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Microfold (M) cells are located in the epithelium covering mucosa-associated lymphoid tissues, such as the Peyer's patches (PPs) of the small intestine. M cells actively transport luminal antigens to the underlying lymphoid follicles to initiate an immune response. The molecular machinery of M-cell differentiation and function has been vigorously investigated over the last decade. Studies have shed light on the role of M cells in the mucosal immune system and have revealed that antigen uptake by M cells contributes to not only mucosal but also systemic immune responses. However, M-cell studies usually focus on infectious diseases; the contribution of M cells to autoimmune diseases has remained largely unexplored. Accumulating evidence suggests that dysbiosis of the intestinal microbiota is implicated in multiple systemic diseases, including autoimmune diseases. This implies that the uptake of microorganisms by M cells in PPs may play a role in the pathogenesis of autoimmune diseases. We provide an outline of the current understanding of M-cell biology and subsequently discuss the potential contribution of M cells and PPs to the induction of systemic autoimmunity, beyond the mucosal immune response.

Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine. Polyamines produced by intestinal bacteria are thought to have beneficial effects on the host. Here the authors show that these polyamines increase regulatory macrophage abundance and are taken up by colonic epithelial cells to enhance colonic barrier function and immunity in mice.

Currently, lipid/polymer membranes are used in taste sensors to quantify food taste. This research aims to improve sweetness sensors by more selectively detecting uncharged sweetening substances, which have difficulty obtaining a potentiometric response. Lipid/polymer membranes with varying amounts of tetradodecylammonium bromide (TDAB) and 1,2,4-benzene tricarboxylic acid (trimellitic acid) were prepared. The carboxyl groups of trimellitic acid bind metal cations, and the sweetness intensity is estimated by measuring the potential change, as a sensor response, when these cations are complexed with sugars. This research showed that the potential of a sensor using the membrane with enough trimellitic acid in a sucrose solution remained constant, regardless of TDAB amounts, but the potential in the tasteless, so-called reference solution, depended on TDAB. By optimizing the content of TDAB and trimellitic acid, a sensor response of −100 mV was achieved, which is over 20% more sensitive than a previous sensor. This sensor also demonstrated increased selectivity to sweetness, with similar interference from other tastes (saltiness, sourness, umami, and bitterness) compared to previous sensors. As a result, the sensitivity to sweetness was successfully improved. This result contributes to the development of novel sensors, further reducing the burden on humans in quality control and product development.

Far infrared light has been used in many medical procedures. However, the detailed biological mechanisms of infrared light’s effects have not yet been elucidated. Many researchers have pointed out the thermal effects of treatments such as infrared saunas, which are known to increase blood flow. Alzheimer’s disease (AD) is associated with gradual decreases in brain blood flow and resulting dementia. In this study, we attempted to clarify the beneficial effects of far infrared light using the 5xFAD mouse, a transgenic model of AD. We exposed 5xFAD mice to far infrared light for 5 months. Among the far infrared-exposed AD mice, body weights were significantly decreased, and the levels of nerve growth factor and brain-derived neurotrophic factor protein were significantly increased in selected brain areas (compared to those in non-irradiated AD mice). However, cognition and motor function (as assessed by Morris water maze and Rota Rod tests, respectively) did not differ significantly between the irradiated and non-irradiated AD mouse groups. These results indicated that exposure to far infrared light may have beneficial biological effects in AD mice. However, the experimental schedule and methods may need to be modified to obtain clearer results.

The follicle-associated epithelium (FAE) covering mucosa-associated lymphoid tissue is distinct from the villous epithelium in cellular composition and functions. Interleukin-22 binding protein (IL-22BP), provided by dendritic cells at the sub-epithelial dome region, inhibits the IL-22-mediated secretion of antimicrobial peptides by the FAE. The Notch signal from stromal cells underneath the FAE diminishes goblet cell differentiation. These events dampen the mucosal barrier functions to allow luminal microorganisms to readily gain access to the luminal surface of the FAE. Furthermore, receptor activator of nucleic factor-kappa B ligand (RANKL) from a certain stromal cell type induces differentiation into microfold (M) cells that specialize in antigen uptake in the mucosa. Microfold (M) cells play a key role in mucosal immune surveillance by actively transporting external antigens from the gut lumen to the lymphoid follicle. The molecular basis of antigen uptake by M cells has been gradually identified in the last decade. For example, GPI-anchored molecules (e.g., glycoprotein 2 (GP2) and cellular prion protein (PrP )) and β1-integrin facilitate the transport of specific types of xenobiotics. The antigen transport by M cells initiates antigen-specific mucosal immune responses represented by the induction of secretory immunoglobulin A (S-IgA). Meanwhile, several invasive pathogens exploit M cells as a portal to establish a systemic infection. Recent findings have uncovered the molecular machinery of differentiation and functions of M cells.

Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface. Microfold cells (M cells) sit at the gut epithelial surface to sample antigens and maintain local immune homeostasis. Here the authors show that M cells are feedback-regulated by M cell-originated osteoprotegerin (OPG) to suppress RNAKL-induced M cell differentiation, and that OPG deficiency alters both gut colitis and infection phenotypes.

Residual ridge resorption (RRR) is a chronic and progressive bone resorption following tooth loss. It causes deterioration of the oral environments and leads to the pathogenesis of various systemic diseases. However, the molecular mechanisms and risk factors for RRR progression are still unclear and controversial. In this study, we developed a tooth extraction model using mice for analyzing long-term morphological and gene expression changes in the alveolar bone. We further applied ovariectomy to this model to elucidate the effects of osteoporosis on RRR progression. As a result, the alveolar bone loss was biphasic and consisted of rapid loss in the early stages and subsequently slow and sustained bone loss over a long period. Histological analysis indicated that ovariectomy prolonged the activation of osteoclasts in the alveolar bone. Furthermore, the expressions of Tnfsf11 and Sema4d kept increasing for a long time in OVX mice. Administration of neutralization antibodies for receptor activator of NF-κB ligand (RANKL) effectively suppressed RRR. Similarly, inhibition of Semaphorin 4D (Sema4D) also improved alveolar bone loss. This study demonstrated that reduced ovarian function may be a risk factor for RRR and that RANKL and Sema4D suppression are potential treatments.

Expression of taste 2 receptor (T2R) genes, also known as bitter taste receptor genes, has been reported in a variety of tissues. The white adipose tissue of mice has been shown to express Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, but the function of T2Rs in adipocytes remains unclear. Here, we show that fasting and stimulation by bitter compounds both increased Tas2r expression in mouse white adipose tissue, and serum starvation and stimulation by bitter compounds both increased the expression of Tas2r genes in 3T3-L1 adipocytes, suggesting that T2Rs have functional roles in adipocytes. RNA sequencing analysis of 3T3-L1 adipocytes stimulated by epicatechin, the ligand of Tas2r126, suggested that this receptor may play a role in the differentiation of adipocytes. Overexpression of Tas2r126 in 3T3-L1 preadipocytes decreases fat accumulation after induction of differentiation and reduces the expression of adipogenic genes. Together, these results indicate that Tas2r126 may be involved in adipocyte differentiation.

The saltiness enhancement effect can be produced by adding specific substances to dietary salt (sodium chloride). This effect has been used in salt-reduced food to help people forge healthy eating habits. Therefore, it is necessary to objectively evaluate the saltiness of food based on this effect. In a previous study, sensor electrodes based on lipid/polymer membrane with Na+ ionophore have been proposed to quantify the saltiness enhanced by branched-chain amino acids (BCAAs), citric acid, and tartaric acid. In this study, we developed a new saltiness sensor with the lipid/polymer membrane to quantify the saltiness enhancement effect of quinine by replacing a lipid that caused an unexpected initial drop in the previous study with another new lipid. As a result, the concentrations of lipid and ionophore were optimized to produce an expected response. Logarithmic responses have been found on both NaCl samples and quinine-added NaCl samples. The findings indicate the usage of lipid/polymer membranes on novel taste sensors to evaluate the saltiness enhancement effect accurately.

Currently, taste sensors utilizing lipid polymer membranes are utilized to assess the taste of food products quantitatively. During this process, it is crucial to identify and quantify basic tastes, e.g., sourness and sweetness, while ensuring that there is no response to tasteless substances. For instance, suppression of responses to anions, like tasteless NO3− ions contained in vegetables, is essential. However, systematic electrochemical investigations have not been made to achieve this goal. In this study, we fabricated three positively charged lipid polymer membranes containing oleylamine (OAm), trioctylemethylammonium chloride (TOMACl), or tetradodecylammonium bromide (TDAB) as lipids, and sensors that consist of these membranes to investigate the potential change characteristics of these sensors in solutions containing different anions (F−, Cl−, Br−, NO3−, I−). The ability of each anion solution to reduce the positive charge on membranes and shift the membrane potential in the negative direction was in the following order: I− > NO3− > Br− > Cl− > F−. This order well reflected the order of size of the hydrated ions, related to their hydration energy. Additionally, the OAm sensor displayed low ion selectivity, whereas the TOMACl and TDAB sensors showed high ion selectivity related to the OAm sensor. Such features in ion selectivity are suggested to be due to the variation in positive charge with the pH of the environment and packing density of the OAm molecule in the case of the OAm sensor and due to the strong and constant positive charge created by complete ionization of lipids in the case of TOMACl and TDAB sensors. Furthermore, it was revealed that the ion selectivity varies by changing the lipid concentration in each membrane. These results contribute to developing sensor membranes that respond to different anion species selectively and creating taste sensors capable of suppressing responses to tasteless anions.