Nicolaas H. Fourie

Elevated circulating miR-150 and miR-342-3p in patients with irritable bowel syndrome.

BACKGROUND AND AIMS MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression and are thus of interest as diagnostic markers, and as clues to etiology and targets of intervention. This pilot study examined whether circulating miRNAs are differentially expressed in patients with IBS. METHODS miRNA microarrays (NanoString) were run on the whole blood of 43 participants. RESULTS hsa-miR-150 and hsa-miR-342-3p were found to be significantly elevated (FDR adjusted p≤0.05, ≥1.6 fold change) in IBS patients compared to healthy controls. Neither of these miRNAs showed any relationship to race or sex. hsa-miR-150 is associated with inflammatory bowel disorders and pain, and interacts with a protein kinase (AKT2) through which it may affect inflammatory pathways. hsa-miR-342-3p is predicted to interact with mRNAs involved in pain signaling, colonic motility, and smooth muscle function. CONCLUSIONS This preliminary study reports the association of two miRNAs, detected in whole blood, with IBS. These miRNAs link to pain and inflammatory pathways both of which are thought to be dysregulated in IBS. Larger sample sizes are needed to confirm their importance and potential as biomarkers.

Hair cortisol levels track phylogenetic and age related differences in hypothalamic-pituitary-adrenal (HPA) axis activity in non-human primates.

Hair has been shown to archive a uniquely time averaged signal of endocrine activity, and holds attractive advantages for both laboratory and field research. Prior research has explored the potential of hair hormone analysis to examine hormone-behavior relationships. To date, no research has focused on the potential of the technique to investigate age-related changes or taxon differences in endocrine function. It is known that non-human primate infants of many taxa exhibit high cortisol levels after parturition, which rapidly decline with age. It has also been shown that hypercortisolism generally characterizes platyrrhine (New World monkey) endocrine function. These endocrine trends have been characterized using cortisol levels determined from serum, plasma, and feces. Here we test whether cortisol levels determined from hair recover similar phylogenetic and age related patterns in endocrine function in non-human primates. In order to test whether hair cortisol reflect infant hypercortisolism with significant age-related decline, hair cortisol levels are measured in samples from wild vervet monkeys (Chlorocebus aethiops) and captive Guinea baboons (Papio hamadryas papio), ranging in age from infants through juveniles. Further, in order to test whether platyrrhines exhibit significantly higher hair cortisol levels compared to strepsirrhines and catarrhines, and therefore faithfully recover similar signals as more traditionally used substrates (e.g. serum), hair cortisol levels are quantified in adult female hair samples collected from a broad range of non-human primate taxa. Results confirm that hair cortisol levels accurately reflect known phylogenetic and age related patterns of circulating cortisol levels. Therefore, these results suggest that hair may be an ideal hormone bearing substrate for research focused on the examination of population endocrine profiles, cross-sectional studies of endocrine function and taxon variation in hormone levels, as well as stable behavioral trends.

Variation in vervet (Chlorocebus aethiops) hair cortisol concentrations reflects ecological disturbance by humans

AbstractVervet monkeys (Chlorocebus aethiops) often live in close proximity to humans. Vervets are known to raid crops, homes and gardens in suburban areas leading to human–vervet conflict. In general, primate groups with access to human foods experience increased population densities and intra-group aggression. This suggests high stress loads for vervets living in environments with high levels of human habitat disturbance and close proximity to humans. We tested the hypothesis that populations characterized by high levels of human impact are more physiologically stressed than low human impact populations, and that this increased stress would be reflected in higher concentrations of hair cortisol. We predicted that because females would be less likely to engage in high risk foraging activities, and hence keep more distance from humans than males, their hair cortisol levels should be lower than those in males. We quantified cortisol in the hair of wild caught individuals from populations that experienced different degrees of human habitat disturbance and differences in access to human food. We found that males in high human impact groups had significantly higher hair cortisol concentrations than those in low human impact groups, although this difference was not observed in female vervets. Human impacts on vervet behavioral ecology appear to be a significant source of stress for male animals in particular.

Variation of hair cortisol concentrations among wild populations of two baboon species ( Papio anubis , P. hamadryas ) and a population of their natural hybrids

Male olive (Papio anubis) and hamadryas (P. hamadryas) baboons have distinctive sociobehavioral and physical characteristics. In the Awash National Park, Ethiopia, a hybrid population at the contact zone between these two species, exhibits heterogeneous sociobehavioral and physical characteristics. The ambiguity of the hybrid social environment and disruption of parental stress genotypes may be sources of physiological stress for hybrids. We examined levels of chronic stress among males of the three populations and tested the prediction that chronic cortisol levels would be higher among the hybrids. Animals were captured, sampled, and released during the wet season, and a hair sample was taken for assay. Cortisol was extracted from 182 hair samples with methanol and quantified by ELISA. We included age, age class, rainfall variation, and species affiliation in models examining variation in hair cortisol levels. Species and age significantly contributed to models explaining variation in hair cortisol. Infant hypercortisolism was observed in all three groups, and a decline in cortisol through juvenile and adolescent stages, with a subsequent rise in adulthood. This rise occurred earliest in hamadryas, corroborating other evidence of the precocious development of hamadryas baboons. As expected, hybrids had significantly elevated hair cortisol compared with olive baboons and hamadryas, irrespective of age, except for very young animals. Infant hypercortisolism was also less pronounced among hybrids. Species differences and age-related differences in cortisol levels suggest a dysregulated cortisol phenotype in hybrids, and possibly reflect some form of hybrid disadvantage. More work will be required to disentangle the effects of genetic factors and the social environment.

Sources of variation in hair cortisol in wild and captive non-human primates.

Hair cortisol analysis is a potentially powerful tool for evaluating adrenal function and chronic stress. However, the technique has only recently been applied widely to studies of wildlife, including primates, and there are numerous practical and technical factors that should be considered to ensure good quality data and the validity of results and conclusions. Here we report on various intrinsic and extrinsic sources of variation in hair cortisol measurements in wild and captive primates. Hair samples from both wild and captive primates revealed that age and sex can affect hair cortisol concentrations; these effects need to be controlled for when making comparisons between individual animals or populations. Hair growth rates also showed considerable inter-specific variation among a number of primate species. We describe technical limitations of hair analyses and variation in cortisol concentrations as a function of asynchronous hair growth, anatomical site of collection, and the amount and numbers of hair/s used for cortisol extraction. We discuss these sources of variation and their implications for proper study design and interpretation of results.

Sleep quality, BDNF genotype and gene expression in individuals with chronic abdominal pain

BackgroundSleep quality and genetics may contribute to the etiology of gastrointestinal (GI) symptoms. Individuals with impaired sleep often have a number of associated symptoms including chronic abdominal pain (CAP). The current study examined the interactions of brain-derived neurotrophic factor (BDNF) genotype with sleep quality in persons with CAP and healthy controls. In addition, associations among sleep quality, BDNF genotype, and gene expression were explored in the participants.MethodsData were collected on 59 participants (46% male, 61% White, 26.9 ± 6.6 years; CAP (n=19) and healthy controls (n=40)). Participants with CAP reported poorer sleep quality compared to healthy controls. BDNF genotype, categorized as Val/Val homozygotes versus the Met carriers.ResultsMicroarray analysis found twenty-four differentially expressed genes by a two-fold magnitude in participants with poor sleep quality compared to good sleep quality, and seven differentially expressed genes comparing CAP to healthy control. Three specific genes in the pain group overlap with sleep quality, including insulin-like growth factor 1 (IGF1), spermatogenesis associated serine-rich 2-like (SPATS2L), and immunoglobulin heavy constant gamma 1 or mu (IGHG1/// IGHM). BDNF was shown to have an interaction effect with GI and sleep symptoms.ConclusionsParticipants with CAP reported poor sleep quality compared to healthy controls. The role of the BDNF Met allele on differential gene expression was not distinct as main factor, but impacted interactions with sleep quality and CAP. Down-regulation of IGF1, SPATS2L, and IGHG1 expression may be related to the etiology of poor sleep quality and CAP.Trial registrationClinicaltrial.gov # NCT00824941

The microbiome of the oral mucosa in irritable bowel syndrome

abstract Irritable bowel syndrome (IBS) is a poorly understood disorder characterized by persistent symptoms, including visceral pain. Studies have demonstrated oral microbiome differences in inflammatory bowel diseases suggesting the potential of the oral microbiome in the study of non-oral conditions. In this exploratory study we examine whether differences exist in the oral microbiome of IBS participants and healthy controls, and whether the oral microbiome relates to symptom severity. The oral buccal mucosal microbiome of 38 participants was characterized using PhyloChip microarrays. The severity of visceral pain was assessed by orally administering a gastrointestinal test solution. Participants self-reported their induced visceral pain. Pain severity was highest in IBS participants (P = 0.0002), particularly IBS-overweight participants (P = 0.02), and was robustly correlated to the abundance of 60 OTUs, 4 genera, 5 families and 4 orders of bacteria (r2 > 0.4, P < 0.001). IBS-overweight participants showed decreased richness in the phylum Bacteroidetes (P = 0.007) and the genus Bacillus (P = 0.008). Analysis of β-diversity found significant separation of the IBS-overweight group (P < 0.05). Our oral microbial results are concordant with described fecal and colonic microbiome-IBS and -weight associations. Having IBS and being overweight, rather than IBS-subtypes, was the most important factor in describing the severity of visceral pain and variation in the microbiome. Pain severity was strongly correlated to the abundance of many taxa, suggesting the potential of the oral microbiome in diagnosis and patient phenotyping. The oral microbiome has potential as a source of microbial information in IBS.

Baboons, Water, and the Ecology of Oxygen Stable Isotopes in an Arid Hybrid Zone

Baboons regularly drink surface waters derived from atmospheric precipitation, or meteoric water. As a result, the oxygen isotope (δ18O) composition of their tissues is expected to reflect that of local meteoric waters. Animal proxies of the oxygen isotope composition of meteoric water have practical applications as paleoenvironmental recorders because they can be used to infer aridity and temperature in historic and fossil systems. To explore this premise, we measured the δ18O values of hair from two baboon species, Papio anubis and Papio hamadryas, inhabiting Awash National Park, Ethiopia. The hybridizing taxa differ in their ranging behavior and physiological response to heat. Papio hamadryas ranges more widely in the arid thornbush and is inferred to ingest a greater proportion of leaf water that is enriched in 18O as a result of evaporative fractionation. It is also better able to conserve body water, which reduces its dependence on meteoric waters depleted in 18O. Taken together, these factors would predict relatively higher δ18O values in the hair (δ18Ohair) of P. hamadryas. We found that the δ18Ohair values of P. hamadryas were higher than those of P. anubis, yet the magnitude of the difference was marginal. We attribute this result to a common source of drinking water, the Awash River, and the longer drinking bouts of P. hamadryas. Our findings suggest that differences in δ18O values among populations of Papio (modern or ancient) reflect different sources of drinking water (which might have ecological significance) and, further, that Papio has practical value as a paleoenvironmental recorder.

Structural and functional alterations in the colonic microbiome of the rat in a model of stress induced irritable bowel syndrome

ABSTRACT Stress is known to perturb the microbiome and exacerbate irritable bowel syndrome (IBS) associated symptoms. Characterizing structural and functional changes in the microbiome is necessary to understand how alterations affect the biomolecular environment of the gut in IBS. Repeated water avoidance (WA) stress was used to induce IBS-like symptoms in rats. The colon-mucosa associated microbiome was characterized in 13 stressed and control animals by 16S sequencing. In silico analysis of the functional domains of microbial communities was done by inferring metagenomic profiles from 16S data. Microbial communities and functional profiles were compared between conditions. WA animals exhibited higher α-diversity and moderate divergence in community structure (β-diversity) compared with controls. Specific clades and taxa were consistently and significantly modified in the WA animals. The WA microbiome was particularly enriched in Proteobacteria and depleted in several beneficial taxa. A decreased capacity in metabolic domains, including energy- and lipid-metabolism, and an increased capacity for fatty acid and sulfur metabolism was inferred for the WA microbiome. The stressed condition favored the proliferation of a greater diversity of microbes that appear to be functionally similar, resulting in a functionally poorer microbiome with implications for epithelial health. Taxa, with known beneficial effects, were found to be depleted, which supports their relevance as therapeutic agents to restore microbial health. Microbial sulfur metabolism may form a key component of visceral nerve sensitization pathways and is therefore of interest as a target metabolic domain in microbial ecological restoration.

Gender and Weight Influence Quality of Life in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain and bowel dysfunction in the absence of structural abnormality. Diagnosis can be challenging and often leads to extensive medical tests, non-effective therapeutic modalities, and reduced quality of life (QOL). Identifying factors associated with dysfunction have the potential to enhance outcomes. Participants with IBS (n = 41) and healthy volunteers (n = 74) were recruited into this cross-sectional, descriptive, natural history protocol at the National Institute of Health, Clinical Center. Demographic characteristics were self-reported. QOL was assessed with the Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire. Statistical analysis included descriptive statistics, factorial ANOVA, and multiple regression. Individuals with IBS reported lower QOL scores across all QOL-subscales compared to healthy controls. Normal-weight women and overweight men with IBS reported the greatest QOL impairment. Body fat percent had confounding effects on the relationship between IBS and QOL. The disparity between QOL scores in participants with IBS by both gender and weight groups may reflect different social pressures perceived by normal and overweight women and men. These findings enhance the recognition of the disparities in patients with chronic symptoms and thereby lead to personalized assessment and interventions to improve their QOL.