Emerging findings indicate there is a vital cross-talk between gut microbiota and the lungs, which is known as gut-lung axis. The gut disturbances in lung diseases including allergy, asthma, chronic obstructive pulmonary disease, cystic fibrosis and lung cancer were observed by extensive studies. Investigating how gut microbiota impact other distant organs is of great interest in recent years. Although it has not been fully understood whether the disturbance is the cause or effect of lung diseases, alterations in the gut microbial species and metabolites have been linked to changes in immune responses and inflammation as well as the disease development in the lungs. In this article, we systemically review the role and mechanisms underlying the changes in the constituent of gut microbiota and metabolites in lung diseases. In particular, the roles of gut-lung axis in mediating immune responses and reshaping inflammation are highlighted. Furthermore, we discuss the potential of strategies to manipulate the gut microbiota and metabolites as the therapeutic approach for lung diseases.

Interstitial cells of Cajal (ICC) generate the electrical slow wave required for normal gastrointestinal motility. The ionic conductances expressed in human intestinal ICC are unknown. The aim of this study was to determine expression of a Na+ current in human intestinal ICC and to determine the effects of the Na+ current on the slow wave. Visually identified, freshly dissociated, single ICC were verified by the presence of c-kit mRNA by using single-cell RT-PCR. Standard whole cell currents were recorded from patch-clamped ICC held at -100 mV between pulse protocols. A Na+ current was identified in human intestinal ICC. The current activated at -55 mV and peaked at -30 mV. Extracellular N-methyl-d-glucamine abolished and QX-314 (500 microM) blocked the Na+ current, but nifedipine and Ni2+ did not. The Na+ current was activated by shear stress. Single-cell RT-PCR detected mRNA for the Na+ alpha-subunit SCN5A in single human intestinal ICC. Lidocaine (200 microm) and QX-314 (500 microM) decreased slow wave frequency, and stretch increased slow wave frequency. A mechanosensitive Na+ channel current is present in human intestinal ICC and appears to play a role in the control of intestinal motor function.

The gaseous molecule hydrogen sulfide (H 2 S) has been proposed as an endogenous signal molecule and neuromodulator in mammals. Using a newly developed method, we report here for the first time the ability of intact and living brain and colonic tissue in the mouse to generate and release H 2 S. This production occurs through the activity of two enzymes, cystathionine-c-lyase and cystathionine-b-synthase. The quantitative expression of messenger RNA and protein localization for both enzymes are described in the liver, brain, and colon. Expression levels of the enzymes vary between tissues and are differentially distributed. The observation that, tissues that respond to exogenously applied H 2 S can endogenously generate the gas, strongly supports its role as an endogenous signal molecule.

Group 1 CD1 (CD1a, CD1b, and CD1c)–restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)–infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human group 1 CD1 transgenic (hCD1Tg) mice that express all three human group 1 CD1 isoforms and support the development of group 1 CD1–restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit group 1 CD1–restricted Mtb lipid–specific T cell responses in hCD1Tg mice. In contrast to CD1d-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon reexposure, group 1 CD1–restricted T cells exhibit delayed primary responses and more rapid secondary responses, similar to conventional T cells. Collectively, our data demonstrate that group 1 CD1–restricted T cells participate in adaptive immune responses upon mycobacterial infection and could serve as targets for the development of novel Mtb vaccines.

Polyamines are tightly regulated polycations that are essential for life. Loss-of-function mutations in spermine synthase (SMS), a polyamine biosynthesis enzyme, cause Snyder-Robinson syndrome (SRS), an X-linked intellectual disability syndrome; however, little is known about the neuropathogenesis of the disease. Here we show that loss of dSms in Drosophila recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. SMS deficiency leads to excessive spermidine catabolism, which generates toxic metabolites that cause lysosomal defects and oxidative stress. Consequently, autophagy–lysosome flux and mitochondrial function are compromised in the Drosophila nervous system and SRS patient cells. Importantly, oxidative stress caused by loss of SMS is suppressed by genetically or pharmacologically enhanced antioxidant activity. Our findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyamine metabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders.

Carbon monoxide (CO) is proposed as a physiological messenger. CO activates cGMP and has a direct effect on potassium channels. Both actions of CO lead to hyperpolarization of a cell's resting membrane potential, suggesting that CO may function as a hyperpolarizing factor, although direct evidence is still lacking. Here we take advantage of the known membrane potential gradient that exists in the muscle layers of the gastrointestinal tract to determine whether CO is an endogenous hyperpolarizing factor. We find that heme oxygenase-2-null mice have depolarized smooth muscle cells and that the membrane potential gradient in the gut is abolished. Exogenous CO hyperpolarizes the membrane potential. Regions of the canine gastrointestinal tract that are more hyperpolarized generate more CO and have higher heme oxygenase activity than more depolarized regions. Our results suggest that CO is a critical hyperpolarizing factor required for the maintenance of intestinal smooth muscle membrane potential and gradient.A role for carbon monoxide (CO) is proposed in cell signaling and neurotransmission (1, 2), hormone release (3, 4), as a cytoprotective agent (5), and in regulation of vascular tone (6, 7). The major source of CO is from the breakdown of heme by heme oxygenase (HO); the absence of HO-2, the constitutive HO isoform, significantly impairs the production of CO in gut and other tissues (8). HO-2 is widely expressed in tissues containing smooth muscle, including blood vessels (6), the pulmonary system (9), and the gastrointestinal tract (10), suggesting that CO is continually produced in these tissues. Multiple mechanisms of action for CO have been proposed, including activation of guanylyl cyclase and direct activation of K ϩ channels (11). Both mechanisms can result in membrane hyperpolarization, raising the possibility that CO can act as an endogenous hyperpolarizing factor. To determine whether CO is an endogenous hyperpolarizing factor, we took advantage of the known membrane potential gradients that exist in the muscle layers of the gastrointestinal tract. We chose the gastrointestinal tract as our model because our previous studies in the HO-2-null mouse demonstrate that intestinal smooth muscle is depolarized in the HO-2-null mouse (2), and because of the presence of a measurable smooth muscle membrane potential gradient that has not been reported in vascular smooth muscle. We hypothesized that if CO acts as a physiologically relevant hyperpolarizing factor, then CO production should mirror the membrane potential gradient along the long axis of the stomach as well as across the gut wall and that these resting membrane potential gradients would be diminished or abolished in HO-2-null mice. In the gastrointestinal tract of all species studied, there is a large gradient (Ϸ30 mV) in membrane potential along the long axis of the stomach from the fundus (proximal stomach) to the pylorus (distal stomach) (12). There is also a membrane potential gradient across the thickness of circular muscle layer (12, 13). In the ...

Type 2 diabetes mellitus (T2DM) is closely correlated with chronic low-grade inflammation and gut dysbiosis.

Background: Type 2 diabetes mellitus (T2DM) is closely associated with hyperglycemia, abnormal lipid profiles, chronic low-grade inflammation and gut dysbiosis. Dietary intervention plays a crucial role in the control of diabetes. Flaxseed oil (FO), a plant-derived omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), is rich in α-linolenic acid (ALA) which has been proved to benefit for chronic metabolic disease. However, the exact effects of dietary FO on T2DM remains largely unclear.Methods: In the present study, SD rats were randomly allocated into four groups: pair-fed (PF) with corn oil (CO) group (PF/CO); DM with CO group (DM/CO); PF with FO group (PF/FO); DM with FO group (DM/FO). A diabetic rat model was generated by a single intraperitoneal injection of streptozotocin-nicotinamide (STZ-NA). After 5 weeks of intervention, rats were euthanized and associated indications were investigated.Results: Dietary FO significantly reduced fasting blood glucose (FBG), glycated hemoglobin (GHb), blood lipid, plasma lipopolysaccharide (LPS), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-17A and malondialdehyde (MDA), compared to control group, respectively. Moreover, body mass (BM) and superoxide dismutase (SOD) in DM/FO group were dramatically increased respectively, compared with those in DM/CO group. But insulin (INS) and homeostasis model assessment of insulin resistance (HOMA-IR) remained no significant difference between DM/CO group and DM/FO group. Sequencing analysis of gut microbiota showed a reduction in the relative abundance of Firmicutes and Blautia, as well as a reduction in the ratio of Bacteroidetes-Firmicutes in DM/FO group compared to DM/CO group. An elevation in the relative abundance of Bacteroidetes and Alistipes were detected in DM/FO group. Acetic acid, propionic acid and butyric acid belonging to short chain fatty acids (SCFAs) as gut microbiota metabolites, were dramatically increased after FO intervention. Correlation analysis revealed that the relative abundance of Firmicutes and Blautia were positively correlated with IL-1β, TNF-α, IL-6, IL-17A or LPS, respectively. Additionally, Bacteroidetes and Alistipes were negatively correlated with LPS.Conclusions: Taken together, dietary FO ameliorated T2DM via suppressing inflammation and modulating gut microbiota, which may potentially contribute to dietary control of diabetes.