Showing papers by "Fergus Shanahan published in 2016"

Regulation of prefrontal cortex myelination by the microbiota.

Abstract: The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC.

Adult microbiota‐deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus

Abstract: Increasing evidence implicates the microbiota in the regulation of brain and behaviour. Germ-free mice (GF; microbiota deficient from birth) exhibit altered stress hormone signalling and anxiety-like behaviours as well as deficits in social cognition. Although the mechanisms underlying the ability of the gut microbiota to influence stress responsivity and behaviour remain unknown, many lines of evidence point to the amygdala and hippocampus as likely targets. Thus, the aim of this study was to determine if the volume and dendritic morphology of the amygdala and hippocampus differ in GF versus conventionally colonized (CC) mice. Volumetric estimates revealed significant amygdalar and hippocampal expansion in GF compared to CC mice. We also studied the effect of GF status on the level of single neurons in the basolateral amygdala (BLA) and ventral hippocampus. In the BLA, the aspiny interneurons and pyramidal neurons of GF mice exhibited dendritic hypertrophy. The BLA pyramidal neurons of GF mice had more thin, stubby and mushroom spines. In contrast, the ventral hippocampal pyramidal neurons of GF mice were shorter, less branched and had less stubby and mushroom spines. When compared to controls, dentate granule cells of GF mice were less branched but did not differ in spine density. These findings suggest that the microbiota is required for the normal gross morphology and ultrastructure of the amygdala and hippocampus and that this neural remodelling may contribute to the maladaptive stress responsivity and behavioural profile observed in GF mice.

Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene

Abstract: Aims:To review the burden of allergic and infectious diseases and the evidence for a link to microbial exposure, the human microbiome and immune system, and to assess whether we could develop lifestyles which reconnect us with exposures which could reduce the risk of allergic disease while also protecting against infectious disease.Methods:Using methodology based on the Delphi technique, six experts in infectious and allergic disease were surveyed to allow for elicitation of group judgement and consensus view on issues pertinent to the aim.Results:Key themes emerged where evidence shows that interaction with microbes that inhabit the natural environment and human microbiome plays an essential role in immune regulation. Changes in lifestyle and environmental exposure, rapid urbanisation, altered diet and antibiotic use have had profound effects on the human microbiome, leading to failure of immunotolerance and increased risk of allergic disease. Although evidence supports the concept of immune regulation d...

Unconjugated Bile Acids Influence Expression of Circadian Genes: A Potential Mechanism for Microbe-Host Crosstalk.

Abstract: Disruptions to circadian rhythm in mice and humans have been associated with an increased risk of obesity and metabolic syndrome. The gut microbiota is known to be essential for the maintenance of circadian rhythm in the host suggesting a role for microbe-host interactions in the regulation of the peripheral circadian clock. Previous work suggested a role for gut bacterial bile salt hydrolase (BSH) activity in the regulation of host circadian gene expression. Here we demonstrate that unconjugated bile acids, known to be generated through the BSH activity of the gut microbiota, are potentially chronobiological regulators of host circadian gene expression. We utilised a synchronised Caco-2 epithelial colorectal cell model and demonstrated that unconjugated bile acids, but not the equivalent tauro-conjugated bile salts, enhance the expression levels of genes involved in circadian rhythm. In addition oral administration of mice with unconjugated bile acids significantly altered expression levels of circadian clock genes in the ileum and colon as well as the liver with significant changes to expression of hepatic regulators of circadian rhythm (including Dbp) and associated genes (Per2, Per3 and Cry2). The data demonstrate a potential mechanism for microbe-host crosstalk that significantly impacts upon host circadian gene expression.

Differential expression of key regulators of Toll‐like receptors in ulcerative colitis and Crohn's disease: a role for Tollip and peroxisome proliferator‐activated receptor gamma?

Abstract: The innate immune system is currently seen as the probable initiator of events which culminate in the development of inflammatory bowel disease (IBD) with Toll-like receptors (TLRs) known to be involved in this disease process. Many regulators of TLRs have been described, and dysregulation of these may also be important in the pathogenesis of IBD. The aim of this study was to perform a co-ordinated analysis of the expression levels of both key intestinal TLRs and their inhibitory proteins in the same IBD cohorts, both ulcerative colitis (UC) and Crohn's disease (CD), in order to evaluate the potential roles of these proteins in the pathogenesis of IBD. Of the six TLRs (TLRs 1, 2, 4, 5, 6 and 9) examined, only TLR-4 was increased significantly in IBD, specifically in active UC. In contrast, differential alterations in expression of TLR inhibitory proteins were observed. A20 and suppressor of cytokine signalling 1 (SOCS1) were increased only in active UC while interleukin-1 receptor-associated kinase 1 (IRAK-m) and B cell lymphoma 3 protein (Bcl-3) were increased in both active UC and CD. In contrast, expression of both peroxisome proliferator-activated receptor gamma (PPARγ) and Toll interacting protein (Tollip) was decreased in both active and inactive UC and CD and at both mRNA and protein levels. In addition, expression of both PPARγ and A20 expression was increased by stimulation of a colonic epithelial cell line Caco-2 with both TLR ligands and commensal bacterial strains. These data suggest that IBD may be associated with distinctive changes in TLR-4 and TLR inhibitory proteins, implying that alterations in these may contribute to the pathogenesis of IBD.

Exercise, fitness, and the gut

Abstract: Purpose of reviewExercise and gut symptomatology have long been connected. The possibility that regular exercise fosters intestinal health and function has been somewhat overlooked in the scientific literature. In this review, we summarize current knowledge and discuss a selection of recent, relevan

Microbial contributions to chronic inflammation and metabolic disease.

Abstract: Purpose of review It is long known that immune and metabolic cascades intersect at various cross-points. More recently, the regulatory influence of the microbiota on both of these cascades has emerged. Advances with therapeutic implications for chronic immunologic and metabolic disorders are examined. Recent findings Disturbances of the microbiota, particularly in early life, may be the proximate environmental risk factor in socioeconomically developed societies for development of chronic immune-allergic and metabolic disorders, including obesity. Antibiotics and dietary factors contribute to this risk. Multiple microbial signalling molecules mediate host-microbe interactions including bacterial metabolites such as short-chain fatty acids, bile salts and others. Summary New strategies for manipulating the composition and metabolic activity of the gut microbiota have emerged and offer a realistic prospect of personalized therapeutic options in immune and metabolic diseases.

The Changing Phenotype of Inflammatory Bowel Disease

Abstract: It is widely known that there have been improvements in patient care and an increased incidence of Inflammatory Bowel Disease (IBD) worldwide in recent decades. However, less well known are the phenotypic changes that have occurred; these are discussed in this review. Namely, we discuss the emergence of obesity in patients with IBD, elderly onset disease, mortality rates, colorectal cancer risk, the burden of medications and comorbidities, and the improvement in surgical treatment with a decrease in surgical rates in recent decades.

Pure Iterative Reconstruction Improves Image Quality in Computed Tomography of the Abdomen and Pelvis Acquired at Substantially Reduced Radiation Doses in Patients With Active Crohn Disease.

Abstract: UNLABELLED We assessed diagnostic accuracy and image quality of modified protocol (MP) computed tomography (CT) of the abdomen and pelvis reconstructed using pure iterative reconstruction (IR) in patients with Crohn disease (CD). METHODS Thirty-four consecutive patients with CD were referred with suspected extramural complications. Two contemporaneous CT datasets were acquired in all patients: standard protocol (SP) and MP. The MP and SP protocols were designed to impart radiation exposures of 10% to 20% and 80% to 90% of routine abdominopelvic CT, respectively. The MP images were reconstructed with model-based IR (MBIR) and adaptive statistical IR (ASIR). RESULTS The MP-CT and SP-CT dose length product were 88 (58) mGy.cm (1.27 [0.87] mSv) and 303 [204] mGy.cm (4.8 [2.99] mSv), respectively (P < 0.001). Median diagnostic acceptability, spatial resolution, and contrast resolution were significantly higher and subjective noise scores were significantly lower on SP-ASIR 40 compared with all MP datasets. There was perfect clinical agreement between MP-MBIR and SP-ASIR 40 images for detection of extramural complications. CONCLUSIONS Modified protocol CT using pure IR is feasible for assessment of active CD.

In the performing art of medicine: the doctor as actor.

Abstract: ‘I've learned that people will forget what you said, people will forget what you did, but people will never forget how you made them feel.’ Maya Angelou1 How much of a doctor–patient interaction is acting by one or both participants? Doctors seem to dislike the word acting as a descriptor for the part they play in a clinical consultation, preferring words like professionalism to account for their approach and behaviour with patients. Having no difficulty with the concept of patients being cast in a sick role, they demur from the notion of themselves acting, perhaps considering it a mark of insincerity, something phony. Previous suggestions that the ability to act confers on a doctor the gift, irrespective of their mood, to respond appropriately to a patient’s concerns, seem to have gone unheeded.2,3 Once an important part of a doctor’s interaction with patients, acting is a lost part of the art of medicine, worthy of reconsideration. Acting, in this context, is a willingness to release one’s personality, that is, to act out one’s personality—from within, and not a pretense or an affectation of deception. While primarily for patients’ benefit, this form of acting can also help clinicians enjoy and embrace the ordinary, turning routine into extraordinary. The clinical consultation has been likened to a duet, the patient leading, setting the tune and tempo, to which the doctor responds. Jazz is produced when the doctor’s improvizations are effective; occasionally, the duet falls out of tune and sometimes there is noise.4,5 ‘Most people who fall ill have chosen to cast themselves in the role of patient’ according to Jonathan Miller.6 ‘Viewing their unfortunate situation, they see themselves as sick people and begin to act differently.’ Anatole Broyard’s brilliant analysis of his …