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Background: Fermentation of dietary fiber by the gut microbiota leads to the production of metabolites called short-chain fatty acids, which lower blood pressure and exert cardioprotective effects. Short-chain fatty acids activate host signaling responses via the functionally redundant receptors GPR41 (G-protein-coupled receptor 41) and GPR43 (G-protein-coupled receptor 43), which are highly expressed by immune cells. Whether and how these receptors protect against hypertension or mediate the cardioprotective effects of dietary fiber remains unknown., Methods: Cardiovascular phenotype was assessed in untreated and Ang II (angiotensin II) treated hypertensive wild-type and GPR41/43 knockout (KO) double knockout male mice fed diets with different levels of fiber content. Some mice received TLR4 (toll-like receptor 4)-antagonist treatment and bone marrow chimeras. SNPs (single-nucleotide polymorphisms) associated with GPR41 and GPR43 expression were assessed in UK Biobank participants., Results: Untreated GPR41/43KO mice had unaltered blood pressure but had greater cardiac and renal collagen deposition with higher macrophage numbers in the kidney compared with wild-type mice. Ang II-treated GPR41/43KO mice showed higher systolic blood pressure, cardiorenal weights and collagen deposition, and increased gut permeability, which allows the translocation of gastrointestinal bacterial components such as lipopolysaccharides into the circulation. The use of an antagonist to the lipopolysaccharide receptor, TLR4, a potent proinflammatory signaling molecule, restored the cardiovascular phenotype in GPR41/43KO mice. The lack of GPR41/43 expression in the immune compartment was sufficient to lead to a worsened hypertensive phenotype. We also demonstrate that GPR41/43 is, at least partially, responsible for the blood pressure-lowering and cardioprotective effects of a high-fiber diet. Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41 and GPR43 are more prevalent in participants with hypertension., Conclusions: Our findings highlight that lack of short-chain fatty acid-receptor signaling via both GPR41 and GPR43 increases risk of high blood pressure, suggesting treatments that target these receptors could be a novel strategy to prevent or treat hypertension., Competing Interests: None.

Cardiorenal fibrosis is a common feature of chronic cardiovascular disease and recent data suggests that cytokines and chemokines may also drive fibrosis. Here we tested the hypothesis that CXCR7, a highly conserved chemokine receptor, contributes to cardiac and renal fibrosis. We generated an anti-mouse CXCR7-specific monoclonal antibody (CXCR7 mAb) and tested its anti-fibrotic actions in cardiorenal fibrosis induced using the deoxycorticosterone acetate/uni-nephrectomy (DOCA-UNX) model. CXCR7 mAb treatment (10 mg/kg, twice weekly for 6 weeks) significantly attenuated the development of cardiac and renal fibrosis, and reduced fibrotic and inflammatory gene expression levels, in the absence of an effect on blood pressure. Immunohistochemical analysis demonstrated an increase in the vascular expression of CXCR7 in DOCA-UNX-treated mice. This study demonstrated that a CXCR7 mediated pathway plays a significant role in cardiac and renal fibrosis induced by DOCA-UNX treatment. Accordingly, antagonism of CXCR7 may provide a therapeutic opportunity to mitigate against fibrosis in the setting of mineralocorticoid excess., (© 2024. The Author(s).)

Background: Accumulating research suggests that metabolites produced by gut microbiota are essential for maintaining a balanced gut and immune system. Indole-3-acetic acid (IAA), one of tryptophan metabolites from gut microbiota, is critical for gut health through mechanisms such as activating aryl hydrocarbon receptor. Delivery of IAA to colon is beneficial for treatment of gastrointestinal diseases, and one promising strategy is IAA esterified starch, which is digested by gut microbes in colon and releases loaded IAA. Amylose content is a key structural characteristic that controls the physicochemical properties and digestibility of starch., Methods: In the current study, IAA was esterified with three typical starches with distinct amylose content to obtain indolyl acetylated waxy maize starch (WMSIAA), indolyl acetylated normal maize starch (NMSIAA), and indolyl acetylated high-amylose maize starch (HAMSIAA). The study comparatively analyzed their respective physicochemical properties, how they behave under in vitro digestion conditions, their ability to deliver IAA directly to the colon, and their effects on the properties of the gut microbiota., Results: The new characteristic peak of 1 H NMR at 10.83 ppm, as well as the new characteristic peak of FTIR spectra at 1729 cm -1 , represented the successful esterification of IAA on starch backbone. The following in vitro digestion study further revealed that treatment with indolyl acetylation significantly elevated the resistant starch content in the starch samples. In vivo experimental results demonstrated that WMSIAA exhibited the most significant increase in IAA levels in the stomach, whereas HAMSIAA and NMSIAA demonstrated the most remarkable increases in IAA levels in the small intestine and colon, respectively. The elevated IAA levels in the colon are conducive to promoting the growth of beneficial intestinal bacteria and significantly alleviating DSS-induced colitis., Conclusions: This research presents innovative insights and options for the advancement of colon-specific drug delivery systems aimed at preventing and curing gastrointestinal disorders.

Background and Aims: There is increased interest in utilizing dietary interventions to alter the progression of autoimmune diseases. These efforts are driven by associations of gut microbiota/metabolites with levels of short-chain fatty acids (SCFAs). Propionate is a key SCFA that is commonly used as a food preservative and is endogenously generated by bacterial fermentation of non-digestible carbohydrates in the gut. A thesis has suggested that a diet rich in propionate and other SCFAs can successfully modulate autoimmunity. Herein, we investigated the effect of long-term administration of propionylated high-amylose resistant starches (HAMSP) on the course of murine primary biliary cholangitis., Materials and Methods: Groups of female ARE-Del mice were fed an HAMSP diet either before or after disease onset. A detailed immunobiological analysis was performed involving autoantibodies and rigorous T-cell phenotyping, including enumeration of T-cell subsets in the spleen, liver, intestinal intraepithelial lymphocytes and lamina propria by flow cytometry. Histopathological scores were used to assess the frequency and severity of liver inflammation and damage to hepatocytes and bile ducts., Results: Our results demonstrate that a long-term propionate-yielding diet re-populated the T-cell pool with decreased naïve and central memory T-cell subsets and an increase in the effector memory T cells in mice. Similarly, long-term HAMSP intake reduced CD4 + CD8 + double-positive T cells in intraepithelial lymphocytes and the intestinal lamina propria. Critically, HAMSP consumption led to moderate-to-severe hepatocellular steatosis in ARE-Del mice, independent of the stage of autoimmune cholangitis., Conclusions: Our data suggest that administration of HAMSP induces both regulatory and effector T cells. Furthermore, HAMSP administration resulted in hepatocellular steatosis. Given the interest in dietary modulation of autoimmunity and because propionate is widely used as a food preservative, these data have significant implications. This study also provides new insights into the immunological and pathological effects of chronic propionate exposure., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Aims: Animal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II hypertensive model. However, the gut microbiome is influenced by internal and external experimental factors, which are not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations., Methods and Results: We conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomized into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced α-diversity (P = 0.0137) and β-diversity (i.e. composition of the microbiome, P < 0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both α- and β-diversity (all P < 0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%)., Conclusion: Our large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Alcoholic liver disease (ALD) is a globally prevalent form of liver disease for which there is no effective treatment. Recent studies have found that a significant decrease in butyrate was closely associated with ALD development. Given the low compliance and delivery efficiency associated with oral-route butyrate administration, a highly effective butyrate-yielding dietary supplement, butyrylated high-amylose maize starch (HAMSB), is a good alternative approach. Here, we synthesized HAMSB, evaluated the effect of HAMSB on acute ALD in mice, compared its effect with that of oral administration of butyrate, and further studied the potential mechanism of action. The results showed HAMSB alleviated acute ALD in mice, as evidenced by the inhibition of hepatic-function impairment and the improvement in liver steatosis and lipid metabolism; in these respects, HAMSB supplementation was superior to oral sodium butyrate administration. These improvements can be attributed to the reduction of oxidative stress though the regulation of Nrf2-mediated antioxidant signaling in the liver and the improvement in the composition and function of microbiota in the intestine. In conclusion, HAMSB is a safe and effective dietary supplement for preventing acute ALD that could be useful as a disease-modifying functional food or candidate medicine.

Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis., (© 2024. The Author(s).)

Microbiota-derived catabolism of nutrients is closely related to ulcerative colitis (UC). The level of indole-3-acetic acid (IAA), a microbiota-dependent metabolite of tryptophan, was decreased significantly in the feces of UC patients. Thus supplementation with IAA could be a potential therapeutic method for ameliorating colitis. In this work, the protective effect of supplementation with IAA on dextran sulfate sodium (DSS)-induced colitis was evaluated, and the underlying mechanism was elucidated. The results indicated that the administration of IAA significantly relieved DSS-induced weight loss, reduced the disease activity index (DAI), restored colon length, alleviated intestinal injury, and improved the intestinal tight junction barrier. Furthermore, IAA inhibited intestinal inflammation by reducing the expression of proinflammatory cytokines and promoting the production of IL-10 and TGF-β1. In addition, the ERK signaling pathway is an important mediator of various physiological processes including inflammatory responses and is closely associated with the expression of IL-10. Notably, IAA treatment induced the activation of extracellular signal-regulated kinase (ERK), which is involved in the progression of colitis, while the ERK inhibitor U0126 attenuated the beneficial effects of IAA. In summary, IAA could attenuate the clinical symptoms of colitis, and the ERK signaling pathway was involved in the underlying mechanism. Supplementation with IAA could be a potential option for preventing or ameliorating UC., (© 2024. The Pharmaceutical Society of Korea.)

Targeting CXCR1 and CXCR2 chemokine receptors to block neutrophil migration to sites of inflammation is a promising therapeutic approach for various inflammatory and autoimmune diseases. However, assessing the translational potential of such therapies using mouse models is challenging due to the unclear expression of CXCR1 at the protein level. Although CXCR2 has been well characterized in both mice and humans, the protein-level expression of CXCR1 in mice (mCXCR1) remains controversial. To address this issue, we generated a novel human CXCR1 knock-in (hCXCR1 KI) mouse model in which the transgene is under the control of the native mouse promoter and regulatory elements. Using an anti-human CXCR1 monoclonal antibody (anti-hCXCR1 monoclonal antibody), we found that hCXCR1 was highly expressed on neutrophils in the hCXCR1 KI mice, comparable to levels observed in human neutrophils. This successful expression of hCXCR1 in this mouse model suggests that functional mCXCR1 likely exists. To investigate the functional role of CXCR1, we investigated how antagonizing this receptor using anti-hCXCR1 monoclonal antibody in the arthritis model would affect disease outcomes. Antibody treatment significantly alleviated all signs of joint inflammation. In summary, our newly generated hCXCR1 KI transgenic mice provide a valuable tool to investigate the therapeutic efficacy of small molecules or monoclonal antibodies that antagonize this receptor in neutrophil-mediated pathologies., Competing Interests: Conflict of interest. The authors have no conflicts of interest relevant to this article to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alzheimer's disease (AD) is a neurodegenerative disorder with poorly understood etiology. AD has several similarities with other "Western lifestyle" inflammatory diseases, where the gut microbiome and immune pathways have been associated. Previously, we and others have noted the involvement of metabolite-sensing GPCRs and their ligands, short-chain fatty acids (SCFAs), in protection of numerous Western diseases in mouse models, such as Type I diabetes and hypertension. Depletion of GPR43, GPR41, or GPR109A accelerates disease, whereas high SCFA yielding diets protect in mouse models. Here, we extended the concept that metabolite-sensing receptors and SCFAs may be a more common protective mechanism against Western diseases by studying their role in AD pathogenesis in the 5xFAD mouse model. Both male and female mice were included. Depletion of GPR41 and GPR43 accelerated cognitive decline and impaired adult hippocampal neurogenesis in 5xFAD and WT mice. Lack of fiber/SCFAs accelerated a memory deficit, whereas diets supplemented with high acetate and butyrate (HAMSAB) delayed cognitive decline in 5xFAD mice. Fiber intake impacted on microglial morphology in WT mice and microglial clustering phenotype in 5xFAD mice. Lack of fiber impaired adult hippocampal neurogenesis in both W and AD mice. Finally, maternal dietary fiber intake significantly affects offspring's cognitive functions in 5xFAD mice and microglial transcriptome in both WT and 5xFAD mice, suggesting that SCFAs may exert their effect during pregnancy and lactation. Together, metabolite-sensing GPCRs and SCFAs are essential for protection against AD, and reveal a new strategy for disease prevention. Significance Statement Alzheimer's disease (AD) is one of the most common neurodegenerative diseases; currently, there is no cure for AD. In our study, short-chain fatty acids and metabolite receptors play an important role in cognitive function and pathology in AD mouse model as well as in WT mice. SCFAs also impact on microglia transcriptome, and immune cell recruitment. Out study indicates the potential of specialized diets (supplemented with high acetate and butyrate) releasing high amounts of SCFAs to protect against disease., (Copyright © 2023 the authors.)

Nonpathogenic commensal microbiota and their metabolites and components are essential to maintain a tolerogenic environment and promote beneficial health effects. The metabolic environment critically impacts the outcome of immune responses and likely impacts autoimmune and allergic responses. Short-chain fatty acids (SCFAs) are the main metabolites produced by microbial fermentation in the gut. Given the high concentration of SCFAs in the gut and portal vein and their broad immune regulatory functions, SCFAs significantly influence immune tolerance and gut-liver immunity. Alterations of SCFA-producing bacteria and SCFAs have been identified in a multitude of inflammatory diseases. These data have particular significance in primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis because of the close proximity of the liver to the gut. In this focused review, we provide an update on the immunologic consequences of SCFA-producing microbiota and in particular on three dominant SCFAs in autoimmune liver diseases., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Diet and the gut microbiota have a profound influence on physiology and health, however, mechanisms are still emerging. Here we outline several pathways that gut microbiota products, particularly short-chain fatty acids (SCFAs), use to maintain gut and immune homeostasis. Dietary fibre is fermented by the gut microbiota in the colon, and large quantities of SCFAs such as acetate, propionate, and butyrate are produced. Dietary fibre and SCFAs enhance epithelial integrity and thereby limit systemic endotoxemia. Moreover, SCFAs inhibit histone deacetylases (HDAC), and thereby affect gene transcription. SCFAs also bind to 'metabolite-sensing' G-protein coupled receptors (GPCRs) such as GPR43, which promotes immune homeostasis. The enormous amounts of SCFAs produced in the colon are sufficient to lower pH, which affects the function of proton sensors such as GPR65 expressed on the gut epithelium and immune cells. GPR65 is an anti-inflammatory Gα s -coupled receptor, which leads to the inhibition of inflammatory cytokines. The importance of GPR65 in inflammatory diseases is underscored by genetics associated with the missense variant I231L (rs3742704), which is associated with human inflammatory bowel disease, atopic dermatitis, and asthma. There is enormous scope to manipulate these pathways using specialized diets that release very high amounts of specific SCFAs in the gut, and we believe that therapies that rely on chemically modified foods is a promising approach. Such an approach includes high SCFA-producing diets, which we have shown to decrease numerous inflammatory western diseases in mouse models. These diets operate at many levels - increased gut integrity, changes to the gut microbiome, and promotion of immune homeostasis, which represents a new and highly promising way to prevent or treat human disease., Competing Interests: Conflict of interest C.R.M is the founder of a company that produces HAMSA, HAMSP to treat human diseases., (Copyright © 2023. Published by Elsevier Ltd.)

Tryptophan metabolites such as indole-3-acetic acid (IAA) are critical for gut health, through their binding to the aryl hydrocarbon receptor (AhR), and may be useful for treatment of gastrointestinal diseases. Delivery of IAA to the colon is necessary, and one strategy is use of esterified starches which get digested in the colon by gut microbes. High amylose maize starch (HAMS) resists digestion in the upper gastrointestinal tract and is fermented by gut microbiota to release short-chain fatty acids (SCFAs), which are also beneficial to intestinal homeostasis. IAA esterified to HAMS (HAMSIAA) was synthesized with different degrees of substitution (DSs) by controlling the ratio of IAA vs HAMS. Successful incorporation of indole acetyl group was verified by NMR and FTIR spectra. XRD revealed that the crystalline type of HAMSIAA changed from B to V-type. SEM showed the destroyed surface of the starch granules. HAMSIAA with DS ~ 0.3 effectively increased IAA in the colon, to levels unachievable by oral IAA delivery. HAMSIAA increased pathways downstream of AhR activation, including CYP1A1 mRNA expression and IL-22 protein levels, and greatly improved DSS-induced colitis. HAMSIAA could serve as an ideal means for colon-targeted delivery of IAA and a promising nutraceutical for amelioration of inflammatory conditions., Competing Interests: Declaration of competing interest HAMSIAA is the subject of a patent application, and CRM is the founder of a company aiming to develop HAMSIAA for human use., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gut bacterial metabolites such as short-chain fatty acids (SCFAs) have important effects on immune cells and the gut. SCFAs derive from the fermentation of dietary fiber by gut commensal bacteria. Insufficient fiber intake thus compromises SCFA production and, as a consequence, the host's physiology (particularly immune functions). We propose that many Western diseases, including those associated with impaired mucosal responses such as food allergy and asthma, may be affected by insufficient fiber intake and reduced SCFA levels in the gut and blood. Insufficient fiber intake is 1 alternative, or contributor, on top of the "hygiene hypothesis" to the rise of Western lifestyle diseases, and the 2 ideas need to be reconciled. The mechanisms by which SCFAs influence immunity and gut homeostasis are varied; they include stimulation of G protein-coupled receptors (GPCRs), such as GPR43 or GPR41; inhibition of histone deacetylases (and hence, gene transcription changes); and induction of intracellular metabolic changes. SCFAs modulate at many different levels to alter mucosal homeostasis, including changes to gut epithelial integrity, increases in regulatory T-cell numbers and function, and decreased expression of numerous inflammatory cytokines. There is scope for preventing and/or treating diseases by using diets that alter SCFA levels., (Copyright © 2022. Published by Elsevier Inc.)

Fibers remain undigested until they reach the colon, where some are fermented by gut microbiota, producing metabolites called short-chain fatty acids (SCFAs), such as acetate and butyrate 1 . SCFAs lower blood pressure in experimental models 2-5 , but their translational potential is unknown. Here we present the results of a phase II, randomized, placebo-controlled, double-blind cross-over trial (Australian New Zealand Clinical Trials Registry ACTRN12619000916145) using prebiotic acetylated and butyrylated high-amylose maize starch (HAMSAB) supplementation 6 . Twenty treatment-naive participants with hypertension were randomized to 40 g per day of HAMSAB or placebo, completing each arm for 3 weeks, with a 3-week washout period between them. The primary endpoint was a reduction in ambulatory systolic blood pressure. Secondary endpoints included changes to circulating cytokines, immune markers and gut microbiome modulation. Patients receiving the HAMSAB treatment showed a clinically relevant reduction in 24-hour systolic blood pressure independent of age, sex and body mass index without any adverse effects. HAMSAB increased levels of acetate and butyrate, shifted the microbial ecosystem and expanded the prevalence of SCFA producers. In summary, a prebiotic intervention with HAMSAB could represent a promising option to deliver SCFAs and lower blood pressure in patients with essential hypertension., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Neutrophils play significant roles in immune homeostasis and as neutralizers of microbial infections. Recent evidence further suggests heterogeneity of neutrophil developmental and activation states that exert specialized effector functions during inflammatory disease conditions. Neutrophils can play multiple roles during viral infections, secreting inflammatory mediators and cytokines that contribute significantly to host defense and pathogenicity. However, their roles in viral immunity are not well understood. In this review, we present an overview of neutrophil heterogeneity and its impact on the course and severity of viral respiratory infectious diseases. We focus on the evidence demonstrating the crucial roles neutrophils play in the immune response toward respiratory infections, using influenza as a model. We further extend the understanding of neutrophil function with the studies pertaining to COVID-19 disease and its neutrophil-associated pathologies. Finally, we discuss the relevance of these results for future therapeutic options through targeting and regulating neutrophil-specific responses., (©2022 Society for Leukocyte Biology.)

Alcohol-related liver disease (ALD) is a major cause of chronic liver disease worldwide with limited therapeutic options. Here, we first revealed the promising beneficial effect of gut microbiota-derived propionate on alcoholic liver injury in mice. This effect was dependent on the modulation of homeostasis of the gut-liver axis, especially the improvement of intestinal permeability. Dietary supplementation with propionate protected against ethanol-induced loss of hepatic function and hepatic steatosis in mice. Meanwhile, propionate treatment attenuated intestinal epithelial barrier dysfunction, restored the expression of intestinal mucus layer components, suppressed intestinal inflammation, and altered intestinal microbiota dysbiosis, which inhibited the intestinal hyperpermeability and subsequently reduced lipopolysaccharide leakage in ALD mice. Furthermore, as a consequence of endotoxemia amelioration, the liver inflammation-related TLR4-NF-κB pathway was inhibited. Collectively, our results suggested that propionate supplementation may be a promising option for the prevention and treatment of ALD.

Background: Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here, we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the gut microbiota in alignment with modulation of the immune system status., Results: HAMSAB supplement was administered for 6 weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control. Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention., Conclusion: Changes in gut microbiota composition, function, and immune profile following 6 weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance, and improve glycemic control for the treatment of T1D., Trial Registration: ACTRN12618001391268. Registered 20 August 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792 Video Abstract., (© 2022. The Author(s).)

The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11b lo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11b hi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4 + GATA3 + helper T cells (T H ), whereas antifungal IL-17 + RORγt + T H cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been shown to acquire immunosuppressive and pro-tumorigenic functions that promote tumor progression and escape. As such, inhibition of their function or depletion of neutrophils are being explored as potential cancer therapies. However, growing evidence of neutrophil diversification in cancer and their potential anti-tumor roles raise many unresolved questions. Here, we review recent advances that address the definition, origin and function of neutrophils in cancer, and elaborate on obstacles that make the study of neutrophils challenging. We envision that this review will provide the groundwork for focused design of therapeutics that will specifically target "tumorreprogrammed" neutrophils while sparing normal neutrophils to improve patient outcomes., (© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Intestinal barrier is essential for dietary products and microbiota compartmentalization and therefore gut homeostasis. When this barrier is broken, cecal content overflows into the peritoneal cavity, leading to local and systemic robust inflammatory response, characterizing peritonitis and sepsis. It has been shown that IL-1β contributes with inflammatory storm during peritonitis and sepsis and its inhibition has beneficial effects to the host. Therefore, we investigated the mechanisms underlying IL-1β secretion using a widely adopted murine model of experimental peritonitis. The combined injection of sterile cecal content (SCC) and the gut commensal bacteria Bacteroides fragilis leads to IL-1β-dependent peritonitis, which was mitigated in mice deficient in NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome components. Typically acting as a damage signal, SCC, but not B. fragilis , activates canonical pathway of NLRP3 promoting IL-1β secretion in vitro and in vivo. Strikingly, absence of fiber in the SCC drastically reduces IL-1β production, whereas high-fiber SCC conversely increases this response in an NLRP3-dependent manner. In addition, NLRP3 was also required for IL-1β production induced by purified dietary fiber in primed macrophages. Extending to the in vivo context, IL-1β-dependent peritonitis was worsened in mice injected with B. fragilis and high-fiber SCC, whereas zero-fiber SCC ameliorates the pathology. Corroborating with the proinflammatory role of dietary fiber, IL-1R-deficient mice were protected from peritonitis induced by B. fragilis and particulate bran. Overall, our study highlights a function, previously unknown, for dietary fibers in fueling peritonitis through NLRP3 activation and IL-1β secretion outside the gut., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Recent studies in both mice and humans have suggested that gut microbiota could modulate tumor responsiveness to chemo- or immunotherapies. However, the underlying mechanism is not clear yet. Here, we found that gut microbial metabolites, especially butyrate, could promote the efficacy of oxaliplatin by modulating CD8 + T cell function in the tumor microenvironment. Butyrate treatment directly boosted the antitumor cytotoxic CD8 + T cell responses both in vitro and in vivo in an ID2-dependent manner by promoting the IL-12 signaling pathway. In humans, the oxaliplatin responder cancer patients exhibited a higher amount of serum butyrate than did non-responders, which could also increase ID2 expression and function of human CD8 + T cells. Together, our findings suggest that the gut microbial metabolite butyrate could promote antitumor therapeutic efficacy through the ID2-dependent regulation of CD8 + T cell immunity, indicating that gut microbial metabolites could be effective as a part of cancer therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)