Gut microbiota shifts from onset to remission in immune checkpoint inhibitor-induced enterocolitis: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis. CASE PRESENTATION: This study investigated the role of the gut microbiota during the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvement in enteritis symptoms. Conversely, genera Fusobacterium, Faecalibacterium, Bacteroides, Prevotella, and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations. CONCLUSIONS: Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs.

Activation of chloride channels and promotion of bowel movements by heat-killed Bifidobacterium longum CLA8013.

Constipation is strongly associated with the deterioration of quality of life (QOL), and patients with constipation desire clear spontaneous defecation without the feeling of incomplete evacuation, rather than improved defecation frequency. The use of common osmotic or stimulant laxatives has not been shown to lead to a satisfactory improvement of bowel movements. In addition, softening of stools by increasing their water content has been reported to increase the frequency of spontaneous defecation and improve hard stools, straining during defecation, and abdominal symptoms, such as abdominal bloating, thereby leading to improvement of QOL deterioration caused by constipation. Thus, the present study screened bacterial strains in vitro using intestinal epithelial T84 cells, aiming to identify one that activates chloride channels involved in water secretion into the intestinal tract. As a result, the conditioned medium of Bifidobacterium longum CLA8013 was found to induce ion transport. Also, this effect was suppressed by cystic fibrosis transmembrane conductance regulator (CFTR) (inh)-172, a CFTR chloride channel inhibitor. Furthermore, both live and heat-killed CLA8013 similarly induced ion transport, suggesting that bacterial cell components are responsible for the effect. In addition, the administration of heat-killed CLA8013 to loperamide-induced constipation rats resulted in an increase in fecal water content and promoted defecation. These results suggest that the active components in CLA8013 act on CFTR chloride channels in the intestinal tract, promote water secretion into the intestinal tract, and soften stools, thereby promoting bowel movements.

Microbial Metabolites and Gut Immunology.

The intestine is the largest peripheral lymphoid organ in animals, including humans, and interacts with a vast array of microorganisms called the gut microbiota. Comprehending the symbiotic relationship between the gut microbiota and our immune system is essential not only for the field of immunology but also for understanding the pathogenesis of various systemic diseases, including cancer, cardiometabolic disorders, and extraintestinal autoimmune conditions. Whereas microbe-derived antigens are crucial for activating the intestinal immune system, particularly T and B cells, as environmental cues, microbes and their metabolites play a critical role in directing the differentiation of these immune cells. Microbial metabolites are regarded as messengers from the gut microbiota, since bacteria have the ability to produce unique molecules that humans cannot, and many immune cells in the intestine express receptors for these molecules. This review highlights the distinct relationships between microbial metabolites and the differentiation and function of the immune system.

A Bcl11bN797K variant isolated from an immunodeficient patient inhibits early thymocyte development in mice.

BCL11B is a transcription factor with six C2H2-type zinc-finger domains. Studies in mice have shown that Bcl11b plays essential roles in T cell development. Several germline heterozygous BCL11B variants have been identified in human patients with inborn errors of immunity (IEI) patients. Among these, two de novo mis-sense variants cause asparagine (N) to lysine (K) replacement in distinct zinc-finger domains, BCL11BN441K and BCL11BN807K. To elucidate the pathogenesis of the BCL11BN807K variant, we generated a mouse model of BCL11BN807K by inserting the corresponding mutation, Bcl11bN797K, into the mouse genome. In Bcl11b+/N797K mice, the proportion of immature CD4-CD8+ single-positive thymocytes was increased, and the development of invariant natural killer cells was severely inhibited in a T-cell-intrinsic manner. Under competitive conditions, γδT cell development was outcompeted by control cells. Bcl11bN797K/N797K mice died within one day of birth. Recipient mice reconstituted with Bcl11bN797K/N797K fetal liver cells nearly lacked CD4+CD8+ double-positive thymocytes, which was consistent with the lack of their emergence in culture from Bcl11bN797K/N797K fetal liver progenitors. Interestingly, Bcl11bN797K/N797K progenitors gave rise to aberrant c-Kit+ and CD44+ cells both in vivo and in vitro. The increase in the proportion of immature CD8 single-positive thymocytes in the Bcl11bN797K mutants is caused, in part, by the inefficient activation of the Cd4 gene due to the attenuated function of the two Cd4 enhancers via distinct mechanisms. Therefore, we conclude that immunodeficient patient-derived Bcl11bN797K mutant mice elucidated a novel role for Bcl11b in driving the appropriate transition of CD4-CD8- into CD4+CD8+ thymocytes.

Characterization of metabolic phenotypes and distinctive genes in mice with low-weight gain.

Being overweight exacerbates various metabolic diseases, necessitating the identification of target molecules for obesity control. In the current study, we investigated common physiological features related to metabolism in mice with low weight gain: (1) G protein-coupled receptor, family C, group 5, member B-knockout; (2) gastric inhibitory polypeptide receptor-knockout; and (3) Iroquois-related homeobox 3-knockout. Moreover, we explored genes involved in metabolism by analyzing differentially expressed genes (DEGs) between low-weight gain mice and the respective wild-type control mice. The common characteristics of the low-weight gain mice were low inguinal white adipose tissue (iWAT) and liver weight despite similar food intake along with lower blood leptin levels and high energy expenditure. The DEGs of iWAT, epididymal (gonadal) WAT, brown adipose tissue, muscle, liver, hypothalamus, and hippocampus common to these low-weight gain mice were designated as candidate genes associated with metabolism. One such gene tetraspanin 7 (Tspan7) from the iWAT was validated using knockout and overexpressing mouse models. Mice with low Tspan7 expression gained more weight, while those with high Tspan7 expression gained less weight, confirming the involvement of the Tspan7 gene in weight regulation. Collectively, these findings suggest that the candidate gene list generated in this study contains potential target molecules for obesity regulation. Further validation and additional data from low-weight gain mice will aid in understanding the molecular mechanisms associated with obesity.

Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches.

Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodal in vivo approaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7 R- ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7 R- ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7 R- ILC1s. IL-7R+ (7R+) ILC1s in the liver, candidate precursors for 7 R- ILC1s, are not essential for 7 R- ILC1 development in physiological conditions. Functionally, 7 R- ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.

Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition.

BACKGROUND AND AIM: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. METHODS: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. RESULTS: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. CONCLUSION: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

Identification of key microRNAs regulating ELOVL6 and glioblastoma tumorigenesis.

ELOVL fatty acid elongase 6 (ELOVL6) controls cellular fatty acid (FA) composition by catalyzing the elongation of palmitate (C16:0) to stearate (C18:0) and palmitoleate (C16:1n-7) to vaccinate (C18:1n-7). Although the transcriptional regulation of ELOVL6 has been well studied, the post-transcriptional regulation of ELOVL6 is not fully understood. Therefore, this study aims to evaluate the role of microRNAs (miRNAs) in regulating human ELOVL6. Bioinformatic analysis identified five putative miRNAs: miR-135b-5p, miR-135a-5p, miR-125a-5p, miR-125b-5p, and miR-22-3p, which potentially bind ELOVL6 3'-untranslated region (UTR). Results from dual-luciferase assays revealed that these miRNAs downregulate ELOVL6 by directly interacting with the 3'-UTR of ELOVL6 mRNA. Moreover, miR-135b-5p and miR-135a-5p suppress cell proliferation and migration in glioblastoma multiforme cells by inhibiting ELOVL6 at the mRNA and protein levels. Taken together, our results provide novel regulatory mechanisms for ELOVL6 at the post-transcriptional level and identify potential candidates for the treatment of patients with glioblastoma multiforme.

The impact of the gut microbiome on extra-intestinal autoimmune diseases.

The prevalence of autoimmune diseases (ADs) worldwide has rapidly increased over the past few decades. Thus, in addition to the classical risk factors for ADs, such as genetic polymorphisms, infections and smoking, environmental triggers have been considered. Recent sequencing-based approaches have revealed that patients with extra-intestinal ADs, such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus, have distinct gut microbiota compositions compared to healthy controls. Faecal microbiota transplantation or inoculation with specific microbes in animal models of ADs support the hypothesis that alterations of gut microbiota influence autoimmune responses and disease outcome. Here, we describe the compositional and functional changes in the gut microbiota in patients with extra-intestinal AD and discuss how the gut microbiota affects immunity. Moreover, we examine how the gut microbiota might be modulated in patients with ADs as a potential preventive or therapeutic approach.

Alterations in the gut microbiome in patients with esophageal carcinoma in response to esophagectomy and neoadjuvant treatment.

PURPOSE: Analyzing the gut microbiome is essential for planning treatment strategies to manage esophageal squamous cell carcinoma. This study aimed to characterize the gut microbiome of patients with esophageal squamous cell carcinoma and to identify alterations in its composition during treatment. METHODS: We observed alterations in the gut microbiome in 21 consecutive patients with esophageal squamous cell carcinoma at five different time points, from neoadjuvant treatment to postoperative surgery. Ten healthy individuals were used as a non-cancer control group. Fecal samples were collected and analyzed using 16S ribosomal ribonucleic acid sequencing. RESULTS: Before treatment, participants with esophageal squamous cell carcinoma had different alpha and beta diversity in comparison to healthy controls. The number of Streptococcus, a facultative anaerobic bacterium, was significantly higher, whereas that of Faecalibacterium, an obligate anaerobic bacterium, was significantly lower. Both alpha and beta diversity remained unchanged during neoadjuvant treatment, but the alterations were pronounced after surgery. The increase in the relative abundance of Streptococcus and the decrease in that of Faecalibacterium also tended to be more pronounced after surgery. CONCLUSIONS: The gut microbiome in patients with esophageal squamous cell carcinoma is altered with surgical intervention.

A circulating subset of iNKT cells mediates antitumor and antiviral immunity.

Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244-CXCR6-), C1 (CD244-CXCR6+), or C2 (CD244+CXCR6+) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell-like features, whereas C1 iNKT cells showed more T cell-like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244+CXCR6+ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell-like properties distinct from conventional tissue-resident iNKT cells.

Hepatocyte- or macrophage-specific SREBP-1a deficiency in mice exacerbates methionine- and choline-deficient diet-induced nonalcoholic fatty liver disease.

Sterol regulatory element-binding proteins (SREBPs) are master transcription factors for lipid synthesis, and SREBP-1 is important for fatty acid and triglyceride synthesis. SREBP-1 has two isoforms, SREBP-1a and SREBP-1c, which are splicing variants transcribed from the Srebf1 gene. Although SREBP-1a exhibits stronger transcriptional activity than SREBP-1c, hepatic SREBP-1c is considered more physiologically important. We generated SREBP-1a flox mice using the CRISPR/Cas9 system and hepatocyte- and macrophage-specific SREBP-1a knockout (KO) mice (LKO, liver-knockout; and mΦKO, macrophage-knockout). There were no significant differences among all the mouse genotypes upon feeding with a normal diet. However, feeding with a methionine- and choline-deficient (MCD) diet resulted in exacerbated liver injury in both KO mice. In LKO mice, fatty liver was unexpectedly exacerbated, leading to macrophage infiltration and inflammation. In contrast, in mΦKO mice, the fatty liver state was similar to that in flox mice, but the polarity of the macrophages in the liver was transformed into a proinflammatory M1 subtype, resulting in the exacerbation of inflammation. Taken together, we found that SREBP-1a does not contribute to hepatic lipogenesis, but in either hepatocytes or macrophages distinctly controls the onset of pathological conditions in MCD diet-induced hepatitis.NEW & NOTEWORTHY Hepatocyte- and macrophage-specific SREBP-1a knockout mice were generated for the first time. This study reveals that SREBP-1a does not contribute to hepatic lipogenesis, but in either hepatocytes or macrophages distinctly controls the onset of pathological conditions in methionine- and choline-deficient diet-induced hepatitis.

Impact of dietary fructooligosaccharides (FOS) on murine gut microbiota and intestinal IgA secretion.

Fructooligosaccharides (FOS) are considered as prebiotics and are well known for their health-promoting properties, including antitumor, allergy-preventive, and infection-protective effects. They exert these effects by modulating the gut microbial composition and dynamics. In the present study, we performed a comparative whole metagenome shotgun sequencing analysis (WMGS) to elucidate the gut microbiota and secretary Immunoglobulin A (SIgA) dynamics as a result of 5% (w/w) FOS supplementation over a period of 7 days (fecal samples were collected every day). A number of taxa including Bacteroides, Lactobacillus, Roseburia, Clostridia, Faecalibaculum, and Enterorhabdus were found to be modulated with SIgA production in the murine gut. The process of SIgA production from FOS metabolization was found to be carried out via the production of short-chain fatty acids in the gut. Species of Bacteroides and Roseburia; namely, B. caccae, B. finegoldii, B. ovatus, B. thetaiotamicron, and Roseburia intestinalis, respectively, are predominantly responsible for FOS metabolization in the murine gut. The abundances of these bacterial species and their corresponding functions involved in FOS metabolization decreased over time even though these prebiotics were administered continuously for seven days. This suggests that there is a decrease in FOS metabolization over time. In addition, the present analysis suggests that the administration of FOS may help to reduce the pathogenic bacteria from the gut via SIgA production. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03116-3.

Analysis of colonic mucosa-associated microbiota using endoscopically collected lavage.

The bacterial composition of the gut lumen and mucosa is distinct and the mucosa-associated bacteria are thought to play a more critical role in interactions with the host immune system. However, limited studies of the gut mucosal microbiota in humans have been available due to methodological challenges. Here, we evaluated the potential use of colonic lavage samples for mucosal microbiota analysis in humans. Among the different types of colonic mucosal samples collected from healthy volunteers, the lavage samples contained a higher amount of bacterial DNA and were less contaminated with host DNA compared to mucosal brushing (brush) and biopsy. Although 16S gene amplicon sequencing showed that the bacterial composition of the lavage was intermediate between that of feces and biopsy, mucosal bacteria abundant in the biopsy were also enriched in lavage samples. Furthermore, differences in mucosal microbes between non-smokers and smokers were detectable in lavage samples. Our data emphasize that colonic lavage is suitable for analysis of the mucosal microbiota. Given its minimal invasiveness and high bacterial DNA content, the colonic lavage will promote research on the human mucosal microbiota, especially in gastrointestinal disorders.

Oral Pathobiont-Induced Changes in Gut Microbiota Aggravate the Pathology of Nonalcoholic Fatty Liver Disease in Mice.

Background & Aims: Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology. Methods: C57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction. Results: CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different. Conclusions: Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.

Bacterial cancer therapy in autochthonous colorectal cancer affects tumor growth and metabolic landscape.

Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. Attenuated strains of Salmonella enterica serovar Typhimurium (STm) have commonly been used in mouse models of BCT in xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using autochthonous mouse models of intestinal cancer and tumor organoid cultures to assess the effectiveness and consequences of oral treatment with aromatase A-deficient STm (STmΔaroA). STmΔaroA delivered by oral gavage significantly reduced tumor burden and tumor load in both a colitis-associated colorectal cancer (CAC) model and in a spontaneous Apcmin/+ intestinal cancer model. STmΔaroA colonization of tumors caused alterations in transcription of mRNAs associated with tumor stemness, epithelial-mesenchymal transition, and cell cycle. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STmΔaroA-treated tumors, suggesting that STmΔaroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro recapitulated effects seen on tumor stemness, mesenchymal markers, and altered metabolome. Furthermore, live STmΔaroA was required, demonstrating active mechanisms including metabolite usage. We have demonstrated that oral BCT is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium affecting tumor stem cells.

Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.

BACKGROUND: Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. METHODS: We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). RESULTS: Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. CONCLUSIONS: These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.

Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.

Future projection of greenhouse gas emissions due to permafrost degradation using a simple numerical scheme with a global land surface model.

The Yedoma layer, a permafrost layer containing a massive amount of underground ice in the Arctic regions, is reported to be rapidly thawing. In this study, we develop the Permafrost Degradation and Greenhouse gasses Emission Model (PDGEM), which describes the thawing of the Arctic permafrost including the Yedoma layer due to climate change and the greenhouse gas (GHG) emissions. The PDGEM includes the processes by which high-concentration GHGs (CO2 and CH4) contained in the pores of the Yedoma layer are released directly by dynamic degradation, as well as the processes by which GHGs are released by the decomposition of organic matter in the Yedoma layer and other permafrost. Our model simulations show that the total GHG emissions from permafrost degradation in the RCP8.5 scenario was estimated to be 31-63 PgC for CO2 and 1261-2821 TgCH4 for CH4 (68th percentile of the perturbed model simulations, corresponding to a global average surface air temperature change of 0.05-0.11 °C), and 14-28 PgC for CO2 and 618-1341 TgCH4 for CH4 (0.03-0.07 °C) in the RCP2.6 scenario. GHG emissions resulting from the dynamic degradation of the Yedoma layer were estimated to be less than 1% of the total emissions from the permafrost in both scenarios, possibly because of the small area ratio of the Yedoma layer. An advantage of PDGEM is that geographical distributions of GHG emissions can be estimated by combining a state-of-the-art land surface model featuring detailed physical processes with a GHG release model using a simple scheme, enabling us to consider a broad range of uncertainty regarding model parameters. In regions with large GHG emissions due to permafrost thawing, it may be possible to help reduce GHG emissions by taking measures such as restraining land development.

IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon.

The physiological stresses that diminish tissue stem-cell characteristics remain largely unknown. We previously reported that type I interferon (IFN), which is essential for host antiviral responses, is a physiological stressor for hematopoietic stem cells (HSCs) and small intestinal stem cells (ISCs) and that interferon regulatory factor-2 (IRF2), which attenuates IFN signaling, maintains their stemness. Here, using a dextran sodium sulfate (DSS)-induced colitis model, we explore the role of IRF2 in maintaining colonic epithelial stem cells (CoSCs). In mice with a conditional Irf2 deletion in the intestinal epithelium (hereafter Irf2ΔIEC mice), both the number and the organoid-forming potential of CoSCs were markedly reduced. Consistent with this finding, the ability of Irf2ΔIEC mice to regenerate colon epithelium after inducing colitis was severely impaired, independently of microbial dysbiosis. Mechanistically, CoSCs differentiated prematurely into transit-amplifying (TA) cells in Irf2ΔIEC mice, which might explain their low CoSC counts. A similar phenotype was induced in wild-type mice by repeated injections of low doses of poly(I:C), which induces type I IFN. Collectively, we demonstrated that chronic IFN signaling physiologically stresses CoSCs. This study provides new insight into the development of colitis and molecular mechanisms that maintain functional CoSCs throughout life.