Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques

Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body’s use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (αHYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (αKetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in α-linolenic acid. Intake of αKetoA, but not αHYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-κB activation in mice and cynomolgus macaques. Administering αKetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that αKetoA is a novel postbiotic derived from α-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.

Diet, lipids, and antitumor immunity

Tumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.

Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα

Intestinal surface changes in size and function, but what propels these alterations and what are their metabolic consequences is unknown. Here we report that the food amount is a positive determinant of the gut surface area contributing to an increased absorptive function, reversible by reducing daily food. While several upregulated intestinal energetic pathways are dispensable, the intestinal PPARα is instead necessary for the genetic and environment overeating–induced increase of the gut absorptive capacity. In presence of dietary lipids, intestinal PPARα knock-out or its pharmacological antagonism suppress intestinal crypt expansion and shorten villi in mice and in human intestinal biopsies, diminishing the postprandial triglyceride transport and nutrient uptake. Intestinal PPARα ablation limits systemic lipid absorption and restricts lipid droplet expansion and PLIN2 levels, critical for droplet formation. This improves the lipid metabolism, and reduces body adiposity and liver steatosis, suggesting an alternative target for treating obesity.

Aberrant Gut-To-Brain Signaling in Irritable Bowel Syndrome - The Role of Bile Acids

Functional bowel disorders such as irritable bowel syndrome (IBS) are common, multifactorial and have a major impact on the quality of life of individuals diagnosed with the condition. Heterogeneity in symptom manifestation, which includes changes in bowel habit and visceral pain sensitivity, are an indication of the complexity of the underlying pathophysiology. It is accepted that dysfunctional gut-brain communication, which incorporates efferent and afferent branches of the peripheral nervous system, circulating endocrine hormones and local paracrine and neurocrine factors, such as host and microbially-derived signaling molecules, underpins symptom manifestation. This review will focus on the potential role of hepatic bile acids in modulating gut-to-brain signaling in IBS patients. Bile acids are amphipathic molecules synthesized in the liver, which facilitate digestion and absorption of dietary lipids. They are also important bioactive signaling molecules however, binding to bile acid receptors which are expressed on many different cell types. Bile acids have potent anti-microbial actions and thereby shape intestinal bacterial profiles. In turn, bacteria with bile salt hydrolase activity initiate the critical first step in transforming primary bile acids into secondary bile acids. Individuals with IBS are reported to have altered microbial profiles and modified bile acid pools. We have assessed the evidence to support a role for bile acids in the pathophysiology underlying the manifestation of IBS symptoms.

Linseed Silesia, Diverse Crops for Diverse Diets. New Solutions to Increase Dietary Lipids in Crop Species

The aim of the work was to compare the new variety of oil flax (Silesia) with already cultivated varieties in terms of plant productivity, oil content, fatty acid composition and significant secondary metabolites. The analyzed linseed varieties are characterized by low (Linola), medium (Silesia) and high (Szafir) content of omega-3 fatty acids. Special attention was paid to the quality of the oil and the characteristics that determine its stability (reduction of susceptibility to oxidation). A number of antioxidant compounds of secondary metabolism (simple phenols, phenolic acids, flavonoids, tannins) were identified in the linseed oils. All of these compounds can affect lipid oxidation by a mechanism that attenuates initiating radicals such as hydroxyl or forms an oxidizing primary product such as peroxides. Chelation of metal ions may also be involved in lipid oxidation. We propose a mechanism that encompasses all these processes and facilitates understanding of the complex relationships between them. The general thesis is that the ratio of polyunsaturated fatty acids is associated with a better metabolic state of flaxseed, and thus with a higher nutritional value. In addition, we find a number of specialized secondary metabolites characteristic of the flax studied, which could be useful for chemotaxonomy.

Molecular Immune-Inflammatory Connections between Dietary Fats and Atherosclerotic Cardiovascular Disease: Which Translation into Clinics?

Current guidelines recommend reducing the daily intake of dietary fats for the prevention of ischemic cardiovascular diseases (CVDs). Avoiding saturated fats while increasing the intake of mono- or polyunsaturated fatty acids has been for long time the cornerstone of dietary approaches in cardiovascular prevention, mainly due to the metabolic effects of these molecules. However, recently, this approach has been critically revised. The experimental evidence, in fact, supports the concept that the pro- or anti-inflammatory potential of different dietary fats contributes to atherogenic or anti-atherogenic cellular and molecular processes beyond (or in addition to) their metabolic effects. All these aspects are hardly translatable into clinics when trying to find connections between the pro-/anti-inflammatory potential of dietary lipids and their effects on CVD outcomes. Interventional trials, although providing stronger potential for causal inference, are typically small sample-sized, and they have short follow-up, noncompliance, and high attrition rates. Besides, observational studies are confounded by a number of variables and the quantification of dietary intakes is far from optimal. A better understanding of the anatomic and physiological barriers for the absorption and the players involved in the metabolism of dietary lipids (e.g., gut microbiota) might be an alternative strategy in the attempt to provide a first step towards a personalized dietary approach in CVD prevention.