Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Endogenous mechanisms that act in the resolution of acute inflammation are essential for host defense and the return to homeostasis. Resolvin D1 (RvD1), biosynthesized during resolution, displays potent and stereoselective anti-inflammatory actions, such as limiting neutrophil infiltration and proresolving actions. Here, we demonstrate that RvD1 actions on human polymorphonuclear leukocytes (PMNs) are pertussis toxin sensitive, decrease actin polymerization, and block LTB₄-regulated adhesion molecules (β2 integrins). Synthetic [³H]-RvD1 was prepared, which revealed specific RvD1 recognition sites on human leukocytes. Screening systems to identify receptors for RvD1 gave two candidates—ALX, a lipoxin A₄ receptor, and GPR32, an orphan—that were confirmed using a β-arrestin-based ligand receptor system. Nuclear receptors including retinoid X receptor-α and peroxisome proliferator-activated receptor-α, -δ, -γ were not activated by either resolvin E1 or RvD1 at bioactive nanomolar concentrations. RvD1 enhanced macrophage phagocytosis of zymosan and apoptotic PMNs, which increased with overexpression of human ALX and GPR32 and decreased with selective knockdown of these G-protein-coupled receptors. Also, ALX and GPR32 surface expression in human monocytes was up-regulated by zymosan and granulocyte-monocyte–colony-stimulating factor. These results indicate that RvD1 specifically interacts with both ALX and GPR32 on phagocytes and suggest that each plays a role in resolving acute inflammation.     

Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins

The resolution of acute inflammation is a process that allows for inflamed tissues to return to homeostasis. Resolution was held to be a passive process, a concept now overturned with new evidence demonstrating that resolution is actively orchestrated by distinct cellular events and endogenous chemical mediators. Among these, lipid mediators, such as the lipoxins, resolvins, protectins, and newly identified maresins, have emerged as a novel genus of potent and stereoselective players that counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution. Given that uncontrolled, chronic inflammation is associated with many cardiovascular pathologies, an appreciation of the endogenous pathways and mediators that control timely resolution can open new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation, as well as correcting the impact of chronic inflammation in cardiovascular disorders. Here, we overview and update the biosynthesis and actions of proresolving lipid mediators, highlighting their diverse protective roles relevant to vascular systems and their relation to aspirin and statin therapies.     

Profiling in resolving inflammatory exudates identifies novel anti‐inflammatory and pro‐resolving mediators and signals for termination

Abstract. Norling LV, Serhan CN (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA). Profiling in resolving inflammatory exudates identifies novel anti‐inflammatory and pro‐resolving mediators and signals for termination (Review). J Intern Med 2010; 268 :15–24. A highly orchestrated inflammatory response and its completion, termed resolution, are essential for ongoing health. Thus, complete understanding of the cellular and molecular events that govern natural resolution is vital. Using an unbiased systems approach to profile self‐limited inflammatory exudates, we identified a novel genus of specialized pro‐resolving lipid mediators (SPMs) comprised of three new families coined the resolvins, protectins and most recently the maresins biosynthesized from ω‐3 fatty acids. These join the lipoxin‐ and aspirin‐triggered lipoxins as anti‐inflammatory and pro‐resolving lipid mediators formed from arachidonic acid with the genus. SPMs have proven stereoselective, and control both the duration and magnitude of inflammation. Mapping these endogenous resolution circuits provides new avenues to probe the molecular basis of many widely occurring diseases where uncontrolled inflammation is characteristic. The focus of this JIM review is to depict recent advances from studies by the authors and colleagues on the biosynthesis and actions of these novel anti‐inflammatory, pro‐resolving and protective lipid mediators. Together these findings indicate that defective mechanisms and pathways in resolution may underlie our current appreciation of the inflammatory phenotype(s) that characterize some prevalent human diseases.     

Interferon-β regulates proresolving lipids to promote the resolution of acute airway inflammation

Aberrant immune responses, including hyperresponsiveness to Toll-like receptor (TLR) ligands, underlie acute respiratory distress syndrome (ARDS). Type I interferons confer antiviral activities and could also regulate the inflammatory response, whereas little is known about their actions to resolve aberrant inflammation. Here we report that interferon-β (IFN-β) exerts partially overlapping, but also cooperative actions with aspirin-triggered 15-epi-lipoxin A₄ (15-epi-LXA₄) and 17-epi-resolvin D1 to counter TLR9-generated cues to regulate neutrophil apoptosis and phagocytosis in human neutrophils. In mice, TLR9 activation impairs bacterial clearance, prolongs Escherichia coli–evoked lung injury, and suppresses production of IFN-β and the proresolving lipid mediators 15-epi-LXA₄ and resolvin D1 (RvD1) in the lung. Neutralization of endogenous IFN-β delays pulmonary clearance of E. coli and aggravates mucosal injury. Conversely, treatment of mice with IFN-β accelerates clearance of bacteria, restores neutrophil phagocytosis, promotes neutrophil apoptosis and efferocytosis, and accelerates resolution of airway inflammation with concomitant increases in 15-epi-LXA₄ and RvD1 production in the lungs. Pharmacological blockade of the lipoxin receptor ALX/FPR2 partially prevents IFN-β–mediated resolution. These findings point to a pivotal role of IFN-β in orchestrating timely resolution of neutrophil and TLR9 activation–driven airway inflammation and uncover an IFN-β–initiated resolution program, activation of an ALX/FPR2-centered, proresolving lipids-mediated circuit, for ARDS.

Acute respiratory distress syndrome (ARDS) is a common syndrome associated with high mortality in patients admitted to intensive care units (1). ARDS is characterized by diffuse alveolar damage that develops in patients with known risk factors, most commonly pneumonia, sepsis, or trauma (2, 3). The initial alveolar damage leads to recruitment of neutrophils and monocytes, which further aggravate injury (3). Treatment of the underlying cause and lung-protective ventilation are the main elements of supportive therapy (4, 5). Importantly, no therapies are available to resolve the aberrant immune responses underlying ARDS.Type I interferons, IFN-α and IFN-β, are well established to confer antiviral activities to host cells and could also regulate the inflammatory response. A delayed type I interferon response triggers the generation of proinflammatory cytokines and facilitates the recruitment of monocytes to the lung, resulting in lethal pneumonia in mice infected with SARS-CoV-1 (6) or SARS-CoV-2 (7). Type I interferons break TNF-induced tolerance to Toll-like receptor (TLR) signals on monocytes/macrophages, rendering them hyperresponsive to additional TLR signals concurrent with inflammatory activation (8). For instance, bacterial DNA (CpG DNA) or mitochondrial DNA through TLR9 impairs neutrophil phagocytosis, delays neutrophil apoptosis, and perpetuates inflammation (9, 10). In contrast, IFN-β protects against lethal polymicrobial sepsis through inhibiting IL-1 production and/or induction of IL-10 (11–13). IFN-β produced by macrophages during resolution of bacterial pneumonia facilitates removal of neutrophils from inflamed tissues and reprograms macrophages to a proresolving phenotype, thereby driving inflammatory resolution in mice (14). However, the underlying mechanisms are incompletely understood; albeit these would be essential for implementing precision treatment with IFN-β.Resolution of inflammation is an active process governed by specialized proresolving lipid and protein mediators (SPMs) (15–19). These mediators converge on select receptors, including the pleiotropic lipoxin A₄ receptor/formyl peptide receptor 2 (ALX/FPR2) (20). ALX/FPR2 plays critical roles in host defense and orchestrating inflammatory resolution (20–23). ALX/FPR2 binds multiple lipid ligands, including aspirin-triggered 15-epi-lipoxin A₄ (15-epi-LXA₄) and 17-epi-resolvin D1 (17-epi-RvD1), generated within the inflammatory microenvironment (17, 18). SPMs inhibit neutrophil recruitment, promote neutrophil apoptosis and efferocytosis, and facilitate tissue repair and return to homeostasis (17, 18, 24). Activation of ALX/FPR2 with 15-epi-LXA₄ or 17-epi-RvD1 counters TLR9-generated cues, restores impaired neutrophil function, and enhances timely resolution of airway bacterial infections (9). Since resolution of inflammation is skewed toward a proresolving lipid profile (18, 25, 26), we investigated whether IFN-β can modulate ALX/FPR2-based resolution mechanisms. Here, we report that IFN-β exerts partially overlapping, but also cooperative actions with 17-epi-RvD1 to counter TLR9-generated signals to regulate neutrophil phagocytosis and apoptosis in vitro. In mice, IFN-β facilitates clearance of bacteria, neutrophil apoptosis and efferocytosis, and promotes the resolution of acute airway inflammation, in part, by stimulating generation of proresolving lipids and activation of ALX/FPR2-centered proresolving circuits. Our results uncover a hitherto unrecognized effector mechanism by which IFN-β may facilitate resolution of ARDS.     

Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets

Endogenous ligands of cannabinoid receptors have been discovered recently and include some N-acylethanolamines (NAEs; e.g., N-arachidonoylethanolamine) and some 2-acylglycerols (e.g., sn-2-arachidonoylglycerol). Previously, we found these compounds to be active biologically when administered per os in large quantities to mice. In the present work, piglets were fed diets with and without 20:4n-6 and 22:6n-3 fatty acid precursors of NAEs, in levels similar to those found in porcine milk, during the first 18 days of life, and corresponding brain NAEs were assessed. In piglets fed diets containing 20:4n-6 and 22:6n-3, there were increases in several biologically active NAEs in brain homogenates-20:4n-6 NAE (4-fold), 20:5n-3 NAE (5-fold), and 22:5n-3 and 22:6n-3 NAE (9- to 10-fold). These results support a mechanism we propose for dietary long-chain polyunsaturated fatty acids influences on brain biochemistry with presumed functional sequelae. This paradigm will enable targeted investigations to determine whether and why specific populations such as infants, elderly, or persons suffering from certain clinical conditions may benefit from dietary long-chain polyunsaturated fatty acids.     

Prevention of cardiac sudden death by N-3 fatty acids: a review of the evidence

The essential n-6 and n-3 polyunsaturated fatty acids can prevent ischaemia-induced ventricular fibrillation in rats, dogs and marmosets. In isolated neonatal rat cardiac myocytes, these have been shown to prevent tachyarrhythmias caused by elevated calcium concentrations, toxic levels of ouabain, a β-adrenergic agent (isoproterenol), lysophosphatidylcholine and acylcarnitine. The antiarrhythmic effect is caused by a reduction in electrical excitability caused by partitioning of the free polyunsaturated fatty acids into the phospholipid cell membranes of the cardiac myocytes, which modulates membrane ion channels. Two clinical trials suggest they could prevent sudden cardiac death in humans.     

Integrative medicine in gastrointestinal disease: evaluating the evidence

Current Western therapies for many gastrointestinal diseases are suboptimal and potentially toxic. The majority of patients with digestive diseases are turning to complementary and alternative medicine for symptom relief and improved quality of life, due to dissatisfaction with conventional medical therapies. There is emerging evidence that many of these complementary and alternative medicine modalities are highly effective in modulating the immune system, disrupting the proinflammatory cascade and restoring digestive health while improving patients’ quality of life. We present evidence to support the potential utility of complementary and alternative medicine modalities for irritable bowel syndrome and inflammatory bowel disease. For each condition, we detail the proposed mechanisms of action and explore the current data for the prevention and/or treatment of disease.     

Activation of protein mediators of inflammation and evidence for endotoxemia in Borrelia recurrentis infection

Fifteen patients with Borrelia recurrentis infection were studied to evaluate the role of certain plasma proteins and endotoxin in the pathophysiology of both the acute illness and the Jarisch-Herxheimer-like reaction. The causative spirochetes disappeared from the blood during the Jarisch-Herxheimer-like reaction, which occurred about 2 hours after antibiotic therapy. The mean titers of Hageman factor, plasma prekallikrein and serum hemolytic complement activity were decreased at the time of admission and 2 hours after treatment, and rose to normal values during convalescence. Serum properdin titers were decreased in 14 patients at the time of admission, in 12 patients 2 hours after treatment, and in none during convalescence. The frequency of elevated levels of fibrinogen-related antigens increased from three patients at the time of admission to 12 patients 2 hours after treatment. Results of plasma limulus tests for endotoxin-like material were positive in 11 patients at the time of admission and in 13 patients 2 hours after treatment. These findings demonstrated that Hageman factor, prekallikrein and proteins of the complement system are activated in B. recurrentis infection and that endotoxin may play a role in both the acute illness and in the development of the Jarisch-Herxheimer-like reaction after treatment.     

Regulatory T cells in inflammation and resolution of acute lung injury

IntroductionAcute respiratory distress syndrome (ARDS) is characterized by hypoxemia and increased lung permeability and would result in acute respiratory failure and with high mortality. In patients who survive from acute lung injury (ALI)/ARDS, it is an active process of the transition from injury to resolution depending on the coordinated immune system. The roles of regulatory CD4⁺T cells (Tregs) are now gradually being clarified during inflammation and resolution of ARDS. However, clear conclusions about roles of Tregs in ALI/ARDS are only a few.ObjectiveThis review provides an overview of phenotype, differentiation, and suppressive mechanisms of Tregs and focuses on keys of biology of Tregs in alveolar space during the inflammatory response and resolution of ALI/ARDS.Data SourceLiterature search of Web of Science, PubMed, and EMBASE was made to find relative articles about Tregs in ALI/ARDS. We used the following search terms: Tregs, ALI, ARDS, inflammation, and resolution.ConclusionMore and more studies have indicated Tregs involved in the processes of inflammation and resolution of ALI/ARDS. A deep understanding of the roles of Tregs may indicate new treatments for patients of ARDS. Therapies aimed at expansion or adaptive transfer of Tregs could be an effective therapy to ARDS patients.     

Gut microbial metabolism defines host metabolism: an emerging perspective in obesity and allergic inflammation

The presence of >100 trillion microorganisms (collectively called gut microbiota) in our large intestine is essential for the maintenance of health. The gut microbiota starts to develop before birth and matures within first three years of life. The Western diet and lifestyle have been implicated in causing an imbalance of gut microbial communities and their metabolites that consequence in disease states, such as obesity and asthma. With more than 13% of the world population currently living with obesity and one out of 10 children diagnosed with asthma, we explore here the recent developments in the biosynthesis and mode of action of the key metabolites in relation to these two chronic inflammatory conditions.     

Dietary fats and cardiovascular disease: Putting together the pieces of a complicated puzzle

Dietary fatty acids play significant roles in the cause and prevention of cardiovascular disease (CVD). Trans fatty acids from partially hydrogenated vegetable oils have well-established adverse effects and should be eliminated from the human diet. CVD risk can be modestly reduced by decreasing saturated fatty acids (SFA) and replacing it by a combination of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). Although the ideal type of unsaturated fat for this replacement is unclear, the benefits of PUFA appear strongest. Both n-6 and n-3 PUFA are essential and reduce CVD risk. However, additional research is needed to better define the optimal amounts of both and to discern the patients and/or general population that would benefit from supplemental n-3 fatty acid intake. Furthermore, consumption of animal products, per se, is not necessarily associated with increased CVD risk, whereas nut and olive oil intake is associated with reduced CVD risk. In conclusion, the total matrix of a food is more important than just its fatty acid content in predicting the effect of a food on CVD risk, and a healthy diet should be the cornerstone of CVD prevention.     

Glucocorticoid-mediated regulation of granulocyte apoptosis and macrophage phagocytosis of apoptotic cells: implications for the resolution of inflammation

Glucocorticoids represent one of the most effective clinical treatments for a range of inflammatory conditions, including severe acute inflammation. Although glucocorticoids are known to affect processes involved in the initiation of inflammation, the influence of glucocorticoids on the mechanisms by which acute inflammation normally resolves have received less attention. Apoptosis of granulocytes present at inflamed sites leads to their rapid recognition and internalisation by macrophages, a process which may be important for resolution of inflammation. However, if clearance of either eosinophils or neutrophils is impaired, these cells rapidly undergo secondary necrosis leading to release of pro-inflammatory mediators from the phagocyte, potentially prolonging inflammatory responses. Physiologically relevant concentrations of glucocorticoids accelerate eosinophil apoptosis whilst delaying neutrophil apoptosis during in vitro culture. Here we discuss key pathways regulating the granulocyte apoptotic programme and summarise the effects of glucocorticoids on monocyte differentiation and the consequent changes to apoptotic cell clearance capacity. Definition of the mechanisms underlying resolution of inflammatory responses following glucocorticoid treatment may unveil new targets for modulation of inflammatory disease, allowing co-ordinated augmentation of granulocyte apoptosis together with increased macrophage capacity for clearance of apoptotic cells.     

Insulin regulation of glucose and lipid metabolism in massive obesity

Summary Eight obese patients and 12 normal individuals underwent a euglycaemic insulin clamp (20 and 40 mU · m^2–1 · min^–1) along with continuous infusion of 3-³H-glucose and 1-¹⁴C-palmitate and indirect calorimetry. Basal plasma glucose concentration (4.7±0.3 vs 4.4±0.2 mmol/l) was similar in the two groups, whereas hepatic glucose production was slightly higher in obese individuals (1.11±0.06 vs 0.84±0.05 mmol/min) in spite of higher plasma insulin levels (17±2 vs 6±1 mU/l; p<0.01). Insulin inhibition of hepatic glucose production was impaired in obese subjects. Glucose disposal by lean body mass was markedly reduced both at baseline (11.7±1.1 vs 15.6±0.6 mol · kg^–1 · min^–1; p<0.05) and during clamp (15.0±1.1 vs 34.4±2.8 and 26.7±3.9 vs 62.2±2.8 mol · kg^–1 · min^–1; p<0.01) Oxidative (12.2±1.1 vs 17.8±1 and 16.1±1.1 vs 51.1±1.7 mol · kg^–1 · min^–1; p<0.05–0.002) and non-oxidative glucose metabolism (3.9±1.1 vs 15.0±2.8 and 12.8±3.3 vs 38.3±2.2 mol · kg^–1 · min^–1; p<0.01–0.001) were impaired. Basal plasma concentrations of non-esterified fatty acids (635±75 vs 510±71 mol/l) and blood glycerol (129±17 vs 56±5 mol/l; p<0.01) were increased in obese patients. Following hyperinsulinaemia, plasma non-esterified fatty acids (244±79 vs 69±16 and 140±2 vs 36±10 mol/l; p<0.01) and blood glycerol levels (79±20 vs 34±6 and 73±22 vs 29±5 mol/l; p<0.01) remained higher in obese subjects. Baseline non-esterified fatty acid production rate per kg of fat body mass was significantly larger in normal weight subjects (37.7±6.7 vs 14.0±1.8 mol/l; p<0.01) and insulin inhibition was reduced in obese patients (–41±9 vs –74±3 and –53±11 vs –82±3%; p<0.05). Basal plasma non-esterified fatty acid utilization by lean body mass was similar in the two groups (9.8±0.9 vs 8.8±2.0 mol · kg^–1 · min^–1), whereas during clamp it remained higher in obese patients (6.0±1.2 vs 2.8±2.5 and 4.9±1.3 vs 1.5±0.6 mol · kg^–1 · min^–1; p<0.1–0.05). Lipid oxidation was higher in obese individuals in spite of hyperinsulinaemia (3.7±0.3 vs 2.4±0.4 and 2.3±0.4 vs 0.9±0.3 mol · kg^–1 · min^–1; p<0.05– 0.02). An inverse correlation was found between lipid oxidation and glucose oxidation (r=0.82 and 0.93; p<0.001) and glucose utilization (r=0.54 and 0.83; p<0.05–0.001) both in obese and control subjects. A correlation between lipid oxidation and non-oxidative glucose metabolism was present only in normal weight individuals (r=0.75; p<0.01). We conclude that in obesity all tissues (muscles, liver, and adipose tissue) are resistant to insulin action. Insulin resistance involves glucose as well as lipid metabolism.     

Isolation and Preliminary Characterization of the Medium-Chain Fatty Acid:CoA Ligase Responsible for Activation of Short- and Medium-Chain Fatty Acids in Colonic Mucosa from Swine

The ATP-dependent activation of short- and medium-chain fatty acids to their respective CoA thioester adducts was investigated in the colonic mucosa from swine. Subcellular fractionation of a homogenate of the mucosa from the entire length of the colon revealed a predominantly mitochondrial localization for activity toward fatty acids ranging from propionate through laurate. These activities could be released from mitochondria in soluble form by freeze–thaw lysis. Purification of these activities revealed that they all appeared to reside with a single enzyme. This suggests that the entire colon contains a single form of medium-chain fatty acid:CoA ligase (MCFA:CoA ligase). The ligase also had activity toward benzoate and salicylate, although this activity was significantly lower than activity toward medium-chain fatty acids. The enzyme had the highest activity at V_max with butyrate as substrate and had the lowest K_m for octanoate. Butyrate and octanoate were mutually inhibitory. Activity toward both substrates was also efficiently inhibited by cyclohexane carboxylate. The molecular weight of the enzyme was estimated by gel filtration chromatography to be ca. 46,500. These data indicate that the colonic MCFA:CoA ligase is significantly different from the hepatic and kidney MCFA:CoA ligases.     

Use of butyrate or glutamine in enema solution reduces inflammation and fibrosis in experimental diversion colitis

AIM: To investigate whether butyrate or glutamine enemas could diminish inflammation in experimental diversion colitis.METHODS: Wistar specific pathogen-free rats were submitted to a Hartmann’s end colostomy and treated with enemas containing glutamine, butyrate, or saline. Enemas were administered twice a week in the excluded segment of the colon from 4 to 12 wk after the surgical procedure. Follow-up colonoscopy was performed every 4 wk for 12 wk. The effect of treatment was evaluated using video-endoscopic and histologic scores and measuring interleukin-1β, tumor necrosis factor-alpha, and transforming growth factor beta production in organ cultures by enzyme linked immunosorbent assay.RESULTS: Colonoscopies of the diverted segment showed mucosa with hyperemia, increased number of vessels, bleeding and mucus discharge. Treatment with either glutamine or butyrate induced significant reductions in both colonoscopic (P < 0.02) and histological scores (P < 0.01) and restored the densities of collagen fibers in tissue (P = 0.015; P = 0.001), the number of goblet cells (P = 0.021; P = 0.029), and the rate of apoptosis within the epithelium (P = 0.043; P = 0.011) to normal values. The high levels of cytokines in colon explants from rats with diversion colitis significantly decreased to normal values after treatment with butyrate or glutamine.CONCLUSION: The improvement of experimental diversion colitis following glutamine or butyrate enemas highlights the importance of specific luminal nutrients in the homeostasis of the colonic mucosa and supports their utilization for the treatment of human diversion colitis.     

Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: mechanisms and therapeutic implications

A multitude of factors, including increased coronary vascular resistance and dysregulated coronary microcirculatory function, contribute to the impairment of coronary blood flow (CBF) regulation and the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. CBF is primarily determined by coronary vascular resistance, which is affected by the balance between various vasodilators and vasoconstrictors. Myocardial I/R causes reduced production of endogenous vasodilators, such as nitric oxide (NO), leaving unopposed vasoconstriction that is caused mainly by continued presence of endothelin-1 (ET-1) and serotonin (5-HT); this imbalance in turn enhances vascular tone, triggers inflammatory response, decreases CBF and exacerbates reperfusion injury. Various inflammatory cytokines participate in the regulation of coronary vasomotor function by affecting the balance between vasodilators and vasoconstrictors. In addition to the enhanced coronary vasoconstriction, coronary microembolization, inflammatory cell infiltration and post-ischemic hyperpermeability contribute to the impairment of coronary microcirculatory function and myocardial perfusion during I/R. Ongoing research examining the role of inflammation in the regulation of CBF and coronary microcirculatory function in myocardial I/R is expected to yield new insights that will lead to therapies for ameliorating the vascular inflammatory response in coronary artery diseases (CADs) in the clinical setting. This article is part of a Special Issue entitled "Coronary Blood Flow".     

Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU study

Aims/hypothesis. The amount and quality of fat in the diet could be of importance for development of insulin resistance and related metabolic disorders. Our aim was to determine whether a change in dietary fat quality alone could alter insulin action in humans. Methods. The KANWU study included 162 healthy subjects chosen at random to receive a controlled, isoenergetic diet for 3 months containing either a high proportion of saturated (SAFA diet) or monounsaturated (MUFA diet) fatty acids. Within each group there was a second assignment at random to supplements with fish oil (3.6 g n-3 fatty acids/d) or placebo. Results. Insulin sensitivity was significantly impaired on the saturated fatty acid diet (-10 %, p = 0.03) but did not change on the monounsaturated fatty acid diet ( + 2 %, NS) (p = 0.05 for difference between diets). Insulin secretion was not affected. The addition of n-3 fatty acids influenced neither insulin sensitivity nor insulin secretion. The favourable effects of substituting a monounsaturated fatty acid diet for a saturated fatty acid diet on insulin sensitivity were only seen at a total fat intake below median (37E %). Here, insulin sensitivity was 12.5 % lower and 8.8 % higher on the saturated fatty acid diet and monounsaturated fatty acid diet respectively (p = 0.03). Low density lipoprotein cholesterol (LDL) increased on the saturated fatty acid diet ( + 4.1 %, p < 0.01) but decreased on the monounsaturated fatty acid diet (MUFA) (–5.2, p < 0.001), whereas lipoprotein (a) [Lp(a)] increased on a monounsaturated fatty acid diet by 12 % (p < 0.001). Conclusions/interpretation. A change of the proportions of dietary fatty acids, decreasing saturated fatty acid and increasing monounsaturated fatty acid, improves insulin sensitivity but has no effect on insulin secretion. A beneficial impact of the fat quality on insulin sensitivity is not seen in individuals with a high fat intake ( > 37E %). [Diabetologia (2001) 44: 312–319] Received: 21 August 2000 and in revised form: 8 November 2000     

Understanding the mechanisms of efficacy of fecal microbiota transplant in treating recurrent Clostridioides difficile infection and beyond: the contribution of gut microbial-derived metabolites

ABSTRACT

Fecal microbiota transplant (FMT) is a highly-effective therapy for recurrent Clostridioides difficile infection (rCDI), and shows promise for certain non-CDI indications. However, at present, its mechanisms of efficacy have remained poorly understood. Recent studies by our laboratory have noted the particular key importance of restoration of gut microbe-metabolite interactions in the ability of FMT to treat rCDI, including the impact of FMT upon short chain fatty acid (SCFAs) and bile acid metabolism. This includes a significant impact of these metabolites upon the life cycle of C. difficile directly, along with potential postulated additional benefits, including effects upon host immune response. In this Addendum, we first present an overview of these recent advancements in this field, and then describe additional novel data from our laboratory on the impact of FMT for rCDI upon several gut microbial-derived metabolites which had not previously been implicated as being of relevance.     

Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women.

AIMS: Intrauterine exposure to diabetes is a significant determinant of the development of obesity and early onset of Type 2 diabetes mellitus in the offspring. Both conditions are characterized by insulin resistance and the latter is associated with reduced membrane arachidonic and docosahexaenoic acids. Hence, we investigated if the membrane arachidonic and docosahexaenoic acids are depressed in the cord blood of babies born to women with gestational diabetes. METHODS: Cord (fetal) and maternal blood were obtained at delivery from control subjects (n = 33) and women with gestational diabetes (n = 40) and analysed for plasma triglycerides and cholinephosphoglycerides, and erythrocyte choline- and ethanolaminephosphoglycerides fatty acids. RESULTS: Babies of gestational diabetic mothers had reduced docosahexaenoic acid in the plasma (5.9 +/- 1.4 vs. 7.1 +/- 2.0, P < 0.01) and erythrocyte (4.0 +/- 2.2 vs. 5.4 +/- 2.9, P < 0.05) cholinephosphoglycerides. Moreover, the total omega-6 and omega-3 fatty acids of the erythrocyte cholinephosphoglycerides were significantly lower (P < 0.05) in these babies. A similar trend was observed in plasma triglycerides and erythrocyte ethanolaminephosphoglycerides. The maternal plasma triglycerides and erythrocyte ethanolaminephosphoglycerides fatty acids profile were not different between the two groups. However, there was a reduction in arachidonic acid and total omega-6 fatty acids in the erythrocyte cholinephosphoglycerides of the gestational diabetic women. CONCLUSION: The altered plasma and erythrocyte fatty acids in the cord blood of babies born to women with gestational diabetes suggests a perturbation in the maternal-fetal nutrient transport and/or fetal lipid metabolism.