Role of gut microbiota-generated short chain fatty acids in metabolic and cardiovascular health

Purpose of this Review: This review assesses the latest evidence linking short-chain fatty acids (SCFA) with host metabolic health and cardiovascular disease (CVD) risk and presents the latest evidence on possible biological mechanisms. Recent Findings: SCFA have a range of effects locally in the gut and at both splanchnic and peripheral tissues which together appear to induce improved metabolic regulation and have direct and indirect effects on markers of CVD risk. Summary: SCFA produced primarily from the microbial fermentation of dietary fibre appear to be key mediators of the beneficial effects elicited by the gut microbiome. Not only does dietary fibre fermentation regulate microbial activity in the gut, SCFA also directly modulate host health through a range of tissue-specific mechanisms related to gut barrier function, glucose homeostasis, immunomodulation, appetite regulation and obesity. With the increasing burden of obesity worldwide, the role for gut microbiota-generated SCFA in protecting against the effects of energy dense diets offers an intriguing new avenue for regulating metabolic health and CVD risk

The role of old-growth forests in frequent-fire landscapes

Classic ecological concepts and forestry language regarding old growth are not well suited to frequent-fire landscapes. In frequent-fire, old-growth landscapes, there is a symbiotic relationship between the trees, the understory graminoids, and fire that results in a healthy ecosystem. Patches of old growth interspersed with younger growth and open, grassy areas provide a wide variety of habitats for animals, and have a higher level of biodiversity. Fire suppression is detrimental to these forests, and eventually destroys all old growth. The reintroduction of fire into degraded frequent-fire, old-growth forests, accompanied by appropriate thinning, can restore a balance to these ecosystems. Several areas require further research and study: 1) the ability of the understory to respond to restoration treatments, 2) the rate of ecosystem recovery following wildfires whose level of severity is beyond the historic or natural range of variation, 3) the effects of climate change, and 4) the role of the microbial community. In addition, it is important to recognize that much of our knowledge about these old-growth systems comes from a few frequent-fire forest types

Investigating structural cerebellar differences associated with schizophrenia pathophysiology

While historically overlooked, there is growing interest in the possible pathophysiological roles played by the cerebellum in various psychiatric and neurodevelopmental disorders, including schizophrenia. While structural cerebellar differences have been noted in individuals with psychiatric diagnoses compared to normative controls, whether these effects reflect true underlying neuropathology, confounding (spurious associations caused by uncontrolled for demographic, medical or imaging factors) or reverse causation (i.e. arising following principal symptom onset) is still to be established. The use of large datasets of homogeneously collected Magnetic Resonance Imaging (MRI), with genetic and health record data will help advance our knowledge in this regard. Chapter 1 provides an overview of the relevant literature around schizophrenia, its genetic aetiology, pathophysiology, genetic neuroimaging techniques, the cerebellum and its relevance to schizophrenia. In Chapter 2 I investigate whether psychiatric disorders are associated with reduced cerebellar volume in a large population-based cohort, when taking into account any shared medical comorbidities, sub-clinical comorbidities and other imaging and non-imaging based confounding measures. In Chapter 3, to circumvent the problem of reverse causation, in a cohort of non-psychiatric participants, I use genetic imaging analyses to investigate whether an individual’s increased common and rare genetic risk burden for schizophrenia is similarly associated with cerebellar reductions. In Chapter 4, I identify the common genetic variants important for cerebellar structure volume and use these results to ascertain the genetic correlation between the cerebellum and schizophrenia liability. Finally, in Chapter 5, I use these introduced cerebellar-associated variants to explore their significance in a clinical cohort, investigating whether those individuals with treatment-resistant schizophrenia, a feature associated with impairment brain development, showed a lower genetic predisposition for cerebellar growth. Chapter 6 provides a summary of the findings presented in this thesis, their relevance to the wider scientific literature and avenues for future research

Implementing positivity constraints in 4-D resistivity time-lapse inversion

Over the last 25 years 2-D and 3-D resistivity surveys have been used for a wide range of engineering, environmental, hydrological and mineral exploration surveys (Loke et al. 2013). In some surveys, the purpose includes the monitoring of subsurface changes with time (Chambers et al. 2014). The 4-D smoothness-constrained inversion method (Loke et al. 2014) has proved to be a stable and robust method for the inversion of time-lapse data sets. This method inverts the data sets measured at different times simultaneously and it includes a temporal smoothness constraint to ensure that the resistivity changes in a smooth manner with time. In some surveys, such as infiltration experiments (Kuras et al. 2016), it is known that the subsurface resistivity should only decrease (or increase) with time. As the standard 4-D inversion method does not explicitly constrain the direction of the changes with time, this could result in artefacts where an increase in the resistivity is obtained in the inverse model while it is only expected to decrease (or vice versa). In this paper we describe a modification of the 4-D smoothness-constrained inversion method to remove such temporal artefacts

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods

Background: Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable. Objectives: We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion. Design: In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level–dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data). Results: Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. Conclusion: Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at clinicaltrials.gov as NCT00750438

The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro

Aims: Diet-derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the effects of increasing colonic delivery of the SCFA propionate on β-cell function in humans and the direct effects of propionate on isolated human islets in vitro. Materials and Methods: For 24 weeks human subjects ingested an inulin-propionate ester that delivers propionate to the colon. Acute insulin, GLP-1 and non-esterified fatty acid (NEFA) levels were quantified pre- and post-supplementation in response to a mixed meal test. Expression of the SCFA receptor FFAR2 in human islets was determined by western blotting and immunohistochemistry. Dynamic insulin secretion from perifused human islets was quantified by radioimmunoassay and islet apoptosis was determined by quantification of caspase 3/7 activities. Results: Colonic propionate delivery in vivo was associated with improved β-cell function with increased insulin secretion that was independent of changes in GLP-1 levels. Human islet β-cells expressed FFAR2 and propionate potentiated dynamic glucose-stimulated insulin secretion in vitro, an effect that was dependent on signalling via protein kinase C. Propionate also protected human islets from apoptosis induced by the NEFA sodium palmitate and inflammatory cytokines. Conclusions: Our results indicate that propionate has beneficial effects on β-cell function in vivo, and in vitro analyses demonstrated that it has direct effects to potentiate glucose-stimulated insulin release and maintain β-cell mass through inhibition of apoptosis. These observations support ingestion of propiogenic dietary fibres to maintain healthy glucose homeostasis