The formation of SCFA is the result of a complex interplay between diet and the gut microbiota within the gut lumen environment. The discovery of receptors, across a range of cell and tissue types ...for which short chain fatty acids SCFA appear to be the natural ligands, has led to increased interest in SCFA as signaling molecules between the gut microbiota and the host. SCFA represent the major carbon flux from the diet through the gut microbiota to the host and evidence is emerging for a regulatory role of SCFA in local, intermediary and peripheral metabolism. However, a lack of well-designed and controlled human studies has hampered our understanding of the significance of SCFA in human metabolic health. This review aims to pull together recent findings on the role of SCFA in human metabolism to highlight the multi-faceted role of SCFA on different metabolic systems.
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.
In recent years, there has been a renewed interest in the role of dietary fibre in obesity management. Much of this interest stems from animal and human studies which suggest that an increased intake ...of fermentable fibre can suppress appetite and improve weight management. A growing number of reports have demonstrated that the principal products of colonic fermentation of dietary fibre, SCFA, contribute to energy homeostasis via effects on multiple cellular metabolic pathways and receptor-mediated mechanisms. In particular, over the past decade it has been identified that a widespread receptor system exists for SCFA. These G-protein-coupled receptors, free fatty acid receptor (FFAR) 2 and FFAR3 are expressed in numerous tissue sites, including the gut epithelium and adipose tissue. Investigations using FFAR2- or FFAR3-deficient animal models suggest that SCFA-mediated stimulation of these receptors enhances the release of the anorectic hormones peptide tyrosine tyrosine and glucagon-like peptide-1 from colonic L cells and leptin from adipocytes. In addition, the SCFA acetate has recently been shown to have a direct role in central appetite regulation. Furthermore, the SCFA propionate is a known precursor for hepatic glucose production, which has been reported to suppress feeding behaviour in ruminant studies through the stimulation of hepatic vagal afferents. The present review therefore proposes that an elevated colonic production of SCFA could stimulate numerous hormonal and neural signals at different organ and tissue sites that would cumulatively suppress short-term appetite and energy intake.
Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian ...target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.
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•mTORC1 regulates glutamine anaplerosis (catabolism)•mTORC1 represses SIRT4 transcription to regulate glutamate dehydrogenase activity•SIRT4 represses cell proliferation and is downregulated in human cancer•Combined glutamine and glucose metabolism inhibition results in death of cancer cells
mTORC1 regulates glutamine catabolism by controlling the levels of SIRT4, thus contributing to the metabolic reprogramming that drives tumor cell growth and proliferation.
The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite ...regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.
To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.
Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.
These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.
NCT00750438.
Self-esteem level has been positioned as a key mediating mechanism accounting for the effects of ostracism on behaviors, invoking the notion that individuals seek to verify their self-perceptions by ...behaving in a way that is consistent with those self-perceptions. However, evidence supporting the relation of ostracism and self-esteem level to behavioral outcomes has been mixed. We argue that such mixed effects arise because individuals may engage in behaviors alternately to verify their self-perceptions (suggesting a relation between self-esteem level and behavioral outcomes) or to selfenhance (suggesting no relation between self-esteem level and behavioral outcomes). Within this framing, the question becomes: When do we self-verify and when do we self-enhance? To that end, we position contingent self-esteem—or the extent to which individuals base their self-worth on outcomes in a particular domain—as a determining factor in whether we self-verify or self-enhance, and present a moderated mediation model to account for varying relations between ostracism and job performance. Our predictions regarding self-verification and self-enhancement motivation are fully supported across two field samples using multi-wave, multi-source study designs. Theoretical and practical implications for self-verification and self-enhancement motivation, as well as negative interpersonal behaviors at work, are discussed.
IMPORTANCE: Firearm injury research in the US has focused on fatal injuries. The incidence and epidemiologic factors associated with nonfatal firearm injuries are less understood. OBJECTIVE: To ...evaluate estimates of incidence and trends over time of fatal and nonfatal firearm injuries. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, ecologic study was conducted using data throughout the US from 2009 to 2017. Data on fatal injuries from the Centers for Disease Control and Prevention were combined with national data on emergency department visits for nonfatal firearm injury from the Nationwide Emergency Department (ED) sample. Data analysis was conducted from August 2019 to September 2020. EXPOSURES: Firearm injuries identified with International Classification of Diseases external cause of injury codes and categorized by intent of injury, age group, and urban-rural location. MAIN OUTCOMES AND MEASURES: Incidence, case fatality rate, and trends over time of firearm injury according to intent, age group, and urban-rural location. RESULTS: From 2009 to 2017, there was a mean of 85 694 ED visits for nonfatal firearm injury and 34 538 deaths each year. An annual mean of 26 445 deaths (76.6%) occurred outside of the hospital. Assault was the most common overall mechanism (38.9%), followed by unintentional injuries (36.9%) and intentional self-harm (19.6%). Self-harm, which accounted for 21 128 deaths (61.2%), had the highest case fatality rate (89.4%; 95% CI, 88.5%-90.4%), followed by assault (25.9%; 95% CI, 23.7%-28.6%) and legal intervention (23.4%; 95% CI, 21.6%-25.5%). Unintentional injuries were the most common nonfatal injuries (43 729 51.0%) and had the lowest case fatality rate (1.2%; 95% CI, 1.1%-1.3%). Self-harm deaths, 87.8% of which occurred outside the hospital, increased in all age groups in both rural and urban areas during the study period and were most common among people aged 55 years and older. The rate of fatal assault injuries was higher in urban than in rural areas (16.6 vs 9.0 per 100 000 per year) and highest among people aged 15 to 34 years (38.6 per 100 000 per year). Rates of unintentional injury were higher in rural than in urban areas (18.5 per 100 000 vs 12.4 per 100 000). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, suicide appears to be the most common cause of firearm injury death in the US, and most people who die from suicide never reach the hospital. These findings suggest that assaults and unintentional injuries account for most nonfatal and overall firearm injuries and for most of the injuries that are treated in hospitals.
Public health approaches to crime and injury prevention are increasingly focused on the physical places and environments where violence is concentrated. In this study, our aim is to explore the ...association between historic place-based racial discrimination captured in the 1937 Home Owners Loan Corporation (HOLC) map of Philadelphia and present-day violent crime and firearm injuries. The creators of the 1937 HOLC map zoned Philadelphia based in a hierarchical system wherein first-grade and green color zones were used to indicate areas desirable for government-backed mortgage lending and economic development, a second-grade or blue zone for areas that were already developed and stable, a third-grade or yellow zone for areas with evidence of decline and influx of a “low grade population,” and fourth-grade or red zone for areas with dilapidated or informal housing and an “undesirable population” of predominately Black residents. We conducted an empirical spatial analysis of the concentration of firearm assaults and violent crimes in 2013 through 2014 relative to zoning in the 1937 HOLC map. After adjusting for socio-demographic factors at the time the map was created from the 1940 Census, firearm injury rates are highest in historically red-zoned areas of Philadelphia. The relationship between HOLC map zones and general violent crime is not supported after adjusting for historical Census data. This analysis extends historic perspective to the relationship between emplaced structural racism and violence, and situates the socio-ecological context in which people live at the forefront of this association.
•Examines the emplacement of racialized housing discrimination documented in a 1937 map of a US city (Philadelphia).•Uses spatial analysis to evaluate the relationship between structural racism and firearm violence.•Reveals how historical discrimination may have shaped the segregation of contemporary urban violence exposure.
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.
Evidence suggests that the consumption of anthocyanin-rich foods beneficially affects cardiovascular health; however, the absorption, distribution, metabolism, and elimination (ADME) of ...anthocyanin-rich foods are relatively unknown.
We investigated the ADME of a (13)C5-labeled anthocyanin in humans.
Eight male participants consumed 500 mg isotopically labeled cyanidin-3-glucoside (6,8,10,3',5'-(13)C5-C3G). Biological samples were collected over 48 h, and (13)C and (13)C-labeled metabolite concentrations were measured by using isotope-ratio mass spectrometry and liquid chromatography-tandem mass spectrometry.
The mean ± SE percentage of (13)C recovered in urine, breath, and feces was 43.9 ± 25.9% (range: 15.1-99.3% across participants). The relative bioavailability was 12.38 ± 1.38% (5.37 ± 0.67% excreted in urine and 6.91 ± 1.59% in breath). Maximum rates of (13)C elimination were achieved 30 min after ingestion (32.53 ± 14.24 μg(13)C/h), whereas (13)C-labeled metabolites peaked (maximum serum concentration: 5.97 ± 2.14 μmol/L) at 10.25 ± 4.14 h. The half-life for (13)C-labeled metabolites ranged between 12.44 ± 4.22 and 51.62 ± 22.55 h. (13)C elimination was greatest between 0 and 1 h for urine (90.30 ± 15.28 μg/h), at 6 h for breath (132.87 ± 32.23 μg/h), and between 6 and 24 h for feces (557.28 ± 247.88 μg/h), whereas the highest concentrations of (13)C-labeled metabolites were identified in urine (10.77 ± 4.52 μmol/L) and fecal samples (43.16 ± 18.00 μmol/L) collected between 6 and 24 h. Metabolites were identified as degradation products, phenolic, hippuric, phenylacetic, and phenylpropenoic acids.
Anthocyanins are more bioavailable than previously perceived, and their metabolites are present in the circulation for ≤48 h after ingestion. This trial was registered at clinicaltrials.gov as NCT01106729.
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