Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease ...(IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.
Fructooligosaccharide (FOS), a prebiotic well known for its health-promoting properties, can improve the human gut ecosystem most likely through changes in its microbial composition. However, the ...detailed mechanism(s) of action of FOS in the modulation of the gut ecosystem remain(s) obscure. Traditional methods of profiling microbes and metabolites could barely show any significant features due to the existence of large interindividual differences, but our novel microbe-metabolite correlation approach, combined with faecal immunoglobulin A (IgA) measurements, has revealed that the induction of mucosal IgA by FOS supplementation correlated with the presence of specific bacteria. Furthermore, the metabolic dynamics of butyrate, L-phenylalanine, L-lysine and tyramine were positively correlated with that of these bacteria and IgA production, whereas p-cresol was negatively correlated. Taken together, our focused intraindividual analysis with omics approaches is a powerful strategy for uncovering the gut molecular network and could provide a new vista for understanding the human gut ecosystem.
Bacterial access to the gut immune system is a crucial process to promote host immune responses. The probiotic L-92 strain of Lactobacillus acidophilus exerts anti-allergic immunomodulatory effects ...upon oral administration in mice. Here, we show that microfold cells (M cells) are responsible for L-92 internalization for evoking L-92-mediated immune responses. L-92 specifically bound to uromodulin, a glycosylphosphatidylinositol-anchored protein expressed exclusively on M cells among intestinal epithelial cells. Internalization of L-92 into M cells was significantly reduced in uromodulin-deficient (Umod-/-) mice compared to Umod+/+ mice. Furthermore, the binding of L-92 to uromodulin was significantly decreased after removal of surface layer protein A (SlpA) from the bacteria. Our study thus revealed a crucial role of uromodulin on the M-cell surface for the uptake of SlpA-positive lactic acid bacteria into M cells, possibly leading to subsequent delivery of the bacteria to dendritic cells closely associated with M cells for immunomodulation. Our study also shed light on the possibility that SlpA and uromodulin could be used as vehicle and target, respectively, for efficient mucosal vaccine delivery.
Tunneling nanotubes (TNTs), the long membrane extensions connecting distant cells, have emerged as a novel form of cell-to-cell communication. However, it is not fully understood how and to what ...extent TNTs contribute to intercellular spread of pathogens including HIV-1. In this study, we show that HIV-1 promotes TNT formation per se via its protein Nef and a cellular protein M-Sec, which appears to mediate approximately half of viral spread among monocyte-derived macrophages (MDMs). A small compound that inhibits M-Sec-induced TNT formation reduced HIV-1 production by almost half in MDMs. Such inhibition was not observed with Nef-deficient mutant HIV-1 that fails to promote TNT formation and replicates less efficiently than the wild-type HIV-1 in MDMs. The TNT inhibitor-sensitive/Nef-promoting viral production was also observed in a T cell line ectopically expressing M-Sec, but not in another M-Sec(-) T cell line. Our results suggest the importance of TNTs in HIV-1 spread among MDMs and might answer the long-standing question how Nef promotes HIV-1 production in a cell type-specific manner.
Abstract
Gain-of-function (GOF) mutations in the gene for signal transducer and activator of transcription 1 (STAT1) account for approximately one-half of patients with chronic mucocutaneous ...candidiasis (CMC) disease. Patients with GOF-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to CMC, and those with severe infections and/or autoimmunity have a poor prognosis. The establishment of safe and effective treatments based on a precise understanding of the molecular mechanisms of this disorder is required to improve patient care. To tackle this problem, we introduced the human R274Q GOF mutation into mice GOF-Stat1 knock-in (GOF-Stat1R274Q). To investigate the immune responses, we focused on the small intestine (SI), which contains abundant Th17 cells. Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1 in CD4+ T cells upon IFN-γ stimulation, consistent with the human phenotype in patients with the R274Q mutation. We identified two subpopulations of CD4+ T cells, those with ‘normal’ or ‘high’ level of basal STAT1 protein in Stat1R274Q/R274Q mice. Upon IFN-γ stimulation, the ‘normal’ level CD4+ T cells were more efficiently phosphorylated than those from WT mice, whereas the ‘high’ level CD4+ T cells were not, suggesting that the level of STAT1 protein does not directly correlate with the level of pSTAT1 in the SI. Inoculation of Stat1R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4+RORγt+ cells. Stat1R274Q/R274Q mice also excreted larger amounts of C. albicans DNA in their feces than control mice. Under these conditions, there was up-regulation of T-bet in CD4+ T cells. GOF-Stat1R274Q mice thus should be a valuable model for functional analysis of this disorder.
GOF-Stat1R274Q mice are a model for CMC disease
Although gut microbiota and early life events are likely involved in the development of irritable bowel syndrome (IBS), it remains unclear how these factors interact in the pathophysiology of IBS. In ...the present study, using rats subjected to maternal separation (MS) as a model of IBS, we investigated interrelationships among gut microbiota, stress susceptibility and intestinal permeability, and examined the effect of the probiotic Bifidobacterium bifidum G9-1 (BBG9-1) on those interrelationships. When compared with the controls at postnatal day 20, MS rats showed hypercorticosteronemia, enhanced intestinal permeability and changes in gut microbiota structure. All of these changes in MS rats were prevented by treatment with BBG9-1. Although the gut microbiota profile and basal serum corticosterone level did not differ between MS and control rats at postnatal day 56, MS rats showed hypersensitivity to restraint stress in terms of serum corticosterone level and fecal frequency. However, such hypersensitivity was not observed in MS rats treated with BBG9-1. These findings suggest that MS initiates the link between gut microbiota alteration and hypersensitivity to stress and that the triggering of this process can be prevented by the treatment with the probiotic BBG9-1.
Atopic dermatitis (AD) and food allergy (FA) are common childhood diseases, which may either be interrelated or be the result of skin barrier disruption and gut mucosal dysbiosis. Although some ...evidence suggests the efficacy of emollients and synbiotics, there is no conclusive evidence on the use of these interventions alone or in combination.
This study is aimed at identifying the efficacy of emollients and synbiotics in preventing AD and FA in children during the first year of life.
The babies of mothers recruited prenatally received either an emollient, synbiotic, both or neither. The intervention was carried out from birth up to 6 months of age. The age of occurrence of AD and FA were reported in multiple questionnaires at 1, 6, and 9 months and at 1 year of age. AD was diagnosed by a pediatrician at 9 months of age.
A -total of 459 babies qualified for the outcome assessment at 1 year of age. Neither the emollient nor the synbiotic showed any effect on reducing the development of AD and FA at 1 year of age.
This study did not provide any evidence to show that emollients and synbiotics, alone or in combination are sufficient to prevent the occurrence of AD or FA in children up to 1 year of age.
Gut microbiota is involved in the induction and functional maturation of various immune cells. However, there are only a few immune mechanisms that directly regulate gut bacteria. Immunoglobulin A ...(IgA) is a major immune mechanism which is important for the regulation of microbiota. It has been known for a long time that gut microbiota is critically involved in the induction of IgA. Recently, with the development of next-generation sequencing technologies, it has gradually been revealed that IgA also plays an important role in the regulation of the composition and function of gut bacteria. In this review, we introduce recent findings on the factors involved in the interaction between IgA and microbiota.
Gastrodin (Gas) is known to exhibit neuroprotective effects in Alzheimer’s disease (AD). However, the detailed mechanism of action is still unclear. In the present study, we focused on the ...microbiome–gut–brain axis to investigate the mechanism of action of Gas using a D-galactose (Dgal)–induced AD model. Gas reversed the memory dysfunction of Dgal-administered mice. Neurons in the cerebral cortex and hippocampus were reduced in the Dgal-administered group, and the decrease of neurons was suppressed in 90 and 210 mg/kg Gas treatment groups. 16S rRNA sequence analysis was carried out to explore the composition of gut microbiota in fecal samples of mice. Gas treatment had a positive correlation with Firmicutes and had a negative correlation with Cyanobacteria, Proteobacteria, and Deferribaceters
.
Importantly, the LPS and proinflammatory cytokines in the brain increased in Dgal-administered mice, but these parameters recovered to normal levels after oral administration of Gas. To determine whether the microbiota–gut–brain axis is involved in the neuroprotective effect of Gas, the mice were given antibiotic cocktail before and during the trial period to decrease the gut microbiota of mice. The antibiotic cocktail partially eliminated the neuroprotective effect of Gas by changing the gut microbiome composition. These results indicated that Gas improves the memory of the AD mouse model
via
partly targeting the microbiota–gut–brain axis and mitigating neuron inflammation.
PDF
