Abstract
The mammalian intestine is home to trillions of microbes, and their colonization contributes to host physiology through the production of indispensable metabolites and competition against ...pathogens. However, it is also important to balance this symbiotic relationship, as overgrowth and translocation of microbes could trigger a fatal infection. IgA is the major immunoglobulin class produced and secreted in the intestine and is considered to play a pivotal role in maintaining homeostasis. In this review, we summarize recent studies exploring the interactions between IgA and the gut microbiota and explain how different types of IgA could coexist to regulate the gut microbiota. In particular, we discuss two important aspects of IgA in controlling the gut microbes: function and specificity. Differences in these two aspects appear attributable to how IgA is induced and are associated with the functions of IgA as well. Together, our review delineates a recent understanding of IgA–microbiome interactions and proposes a future direction to clarify its complexity.
Gut microbiota has extensive and tremendous impacts on human physiology and pathology. The regulation of microbiota is therefore a cardinal problem for the mutualistic relationship, as both microbial ...overgrowth and excessive immune reactions toward them could potentially be detrimental to host homeostasis. Growing evidence suggests that IgA, the most dominant secretory immunoglobulin in the intestine, regulates the colonization of commensal microbiota, and consequently, the microbiota-mediated intestinal and extra-intestinal diseases. In this review, we discuss the interactions between IgA and gut microbiota particularly relevant to human pathophysiology. We review current knowledge about how IgA regulates gut microbiota in humans and about the molecular mechanisms behind this interaction. We further discuss the potential role of IgA in regulating human diseases by extrapolating experimental findings, suggesting that IgA can be a future therapeutic strategy that functionally modulates gut microbiota.
Epithelial-mesenchymal transition (EMT) is a key step toward cancer metastasis, and Snail is a major transcription factor governing EMT. Here, we demonstrate that Snail-induced EMT accelerates cancer ...metastasis through not only enhanced invasion but also induction of immunosuppression. Murine and human melanoma cells with typical EMT features after
snail transduction induced regulatory T cells and impaired dendritic cells in vitro and in vivo partly through TSP1 production. Although Snail
+ melanoma did not respond to immunotherapy, intratumoral injection with
snail-specific siRNA or anti-TSP1 monoclonal antibody significantly inhibited tumor growth and metastasis following increase of tumor-specific tumor-infiltrating lymphocytes and systemic immune responses. These results suggest that inhibition of Snail-induced EMT could simultaneously suppress both tumor metastasis and immunosuppression in cancer patients.
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing pancreatic β-cells are destroyed. Intestinal helminths can cause asymptomatic chronic and immunosuppressive infections and ...suppress disease in rodent models of T1D. However, the underlying regulatory mechanisms for this protection are unclear. Here, we report that CD8
regulatory T (Treg) cells prevent the onset of streptozotocin -induced diabetes by a rodent intestinal nematode. Trehalose derived from nematodes affects the intestinal microbiota and increases the abundance of Ruminococcus spp., resulting in the induction of CD8
Treg cells. Furthermore, trehalose has therapeutic effects on both streptozotocin-induced diabetes and in the NOD mouse model of T1D. In addition, compared with healthy volunteers, patients with T1D have fewer CD8
Treg cells, and the abundance of intestinal Ruminococcus positively correlates with the number of CD8
Treg cells in humans.
The balance between bacterial colonization and its containment in the intestine is indispensable for the symbiotic relationship between humans and their bacteria. One component to maintain ...homeostasis at the mucosal surfaces is immunoglobulin A (IgA), the most abundant immunoglobulin in mammals
. Several studies have revealed important characteristics of poly-reactive IgA
, which is produced naturally without commensal bacteria. Considering the dynamic changes within the gut environment, however, it remains uncertain how the commensal-reactive IgA pool is shaped and how such IgA affects the microbial community. Here we show that acetate-one of the major gut microbial metabolites-not only increases the production of IgA in the colon, but also alters the capacity of the IgA pool to bind to specific microorganisms including Enterobacterales. Induction of commensal-reactive IgA and changes in the IgA repertoire by acetate were observed in mice monocolonized with Escherichia coli, which belongs to Enterobacterales, but not with the major commensal Bacteroides thetaiotaomicron, which suggests that acetate directs selective IgA binding to certain microorganisms. Mechanistically, acetate orchestrated the interactions between epithelial and immune cells, induced microbially stimulated CD4 T cells to support T-cell-dependent IgA production and, as a consequence, altered the localization of these bacteria within the colon. Collectively, we identified a role for gut microbial metabolites in the regulation of differential IgA production to maintain mucosal homeostasis.
Although recent studies have highlighted the impact of gut microbes on the progression of obesity and its comorbidities, it is not fully understood how these microbes promote these disorders, ...especially in terms of the role of microbial metabolites. Here, we report that Fusimonas intestini, a commensal species of the family Lachnospiraceae, is highly colonized in both humans and mice with obesity and hyperglycemia, produces long-chain fatty acids such as elaidate, and consequently facilitates diet-induced obesity. High fat intake altered the expression of microbial genes involved in lipid production, such as the fatty acid metabolism regulator fadR. Monocolonization with a FadR-overexpressing Escherichia coli exacerbated the metabolic phenotypes, suggesting that the change in bacterial lipid metabolism is causally involved in disease progression. Mechanistically, the microbe-derived fatty acids impaired intestinal epithelial integrity to promote metabolic endotoxemia. Our study thus provides a mechanistic linkage between gut commensals and obesity through the overproduction of microbe-derived lipids.
Display omitted
•Fusimonas intestini (FI), a commensal species, exacerbates diet-induced obesity•FI abundantly produces long-chain fatty acids such as elaidate•FI and its fatty acid metabolites impair gut integrity•Fatty acid overproduction by a model bacterial strain aggravates an obese phenotype
The mechanistic linkage between obesity and gut microbiota remains elusive. Takeuchi et al. report that a member of commensal microbiota prevalent in individuals with diabetes and obesity produces abundant long-chain fatty acids such as elaidate, a trans-unsaturated fatty acid, and aggravates diet-induced obesity through the impairment of gut integrity.
We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, the Japanese 4D ...(Disease, Drug, Diet, Daily Life) microbiome cohort, and non-Japanese data sets.
We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non–COVID-19 control individuals matched by important confounders.
Multiple correlations were found between COVID-19–related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan.
Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.
Display omitted
The bacterial microbiota works as a community that consists of many individual organisms, i.e., cells. To fully understand the function of bacterial microbiota, individual cells must be identified; ...however, it is difficult with current techniques. Here, we develop a method, Barcoding Bacteria for Identification and Quantification (BarBIQ), which classifies single bacterial cells into taxa-named herein cell-based operational taxonomy units (cOTUs)-based on cellularly barcoded 16S rRNA sequences with single-base accuracy, and quantifies the cell number for each cOTU in the microbiota in a high-throughput manner. We apply BarBIQ to murine cecal microbiotas and quantify in total 3.4 × 10
bacterial cells containing 810 cOTUs. Interestingly, we find location-dependent global differences in the cecal microbiota depending on the dietary vitamin A deficiency, and more differentially abundant cOTUs at the proximal location than the distal location. Importantly, these location differences are not clearly shown by conventional 16S rRNA gene-amplicon sequencing methods, which quantify the 16S rRNA genes, not the cells. Thus, BarBIQ enables microbiota characterization with the identification and quantification of individual constituent bacteria, which is a cornerstone for microbiota studies.
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.
A water-soluble photoresponsive molecular glue, Azo-(18)Glue, consisting of a photochromic azobenzene core and two adhesive dendritic wedges with a total of 18 peripheral guanidinium ion (Gu(+)) ...pendants tightly adheres to the surface of a phospholipid membrane, even in buffer, via a multivalent salt-bridge formation with phosphate anions. A photomechanical motion of adhering Azo-(18)Glue possibly gives rise to dynamic structural disordering of the phospholipid membrane and activates transmembrane ion permeation. In sharp contrast, no activation of ion permeation results when poorly adhesive Azo-(6)Glue carrying only six Gu(+) pendants is used in place of Azo-(18)Glue.
PDF
