33 expression. Fathers and offspring presented differences in gut microbial signatures. Supplementing a paternal HF/S diet with methyl-donors improved fertility, physiological outcomes, epigenetic and gut microbial signatures intergenerationally.

  View details for DOI 10.3390/ijms22020689

  View details for Web of Science ID 000611322100001

  View details for PubMedID 33445606

  View details for PubMedCentralID PMC7826956

• Concurrent Prebiotic Intake Reverses Insulin Resistance Induced by Early-Life Pulsed Antibiotic in Rats BIOMEDICINES Klancic, T., Laforest-Lapointe, I., Wong, J., Choo, A., Nettleton, J. E., Chleilat, F., Arrieta, M., Reimer, R. A. 2021; 9 (1)

  Abstract

  Pulsed antibiotic treatment (PAT) early in life increases risk of obesity. Prebiotics can reduce fat mass and improve metabolic health. We examined if co-administering prebiotic with PAT reduces obesity risk in rat pups weaned onto a high fat/sucrose diet. Pups were randomized to (1) control [CTR], (2) antibiotic [ABT] (azithromycin), (3) prebiotic [PRE] (10% oligofructose (OFS)), (4) antibiotic + prebiotic [ABT + PRE]. Pulses of antibiotics/prebiotics were administered at d19-21, d28-30 and d37-39. Male and female rats given antibiotics (ABT) had higher body weight than all other groups at 10 wk of age. The PAT phenotype was stronger in ABT males than females, where increased fat mass, hyperinsulinemia and insulin resistance were present and all reversible with prebiotics. Reduced hypothalamic and hepatic expression of insulin receptor substrates and ileal tight junction proteins was seen in males only, explaining their greater insulin resistance. In females, insulin resistance was improved with prebiotics and normalized to lean control. ABT reduced Lactobacillaceae and increased Bacteroidaceae in both sexes. Using a therapeutic dose of an antibiotic commonly used for acute infection in children, PAT increased body weight and impaired insulin production and insulin sensitivity. The effects were reversed with prebiotic co-administration in a sex-specific manner.

  View details for DOI 10.3390/biomedicines9010066

  View details for Web of Science ID 000609844000001

  View details for PubMedID 33445530

  View details for PubMedCentralID PMC7827688

• Dietary Vitamin B6 Deficiency Impairs Gut Microbiota and Host and Microbial Metabolites in Rats BIOMEDICINES Mayengbam, S., Chleilat, F., Reimer, R. A. 2020; 8 (11)

  Abstract

  Vitamin B6 plays a crucial role as a cofactor in various enzymatic reactions but bacteria-produced vitamin B6 is not sufficient to meet host requirements. Our objective was to assess the impact of diet-derived vitamin B6 on gut microbiota and host serum metabolomics. Sprague-Dawley rats (n = 47) were fed a control, low B6 (LB6) or high B6 (HB6) diet for six weeks. Serum and cecal samples were collected for biochemical, metabolomics and gut microbiota profiling. There was a significant sex effect for gut microbiota and several metabolic markers. Bodyweight and percent body fat were significantly reduced in LB6 compared to control and HB6 rats. Microbial beta-diversity differed significantly between LB6 and the control and HB6 rats in both sexes. Lachnospiraceae_NK4A136_group and Bacteroides were the primary taxa driving the difference between LB6 and control. There was a significant separation of cecal and serum metabolites of LB6 compared to control and HB6 rats. In the cecum, arginine biosynthesis was impaired, while vitamin B6 metabolism, lysine degradation and nicotinate and nicotinamide metabolism were impaired in serum metabolite profiles. Cecal propionate and butyrate were significantly reduced in LB6 rats irrespective of sex. Host vitamin B6 deficiency but not excess significantly alters gut microbial composition and its metabolites.

  View details for DOI 10.3390/biomedicines8110469

  View details for Web of Science ID 000592873800001

  View details for PubMedID 33147768

  View details for PubMedCentralID PMC7693528

• Maternal low-dose aspartame and stevia consumption with an obesogenic diet alters metabolism, gut microbiota and mesolimbic reward system in rat dams and their offspring GUT Nettleton, J. E., Cho, N. A., Klancic, T., Nicolucci, A. C., Shearer, J., Borgland, S. L., Johnston, L. A., Ramay, H. R., Noye Tuplin, E., Chleilat, F., Thomson, C., Mayengbam, S., McCoy, K. D., Reimer, R. A. 2020; 69 (10): 1807-1817

  Abstract

  We examined the impact of maternal low-dose aspartame and stevia consumption on adiposity, glucose tolerance, gut microbiota and mesolimbic pathway in obese dams and their offspring.Following obesity induction, female Sprague-Dawley rats were allocated during pregnancy and lactation to: (1) high fat/sucrose diet (HFS) +water (obese-WTR); (2) HFS +aspartame (obese-APM; 5-7 mg/kg/day); (3) HFS +stevia (obese-STV; 2-3 mg/kg/day). Offspring were weaned onto control diet and water and followed until 18 weeks. Gut microbiota and metabolic outcomes were measured in dams and offspring. Cecal matter from offspring at weaning was used for faecal microbiota transplant (FMT) into germ-free (GF) mice.Maternal APM and STV intake with a HFS diet increased body fat in offspring at weaning and body weight long-term with APM. Maternal APM/HFS consumption impaired glucose tolerance in male offspring at age 8 weeks and both APM and STV altered faecal microbiota in dams and offspring. Maternal obesity/HFS diet affected offspring adiposity and glucose tolerance more so than maternal LCS consumption at age 12 and 18 weeks. APM and STV altered expression of genes in the mesolimbic reward system that may promote consumption of a palatable diet. GF mice receiving an FMT from obese-APM and obese-STV offspring had greater weight gain and body fat and impaired glucose tolerance compared with obese-WTR.Maternal low-calorie sweetener consumption alongside HFS may disrupt weight regulation, glucose control and gut microbiota in dams and their offspring most notably in early life despite no direct low-calorie sweetener consumption by offspring.

  View details for DOI 10.1136/gutjnl-2018-317505

  View details for Web of Science ID 000572338600016

  View details for PubMedID 31996393

  View details for PubMedCentralID PMC7497576

• Prebiotic Oligofructose Prevents Antibiotic-Induced Obesity Risk and Improves Metabolic and Gut Microbiota Profiles in Rat Dams and Offspring MOLECULAR NUTRITION & FOOD RESEARCH Klancic, T., Laforest-Lapointe, I., Choo, A., Nettleton, J. E., Chleilat, F., Noye Tuplin, E. W., Alukic, E., Cho, N. A., Nicolucci, A. C., Arrieta, M., Reimer, R. A. 2020; 64 (16): e2000288

  Abstract

  Antibiotics in early life disrupt microbiota and increase obesity risk. Dietary agents such as prebiotics may reduce obesity risk. The authors examine how antibiotics administered with/without prebiotic oligofructose, alter metabolic and microbial outcomes in pregnant rats and their offspring.Pregnant rats are randomized to: 1) Control, 2) Antibiotic (ABT), 3) Prebiotic (PRE), 4) Antibiotic+Prebiotic (ABT+PRE) during the 3rd week of pregnancy and lactation. Offspring were fed a high fat/high sucrose (HFS) diet from 9-17 weeks of age to unmask obesity risk. ABT dams had higher body weight, body fat and leptin during lactation than all other groups. Prebiotics attenuate these outcomes and increase cecal Bifidobacterium. ABT offspring have higher body weight, fat mass, and liver triglycerides after HFS diet, with a stronger phenotype in males; prebiotics attenuate these. At weaning, male ABT offspring have lower Lactobacillus while PRE and ABT+PRE offspring had higher Bifidobacterium and Collinsella. Fecal microbiota transfer of adult offspring cecal matter could not reliably transfer the obese ABT phenotype.Antibiotic use during pregnancy/lactation increases adiposity and impairs post-partum weight loss in dams. Co-administering prebiotics with antibiotics in rat dams prevented obesity risk in offspring and is associated with altered gut microbiota.

  View details for DOI 10.1002/mnfr.202000288

  View details for Web of Science ID 000572312400001

  View details for PubMedID 32610365

• Human Milk Oligosaccharide Supplementation Affects Intestinal Barrier Function and Microbial Composition in the Gastrointestinal Tract of Young Sprague Dawley Rats NUTRIENTS Chleilat, F., Klancic, T., Ma, K., Schick, A., Nettleton, J. E., Reimer, R. A. 2020; 12 (5)

  Abstract

  Human milk oligosaccharides (HMOs) are chief maternal milk constituents that feed the intestinal microbiota and drive maturation of the infant gut. Our objective was to determine whether supplementing individual HMOs to a weanling diet alters growth and gut health in rats. Healthy three-week-old Sprague Dawley rat pups were randomized to control, 2'-O-fucosyllactose (2'FL)- and 3'sialyllactose (3'SL)-fortified diets alone or in combination at physiological doses for eight weeks. Body composition, intestinal permeability, serum cytokines, fecal microbiota composition, and messenger RNA (mRNA) expression in the gastrointestinal tract were assessed. Males fed a control diet were 10% heavier and displayed elevated interleukin (IL-18) (p = 0.01) in serum compared to all HMO-fortified groups at week 11. No differences in body composition were detected between groups. In females, HMOs did not affect body weight but 2'FL + 3'SL significantly increased cecum weight. All female HMO-fortified groups displayed significant reductions in intestinal permeability compared to controls (p = 0.02). All HMO-fortified diets altered gut microbiota composition and mRNA expression in the gastrointestinal tract, albeit differently according to sex. Supplementation with a fraction of the HMOs found in breast milk has a complex sex-dependent risk/benefit profile. Further long-term investigation of gut microbial profiles and supplementation with other HMOs during early development is warranted.

  View details for DOI 10.3390/nu12051532

  View details for Web of Science ID 000542272700209

  View details for PubMedID 32466125

  View details for PubMedCentralID PMC7284880

• The chemo-gut study: investigating the long-term effects of chemotherapy on gut microbiota, metabolic, immune, psychological and cognitive parameters in young adult Cancer survivors; study protocol BMC CANCER Deleemans, J. M., Chleilat, F., Reimer, R. A., Henning, J., Baydoun, M., Piedalue, K., McLennan, A., Carlson, L. E. 2019; 19 (1): 1243

  Abstract

  The gut microbiota is an important modulator of immune, metabolic, psychological and cognitive mechanisms. Chemotherapy adversely affects the gut microbiota, inducing acute dysbiosis, and alters physiological and psychological function. Cancer among young adults has risen 38% in recent decades. Understanding chemotherapy's long-term effects on gut microbiota and psycho-physiological function is critical to improve survivors' physical and mental health, but remains unexamined. Restoration of the gut microbiota via targeted therapies (e.g. probiotics) could potentially prevent or reverse the psycho-physiological deficits often found in young survivors following chemotherapy, ultimately leading to reduced symptom burden and improved health.This longitudinal study investigates chemotherapy induced long-term gut dysbiosis, and associations between gut microbiota, and immune, metabolic, cognitive and psychological parameters using data collected at < 2 month (T1), 3-4 months (T2), and 5-6 months (T3) post-chemotherapy. Participants will be 18-39 year old blood or solid tumor cancer survivors (n = 50), and a healthy sibling, partner or friend as a control (n = 50). Gut microbiota composition will be measured from fecal samples using 16 s RNA sequencing. Psychological and cognitive patient reported outcome measures will include depression, anxiety, post-traumatic stress disorder symptoms, pain, fatigue, and social and cognitive function. Dual-energy X-ray Absorptiometry (DXA) will be used to measure fat and lean mass, and bone mineral concentration. Pro-inflammatory cytokines, C-reactive protein (CRP), lipopolysaccharide (LPS), serotonin, and brain derived neurotrophic factor (BDNF) will be measured in serum, and long-term cortisol will be assayed from hair. Regression and linear mixed model (LMM) analyses will examine associations across time points (T1 - T3), between groups, and covariates with gut microbiota, cognitive, psychological, and physiological parameters.Knowing what bacterial species are depleted after chemotherapy, how long these effects last, and the physiological mechanisms that may drive psychological and cognitive issues among survivors will allow for targeted, integrative interventions to be developed, helping to prevent or reverse some of the late-effects of treatment that many young cancer survivors face. This protocol has been approved by the Health Research Ethics Board of Alberta Cancer Committee (ID: HREBA.CC-19-0018).

  View details for DOI 10.1186/s12885-019-6473-8

  View details for Web of Science ID 000511458800001

  View details for PubMedID 31870331

  View details for PubMedCentralID PMC6927187

• Low-Dose Stevia (Rebaudioside A) Consumption Perturbs Gut Microbiota and the Mesolimbic Dopamine Reward System NUTRIENTS Nettleton, J. E., Klancic, T., Schick, A., Choo, A. C., Shearer, J., Borgland, S. L., Chleilat, F., Mayengbam, S., Reimer, R. A. 2019; 11 (6)

  Abstract

  Stevia is a natural low-calorie sweetener that is growing in popularity in food and beverage products. Despite its widespread use, little is understood of its impact on the gut microbiota, an important environmental factor that can mediate metabolism and subsequent obesity and disease risk. Furthermore, given previous reports of dysbiosis with some artificial low-calorie sweeteners, we wanted to understand whether prebiotic consumption could rescue potential stevia-mediated changes in gut microbiota. Three-week old male Sprague-Dawley rats were randomized to consume: (1) Water (CTR); (2) Rebaudioside A (STV); (3) prebiotic (PRE); (4) Rebaudioside A + prebiotic (SP) (n = 8/group) for 9 weeks. Rebaudioside was added to drinking water and prebiotic oligofructose-enriched inulin added to control diet (10%). Body weight and feces were collected weekly and food and fluid intake biweekly. Oral glucose and insulin tolerance tests, gut permeability tests, dual X-ray absorptiometry, and tissue harvest were performed at age 12 weeks. Rebaudioside A consumption alone did not alter weight gain or glucose tolerance compared to CTR. Rebaudioside A did, however, alter gut microbiota composition and reduce nucleus accumbens tyrosine hydroxylase and dopamine transporter mRNA levels compared to CTR. Prebiotic animals, alone or with Rebaudioside A, had reduced fat mass, food intake, and gut permeability and cecal SCFA concentration. Adding Rebaudioside A did not interfere with the benefits of the prebiotic except for a significant reduction in cecal weight. Long-term low-dose Rebaudioside A consumption had little effect on glucose metabolism and weight gain; however, its impact on gut microbial taxa should be further examined in populations exhibiting dysbiosis such as obesity.

  View details for DOI 10.3390/nu11061248

  View details for Web of Science ID 000474936700054

  View details for PubMedID 31159256

  View details for PubMedCentralID PMC6627124