Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation. Here, the authors describe how metabolic disorders, such as type 2 diabetes and nonalcoholic fatty liver disease, are driven by alterations in the composition of the intestinal microbiota and its metabolites, which translocate from the gut across a disrupted intestinal barrier and contribute to metabolic inflammation.

The intestinal microbiota fuelling metabolic inflammation

The mechanistic target of rapamycin (mTOR) kinase controls growth and metabolism, and its deregulation underlies the pathogenesis of many diseases, including cancer, neurodegeneration, and diabetes. mTOR complex 1 (mTORC1) integrates signals arising from nutrients, energy, and growth factors, but how exactly these signals are propagated await to be fully understood. Recent findings have placed the lysosome, a key mediator of cellular catabolism, at the core of mTORC1 regulation by amino acids. A multiprotein complex that includes the Rag GTPases, Ragulator, and the v-ATPase forms an amino acid-sensing machinery on the lysosomal surface that affects the decision between cell growth and catabolism at multiple levels. The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies.

Amino acids and mTORC1: from lysosomes to disease

Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.

Cancer stem cell-immune cell crosstalk in tumour progression.

Background Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance. Scope of review In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification. Major conclusions A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.

Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.

Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR.

In recent years, chronic overnutrition, such as consumption of a high-fat diet (HFD), has been increasingly viewed as a significant modifiable risk factor for diseases such as diabetes and certain types of cancer. However, the mechanisms by which HFDs exert adverse effects on human health remains poorly understood. Here, this paper will review the recent scientific literature about HFD-induced inflammation and subsequent development of diseases and cancer, with an emphasis on mechanisms involved. Given the expanding global epidemic of excessive HFD intake, understanding the impacts of a HFD on these medical conditions, gaining great insights into possible underlying mechanisms, and developing effective therapeutic strategies are of great importance.

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Inflammatory Links Between High Fat Diets and Diseases.

Obesity increases the risk of developing insulin resistance and diabetes and is a major public health concern. Our previous study shows that dietary β-hydroxy-β-methylbutyrate (HMB) improves lipid metabolism in a pig model. However, it remains unclear whether HMB blocks obesity through gut microbiota. In this study, we found that HMB reduced body weight, alleviated the whitening of brown adipose tissue, and improved insulin resistance in mice fed a high-fat diet (HFD). High-throughput pyrosequencing of the 16S rRNA demonstrated that HMB administration significantly reversed the gut microbiota dysbiosis in HFD-fed mice, including the diversity of gut microbiota and relative abundances of Bacteroidetes and Firmicutes. Moreover, microbiota transplantation from HMB-treated mice attenuated HFD-induced lipid metabolic disorders. Furthermore, HFD-fed mice showed lower short-chain fatty acids, whereas administration of HMB increased the propionic acid production. Correlation analysis identified a significant correlation between propionic acid production and the relative Bacteroidetes abundance. Sodium propionate treatment also attenuated HFD-induced lipid metabolic disorders. Collectively, our results indicated that HMB might be used as a probiotic agent to reverse HFD-induced obesity, and the potential mechanism was associated with reprogramming gut microbiota and metabolism, especially Bacteroidetes-mediated propionic acid production. In future studies, more efforts should be made to confirm and expand the beneficial effects of HMB to human models.-Duan, Y., Zhong, Y., Xiao, H., Zheng, C., Song, B., Wang, W., Guo, Q., Li, Y., Han, H., Gao, J., Xu, K., Li, T., Yin, Y., Li, F., Yin, J., Kong, X. Gut microbiota mediates the protective effects of dietary β-hydroxy-β-methylbutyrate (HMB) against obesity induced by high-fat diets.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201900665RR

Gut microbiota mediates the protective effects of dietary β-hydroxy-β-methylbutyrate (HMB) against obesity induced by high-fat diets.

AIMS The aims were to examine whether oral sodium propionate supplementation regulate lipid metabolism through modulating gut microbiota. METHODS AND RESULTS ICR male mice (26·98 ± 0·30 g) were randomly assigned to three groups (n = 10) and fed control diet (Con), high-fat diet (HFD) and HFD plus propionate (Pro) respectively. In this study, we found that HFD increased the weight of final body, inguinal white adipose tissues (iWAT), epididymal white adipose tissue (eWAT) and perirenal white adipose tissue (pWAT), as well as the adipocyte mean area of iWAT and eWAT in mice (P < 0·05), whereas sodium propionate treatment reduced the weight of iWAT and pWAT as well as adipocyte mean area of iWAT in mice fed a HFD (P < 0·05). Moreover, in the iWAT, the mRNA expression of lipogenesis genes, including peroxisome proliferator activated receptor γ, acetyl-CoA carboxylase and carnitine palmitoyl transferase-1β, was upregulated by HFD challenge (P < 0·05), and the elevation of these genes was nearly reversed to the level of control diet-fed mice by sodium propionate treatment. Meanwhile, sodium propionate treatment increased the hormone-sensitive lipase mRNA expression in the iWAT of HFD-fed mice (P < 0·05). High-throughput pyrosequencing of the 16S rRNA demonstrated that sodium propionate treatment significantly recovered the gut microbiota dysbiosis in HFD-fed mice, including the richness and diversity of microbiota and the ratio of Firmicutes to Bacteroidetes. Furthermore, the HFD-induced reductions in colonic levels of butyrate and valerate were reversed by sodium propionate treatment, which also normalized the serum LPS level seen in HFD-fed mice to the levels of the control diet-fed mice. CONCLUSIONS Collectively, these results indicated that sodium propionate treatment could improve lipid metabolism in HFD-fed mice, and the potential mechanisms might be via regulating gut microbiota. SIGNIFICANCE AND IMPACT OF THE STUDY We demonstrated for the first time that oral sodium propionate significantly improved HFD-induced dysbiosis of gut microbiota, indicating that the mitigative effect of propionate for HFD-induced lipid dysmetabolism might be mediated by gut microbiota in mice.

Propionate alleviates high-fat diet-induced lipid dysmetabolism by modulating gut microbiota in mice.

Aims Leucine supplementation promotes intestinal health, but the mechanism is largely unknown. This study aimed to elucidate the mechanisms underlying the beneficial effects of leucine on intestinal homeostasis. Methods and results Female ICR mice (6-week-old) were randomly assigned into three groups: (i) mice received a basal diet; (ii) mice received a dietary 0·5% crystalline l-leucine supplementation; and (iii) mice received a dietary 1·0% crystalline l-leucine supplementation. Our results showed that leucine supplementation stimulated the secretion of SIgA in mice ileum and expression of cytokines related to SIgA production. Moreover, leucine supplementation improved the expression of mTOR and p70S6K1 expression. Further study showed that leucine supplementation markedly decreased microbiota richness and induced a shift in the Firmicutes : Bacteroidetes ratio in favour of Firmicutes. Conclusions Therefore, our data suggested that leucine supplementation could enhance intestinal health through the regulation of mTOR pathway and promoting SIgA secretion in the mouse intestine, which might be associated with intestinal microbiota. Significance and impact of the study The present study found that dietary leucine supplementation of mice could improve intestinal health by enhancing intestinal SIgA secretion via a nonexclusive mechanism, which might include T cell-dependent pathway, T cell-independent pathway and gut microbiota.

Bo Song

Papers

Inflammatory Links Between High Fat Diets and Diseases.

Gut microbiota mediates the protective effects of dietary β-hydroxy-β-methylbutyrate (HMB) against obesity induced by high-fat diets.

Propionate alleviates high-fat diet-induced lipid dysmetabolism by modulating gut microbiota in mice.

Dietary leucine supplementation improves intestinal health of mice through intestinal SIgA secretion

Dietary supplementation with betaine or glycine improves the carcass trait, meat quality and lipid metabolism of finishing mini-pigs