Gut microbiota bridges dietary nutrients and host immunity.

Dietary nutrients and the gut microbiota are increasingly recognized to cross-regulate and entrain each other, and thus affect host health and immune-mediated diseases. Here, we systematically review the current understanding linking dietary nutrients to gut microbiota-host immune interactions, emphasizing how this axis might influence host immunity in health and diseases. Of relevance, we highlight that the implications of gut microbiota-targeted dietary intervention could be harnessed in orchestrating a spectrum of immune-associated diseases.

Phenylalanine diminishes M1 macrophage inflammation.

Emerging evidence suggests that amino acids dictate the effector functions of immune cells; however, whether and how phenylalanine (Phe) orchestrates the polarization of macrophages is not understood. Here, we determined that Phe attenuated lipopolysaccharide (LPS) and P. multocida serotype A strain CQ2 (PmCQ2) infection-induced inflammation in vivo. Furthermore, we demonstrated that Phe inhibited the production of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α in proinflammatory (M1) macrophages. Phe reprogrammed the transcriptomic and metabolic profiles and enhanced oxidative phosphorylation in M1 macrophages, which reduced the activation of caspase-1. Notably, the valine-succinyl-CoA axis played a critical role in Phe-mediated inhibition of IL-1ß production in M1 macrophages. Taken together, our findings suggest that manipulating the valine-succinyl-CoA axis provides a potential target for preventing and/or treating macrophage-related diseases.

Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1ß-dependent inflammation.

BACKGROUND: Immunotransmitters (e.g., neurotransmitters and neuromodulators) could orchestrate diverse immune responses; however, the elaborated mechanism by which melatonergic activation governs inflammation remains less defined. METHODS: Primary macrophages, various cell lines, and Pasteurella multocida (PmCQ2)-infected mice were respectively used to illustrate the influence of melatonergic signalling on inflammation in vitro and in vivo. A series of methods (e.g., RNA-seq, metabolomics, and genetic manipulation) were conducted to reveal the mechanism whereby melatonergic signalling reduces macrophage inflammation. RESULTS: Here, we demonstrate that melatonergic activation substantially lessens interleukin (IL)-1ß-dependent inflammation. Treatment of macrophages with melatonin rewires metabolic program, as well as remodels signalling pathways which depends on interferon regulatory factor (IRF) 7. Mechanistically, melatonin acts via membrane receptor (MT) 1 to increase heat shock factor (Hsf) 1 expression through lowering the inactive glycogen synthase kinase (GSK3) ß, thereby transcriptionally inhibiting interferon (IFN)-γ receptor (IFNGR) 2 and ultimately causing defective canonical signalling events [Janus kinase (JAK) 1/2-signal transducer and activator of transcription (STAT) 1-IRF7] and lower IL-1ß production in macrophages. Moreover, we find that melatonin amplifies host protective responses to PmCQ2 infection-induced pneumonia. CONCLUSIONS: Our conceptual framework provides potential therapeutic targets to prevent and/or treat inflammatory diseases associating with excessive IL-1ß production.

Transcriptomic Analysis Reveals a Sex-Dimorphic Influence of GAT-2 on Murine Liver Function.

Accumulating evidence shows that the γ-amino butyric acid (GABA)ergic system affects the functions of different organs, and liver is one of the most sex-dimorphic organs in animals. However, whether and how the GABAergic system influences liver function in a sex-specific manner at the intrinsic molecular level remains elusive. In this study, firstly, we find that the levels of GABA are significantly increased in the livers of female mice with GABA transporter (GAT)-2 deficiency (KO) whereas it only slightly increased in male GAT-2 KO mice. Apart from the amino acid profiles, the expressions of toll-like receptors (TLRs) also differ in the livers of female and male KO mice. Moreover, RNA-seq results show 2,227 differentially expressed genes (DEGs) in which 1,030 are upregulated whereas 1,197 that are downregulated in the livers of female KO mice. Notably, oxidative phosphorylation, non-alcoholic fatty liver disease, Huntington's disease, and peroxisome proliferator-activated receptor (PPAR) signaling pathways are highly enriched by GAT-2 deficiency, indicating that these pathways probably meditate the effects of GAT-2 on female liver functions, on the other hand, only 1,233 DEGs, including 474 are upregulated and 759 are downregulated in the livers of male KO mice. Interestingly, retinol metabolism, PPAR signaling pathway, and tuberculosis pathways are substantially enriched by GAT-2 deficiency, suggesting that these pathways may be responsible for the effects of GAT-2 on male liver functions. Collectively, our results reveal the sex-dimorphic effects of GAT-2 in guiding liver functions, and we propose that targeting the GABAergic system (e.g., GATs) in a sex-specific manner could provide previously unidentified therapeutic opportunities for liver diseases.

Bacteriostatic Potential of Melatonin: Therapeutic Standing and Mechanistic Insights.

Diseases caused by pathogenic bacteria in animals (e.g., bacterial pneumonia, meningitis and sepsis) and plants (e.g., bacterial wilt, angular spot and canker) lead to high prevalence and mortality, and decomposition of plant leaves, respectively. Melatonin, an endogenous molecule, is highly pleiotropic, and accumulating evidence supports the notion that melatonin's actions in bacterial infection deserve particular attention. Here, we summarize the antibacterial effects of melatonin in vitro, in animals as well as plants, and discuss the potential mechanisms. Melatonin exerts antibacterial activities not only on classic gram-negative and -positive bacteria, but also on members of other bacterial groups, such as Mycobacterium tuberculosis. Protective actions against bacterial infections can occur at different levels. Direct actions of melatonin may occur only at very high concentrations, which is at the borderline of practical applicability. However, various indirect functions comprise activation of hosts' defense mechanisms or, in sepsis, attenuation of bacterially induced inflammation. In plants, its antibacterial functions involve the mitogen-activated protein kinase (MAPK) pathway; in animals, protection by melatonin against bacterially induced damage is associated with inhibition or activation of various signaling pathways, including key regulators such as NF-κB, STAT-1, Nrf2, NLRP3 inflammasome, MAPK and TLR-2/4. Moreover, melatonin can reduce formation of reactive oxygen and nitrogen species (ROS, RNS), promote detoxification and protect mitochondrial damage. Altogether, we propose that melatonin could be an effective approach against various pathogenic bacterial infections.

Ironing Out the Details: How Iron Orchestrates Macrophage Polarization.

Iron fine-tunes innate immune responses, including macrophage inflammation. In this review, we summarize the current understanding about the iron in dictating macrophage polarization. Mechanistically, iron orchestrates macrophage polarization through several aspects, including cellular signaling, cellular metabolism, and epigenetic regulation. Therefore, iron modulates the development and progression of multiple macrophage-associated diseases, such as cancer, atherosclerosis, and liver diseases. Collectively, this review highlights the crucial role of iron for macrophage polarization, and indicates the potential application of iron supplementation as an adjuvant therapy in different inflammatory disorders relative to the balance of macrophage polarization.

[Distribution and Potential Risk of Organochlorine Pesticides in the Soil of a Submerged Area Around Miyun Reservoir].

Soil samples collected from a submerged area around Miyun Reservoir were analyzed for organochlorine pesticide (OCP) residues using GC-MS. The distribution characteristics and possible sources of OCPs were studied, as well as the potential ecological risk. The results showed the following:① the residuals of OCPs in the surface soil were mainly hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs), and the average contents of HCHs and DDTs were 1.74 ng·g-1 and 1.01 ng·g-1, respectively. In comparison with other lakes and reservoirs in China, the mean value of DDT content of the soil samples from Miyun Reservoir was slightly less, whereas the mean value of HCH content was similar to other waterbodies. ② There was a distinct spatial distribution of OCPs in soils of the submerged area. Specifically, the OCP content in the water-land interlaced soil was generally higher, with distinct differences to the water or in land. In the eastern region of the reservoir and in the Chaohe River inflow area, the residues of OCPs were mainly DDTs, as was the case for the submerged soils of small isolated watersheds. The OCPs in the submerged area of the northern reservoir and the western central reservoir were mainly γ-HCH residues, while HCH and DDT residues were found in high proportions in the flooded area where the Baihe River inflows. These patterns were related to sources of pollutants; ③ the source analysis showed that sources of HCHs could be related to lindane input, while DDTs mainly derived from the early residues in the environment; ④ there was low ecological risk from OCPs in most of the samples, and a potential risk from DDT in the Baihe inflow area and in the central submerged zone of the western reservoir.