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The use of germ-free (GF) isolators for microbiome-related research is exponentially increasing, yet limited by its cost, isolator size and potential for trans-contamination. As such, current isolator technology is highly limiting to researchers engaged in short period experiments involving multiple mouse strains and employing a variety of mono-inoculated microorganisms. In this study, we evaluate the use of positive pressure Isocages as a solution for short period studies (days to 2–3 weeks) of experimentation with GF mice at multiple simultaneous conditions. We demonstrate that this new Isocage technology is cost-effective and room-sparing, and enables maintenance of multiple simultaneous groups of GF mice. Using this technology, transferring GF mice from isolators to Isocage racks for experimentation, where they are kept under fully germ-free conditions, enables parallel inoculation with different bacterial strains and simultaneous experimentation with multiple research conditions. Altogether, the new GF Isocage technology enables the expansion of GF capabilities in a safe and cost-effective manner that can facilitate the growth, elaboration and flexibility of microbiome research. [ABSTRACT FROM AUTHOR]

The mammalian intestinal tract harbors a vast and diverse ecosystem of microbes that are separated from the sterile host milieu by a single layer of epithelial cells. While this bio-geographical configuration is critical for host biological processes, it imposes a risk for microbial penetration and life-threatening systemic invasion. Inflammasomes are cytosolic multi-protein platforms that sense both microbial and damage-associated molecular patterns and initiate a potent innate immune anti-microbial response. In this review, we will highlight the role of inflammasomes in the orchestration and regulation of the intestinal immune response, focusing on the roles of inflammasomes in maintenance of intestinal homeostasis, enteric infection, auto-inflammation, and tumorigenesis. We highlight the centrality of inflammasome signaling in the complex cross-talk between host mucosal immune arms and the environment, in particular the microflora, with emphasis on the spatial and temporal integration of inflammasome activation with signals from other innate signaling platforms. [ABSTRACT FROM AUTHOR]

Excessive ingestion of salt is a well-recognized cause of hypernatraemia in children, is uncommonly recognized in debilitated elderly persons, but is rarely diagnosed in healthy, independent adults. We report a case of fatal salt poisoning in a 20-year-old lady who suffered of post-natal depression and ingested large quantities of salt as part of exorcism ritual. She presented with the highest ever documented serum sodium level of 255 mmol L(-1), associated with severe neurological impairment that was unresponsive to aggressive hypotonic fluid replacement. Post-mortem examination ruled out any other possible probable cause of death. The medical literature was reviewed, and 16 previous cases of severe hypernatraemia in adults secondary to excessive salt ingestion were retrieved. Common features of all reported cases included female gender (95% of cases) and evidence of underlying cognitive or psychiatric disorders (all reported cases). We conclude that women with documented cognitive or psychiatric disorders, in particular depression, are susceptible for psychogenic salt poisoning. Awareness should be raised to the potentially life-risking use of salty beverages as emetics or as part of 'exorcism' rituals. [ABSTRACT FROM AUTHOR]

Ofran Y, Lavi D, Opher D, Weiss TA, Elinav E (Hadassah University Hospital, Jerusalem, Israel). Fatal voluntary salt intake resulting in the highest ever documented sodium plasma level in adults (255 mmol L−1): a disorder linked to female gender and psychiatric disorders (Case Report).J Intern Med2004;256: 525–528.Excessive ingestion of salt is a well-recognized cause of hypernatraemia in children, is uncommonly recognized in debilitated elderly persons, but is rarely diagnosed in healthy, independent adults. We report a case of fatal salt poisoning in a 20-year-old lady who suffered of post-natal depression and ingested large quantities of salt as part of exorcism ritual. She presented with the highest ever documented serum sodium level of 255 mmol L−1, associated with severe neurological impairment that was unresponsive to aggressive hypotonic fluid replacement. Post-mortem examination ruled out any other possible probable cause of death. The medical literature was reviewed, and 16 previous cases of severe hypernatraemia in adults secondary to excessive salt ingestion were retrieved. Common features of all reported cases included female gender (95% of cases) and evidence of underlying cognitive or psychiatric disorders (all reported cases). We conclude that women with documented cognitive or psychiatric disorders, in particular depression, are susceptible for psychogenic salt poisoning. Awareness should be raised to the potentially life-risking use of salty beverages as emetics or as part of‘exorcism’ rituals. [ABSTRACT FROM AUTHOR]

A patient is described who had severe hyperplastic gastropathy as the presenting manifestation of systemic lupus erythematosus (SLE). Aggressive immunosuppressive therapy with systemic corticosteroids and immunoglobulins resulted in complete remission of lupus, and a prompt clinical and radiological regression of hyperplastic gastropathy. Hyperplastic gastropathy is an uncommon gastric illness, which is usually idiopathic but rarely is associated with Helicobacter pylori infection, cytomegalovirus infection or lymphocytic gastritis. Three previous case reports have noted a response of idiopathic hyperplastic gastropathy to systemic corticosteroid treatment, yet none of the presented patients had a systemic inflammatory disease. The presented case is the first in the medical literature in which hyperplastic gastropathy is directly linked to the development of clinical and laboratory manifestations of SLE. We suggest that hyperplastic gastropathy be added to the list of rare gastrointestinal manifestations of SLE, and that autoimmune disease be considered a possible cause of hyperplastic gastropathy. As such, any patient with symptomatic idiopathic hyperplastic gastropathy accompanied by other evidence of systemic inflammation should be considered for SLE evaluation and immunosuppressive treatment. [ABSTRACT FROM AUTHOR]

Hypokalemic paralysis due to licorice consumption is extremely rare, with only 40 cases in the English literature describing paralysis secondary to exposure to licorice in candies, medications, chewing tobacco, and herbal preparations. We describe a patient who suffered life-threatening hypokalemic paralysis caused by consumption of licorice in the form of a tea sweetener superimposed on long-term consumption of licorice candy. Aggressive fluid and potassium replenishment produced complete and lasting recovery. To our knowledge, this is the first report of hypokalemic paralysis due to exposure to licorice as a tea sweetener, a common custom among the Arab population. The case emphasizes the importance of considering patients' cultural backgrounds and local customs, which often may lead the treating physician to the correct clinical diagnosis. [ABSTRACT FROM AUTHOR]

Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy., (Copyright © 2024 American Society of Hematology.)

The microbiome regulates mammalian immune responses from early life to adulthood. Antigen presentation, orchestrating these responses, integrates commensal and pathogenic signals. However, the temporal and spatial specificity of microbiome impacts on antigen presentation and downstream tolerance versus inflammation remain incompletely understood. Herein, we review the influences of antigen presentation of microbiome-related epitopes on immunity; impacts of microbiome-based modulation of antigen presentation on innate and adaptive immune responses; and their ramifications on homeostasis and immune-related disease, ranging from auto-inflammation to tumorigenesis. We highlight mechanisms driving these influences, such as 'molecular mimicry', in which microbiome auto-antigen presentation aberrantly triggers an immune response driving autoimmunity or influences conferred by microbiome-derived metabolites on antigen-presenting cells in inflammatory bowel disease. We discuss unknowns, controversies, and challenges associated with the study of microbiome regulation of antigen presentation while demonstrating how increasing knowledge may contribute to the development of microbiome-based therapeutics modulating immune responses in a variety of clinical contexts., Competing Interests: Declaration of Competing Interest E.E. is a scientific founder of BiomX and GutBioime and a paid consultant to PurposeBio, Aposense, and Zoe in topics unrelated to this work. The other authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Recent developments in microbiome research suggest that the gut microbiome may remotely modulate central and peripheral neuronal processes, ranging from early brain development to age-related changes. Dysbiotic microbiome configurations have been increasingly associated with neurological disorders, such as neurodegeneration, but causal understanding of these associations remains limited. Most mechanisms explaining how the microbiome may induce such remote neuronal effects involve microbially modulated metabolites that influx into the 'sterile' host. Some metabolites are able to cross the blood-brain barrier (BBB) to reach the central nervous system, where they can impact a variety of cells and processes. Alternatively, metabolites may directly signal to peripheral nerves to act as neurotransmitters or exert modulatory functions, or impact immune responses, which, in turn, modulate neuronal function and associated disease propensity. Herein, we review the current knowledge highlighting microbiome-modulated metabolite impacts on neuronal disease, while discussing unknowns, controversies and prospects impacting this rapidly evolving research field., Competing Interests: Declaration of interests E.E. is a scientific founder of BiomX and GutBiome. He is a paid consultant to PurposeBio, Aposense, and ZOE., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The immune system has a vital, albeit complex, relationship with the microbes residing within us, one that we are only beginning to understand. We asked investigators what they felt were the fundamental challenges we currently face in unraveling the impacts of microbes and their metabolites on host immunity and to discuss key opportunities toward achieving future insights and innovation., Competing Interests: Declaration of interests E.E. is a scientific cofounder of BiomX and GutBiome and an advisor to Purposebio, Aposense, and Zoe in topics unrelated to this work. S.Z. is a cofounder of Ibiome, which studies microbial regulation of immune responses in topics unrelated to the subject of this work. F.M. is a scientific advisory board member at Neologics Bio. R.J.P. has patents related to this topic: “Non-invasive assessment of gut function with transcriptional recording sentinel cells,” EP22166075 (2022) and “Transcriptional recording by CRISPR spacer acquisition from RNA,” PCT/EP2019/074267 (2018)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diabetes mellitus (DM) is more common among people living with human immunodeficiency virus (PLWH) compared with healthy individuals. In a prospective multicenter study (N = 248), we identified normoglycemic (48.7%), prediabetic (44.4%), and diabetic (6.9%) PLWH. Glycosylated hemoglobin (HbA1c) and fasting blood glucose (FBG) sensitivity in defining dysglycemia was 96.8%, while addition of oral glucose tolerance test led to reclassification of only 4 patients. Inclusion of 93 additional PLWH with known DM enabled identification of multiple independent predictors of dysglycemia or diabetes: older age, higher body mass index, Ethiopian origin, HIV duration, lower integrase inhibitor exposure, and advanced disease at diagnosis. Shotgun metagenomic microbiome analysis revealed 4 species that were significantly expanded with hyperglycemia/hyperinsulinemia, and 2 species that were differentially more prevalent in prediabetic/diabetic PLWH. Collectively, we uncover multiple potential host and microbiome predictors of altered glycemic status in PLWH, while demonstrating that FBG and HbA1c likely suffice for diabetes screening. These potential diabetic predictors merit future prospective validation., Competing Interests: Potential conflicts of interest. E. E. is a scientific cofounder of DayTwo and BiomX, and an advisor to Purposebio, Aposense, Zoe, and MyGutly in topics unrelated to this work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

There is increasing evidence that interactions between microbes and their hosts not only play a role in determining health and disease but also in emotions, thought, and behavior. Built environments greatly influence microbiome exposures because of their built-in highly specific microbiomes coproduced with myriad metaorganisms including humans, pets, plants, rodents, and insects. Seemingly static built structures host complex ecologies of microorganisms that are only starting to be mapped. These microbial ecologies of built environments are directly and interdependently affected by social, spatial, and technological norms. Advances in technology have made these organisms visible and forced the scientific community and architects to rethink gene-environment and microbe interactions respectively. Thus, built environment design must consider the microbiome, and research involving host-microbiome interaction must consider the built-environment. This paradigm shift becomes increasingly important as evidence grows that contemporary built environments are steadily reducing the microbial diversity essential for human health, well-being, and resilience while accelerating the symptoms of human chronic diseases including environmental allergies, and other more life-altering diseases. New models of design are required to balance maximizing exposure to microbial diversity while minimizing exposure to human-associated diseases. Sustained trans-disciplinary research across time (evolutionary, historical, and generational) and space (cultural and geographical) is needed to develop experimental design protocols that address multigenerational multispecies health and health equity in built environments., Competing Interests: Competing interests statement:The authors declare no competing interest.

Crohn disease (CD) burden has increased with globalization/urbanization, and the rapid rise is attributed to environmental changes rather than genetic drift. The Study Of Urban and Rural CD Evolution (SOURCE, n = 380) has considered diet-omics domains simultaneously to detect complex interactions and identify potential beneficial and pathogenic factors linked with rural-urban transition and CD. We characterize exposures, diet, ileal transcriptomics, metabolomics, and microbiome in newly diagnosed CD patients and controls in rural and urban China and Israel. We show that time spent by rural residents in urban environments is linked with changes in gut microbial composition and metabolomics, which mirror those seen in CD. Ileal transcriptomics highlights personal metabolic and immune gene expression modules, that are directly linked to potential protective dietary exposures (coffee, manganese, vitamin D), fecal metabolites, and the microbiome. Bacteria-associated metabolites are primarily linked with host immune modules, whereas diet-linked metabolites are associated with host epithelial metabolic functions., (© 2024. The Author(s).)

The gut microbiome is acknowledged as a key determinant of human health, and technological progress in the past two decades has enabled the deciphering of its composition and functions and its role in human disorders. Therefore, manipulation of the gut microbiome has emerged as a promising therapeutic option for communicable and non-communicable disorders. Full exploitation of current therapeutic microbiome modulators (including probiotics, prebiotics, and faecal microbiota transplantation) is hindered by several factors, including poor precision, regulatory and safety issues, and the impossibility of providing reproducible and targeted treatments. Artificial microbiota therapeutics (which include a wide range of products, such as microbiota consortia, bacteriophages, bacterial metabolites, and engineered probiotics) have appeared as an evolution of current microbiota modulators, as they promise safe and reproducible effects, with variable levels of precision via different pathways. We describe the landscape of artificial microbiome therapeutics, from those already on the market to those still in the pipeline, and outline the major challenges for positioning these therapeutics in clinical practice., Competing Interests: Declaration of interests AG reports personal fees for consultancy for Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, Sinergie Srl Board MRGE, and SanofiSpA; personal fees for acting as a speaker for Takeda SpA, AbbVie, and Sandoz SpA; and personal fees for acting on advisory boards for VSL3 and Eisai Srl. GI has received personal fees for acting as a speaker for Alfa Sigma, Biocodex, Illumina, Malesci, Sofar, and Tillotts Pharma and personal fees for acting as consultant or advisor for Biocodex, Malesci, and Tillots Pharma. EE is a scientific cofounder of DayTwo and BiomX and an advisor to Hello Inside, Igen, and Aposense. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Inter-individual human variability, driven by various genetic and environmental factors, complicates the ability to develop effective population-based early disease detection, treatment and prognostic assessment. The microbiome, consisting of diverse microorganism communities including viruses, bacteria, fungi and eukaryotes colonizing human body surfaces, has recently been identified as a contributor to inter-individual variation, through its person-specific signatures. As such, the microbiome may modulate disease manifestations, even among individuals with similar genetic disease susceptibility risks. Information stored within microbiomes may therefore enable early detection and prognostic assessment of disease in at-risk populations, whereas microbiome modulation may constitute an effective and safe treatment tailored to the individual. In this Review, we explore recent advances in the application of microbiome data in precision medicine across a growing number of human diseases. We also discuss the challenges, limitations and prospects of analysing microbiome data for personalized patient care., (© 2023. Springer Nature Limited.)

Introduction: Darier disease is a rare inherited disease with dominant skin manifestations including keratotic papules and plaques on sebaceous and flexural areas. Secondary infection of skin lesions is common, and Staphylococcus aureus commonly colonizes these lesions. The aim of the study was to characterize the bacterial microbiome of cutaneous Darier lesions compared to normal-looking skin and disease severity., Methods: All patients with a history of Darier followed up at Emek Medical Center were invited to participate in the study. Patients that did not use antibiotics in the past month and signed informed consent had four skin sites sampled with swabs: scalp, chest, axilla, and palm. All samples were analyzed for bacterial microbiome using 16S rDNA sequencing., Results: Two hundred and eighty microbiome samples obtained from lesional and non-lesional skin of the scalp, chest, axilla, and palm of 42 Darier patients were included in the analysis. The most abundant bacterial genera across all skin sites were Propionibacterium, Corynebacterium, Paracoccus, Micrococcus, and Anaerococcus. Scalp and chest lesions featured a distinct microbiome configuration that was mainly driven by an overabundance of Staphylococci species. Patients with more severe disease exhibited microbiome alterations in the chest, axilla, and palm compared with patients with only mild disease, driven by Peptoniphilus and Moryella genera in scalp and palmar lesions, respectively., Conclusion: Staphylococci were significantly associated with Darier lesions and drove Darier-associated dysbiosis. Severity of the disease was associated with two other bacterial genera. Whether these associations also hold a causative role and may serve as a therapeutic target remains to be determined and requires further investigation., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1 ), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics., (© 2023. The Author(s).)

Bacteriophages have potential as suppressors of disease-contributing commensal bacteria.

Recent evidence suggests that some human cancers may harbor low-biomass microbial ecosystems, spanning bacteria, viruses, and fungi. Bacteria, the most-studied kingdom in this context, are suggested by these studies to localize within cancer cells, immune cells and other tumor microenvironment cell types, where they are postulated to impact multiple cancer-related functions. Herein, we provide an overview of intratumoral bacteria, while focusing on intracellular bacteria, their suggested molecular activities, communication networks, host invasion and evasion strategies, and long-term colonization capacity. We highlight how the integration of sequencing-based and spatial techniques may enable the recognition of bacterial tumor niches. We discuss pitfalls, debates and challenges in decisively proving the existence and function of intratumoral microbes, while reaching a mechanistic elucidation of their impacts on tumor behavior and treatment responses. Together, a causative understanding of possible roles played by intracellular bacteria in cancer may enable their future utilization in diagnosis, patient stratification, and treatment., (© 2023. Springer Nature Limited.)

The postnatal interaction between microbiota and the immune system establishes lifelong homeostasis at mucosal epithelial barriers, however, the barrier-specific physiological activities that drive the equilibrium are hardly known. During weaning, the oral epithelium, which is monitored by Langerhans cells (LC), is challenged by the development of a microbial plaque and the initiation of masticatory forces capable of damaging the epithelium. Here we show that microbial colonization following birth facilitates the differentiation of oral LCs, setting the stage for the weaning period, in which adaptive immunity develops. Despite the presence of the challenging microbial plaque, LCs mainly respond to masticatory mechanical forces, inducing adaptive immunity, to maintain epithelial integrity that is also associated with naturally occurring alveolar bone loss. Mechanistically, masticatory forces induce the migration of LCs to the lymph nodes, and in return, LCs support the development of immunity to maintain epithelial integrity in a microbiota-independent manner. Unlike in adult life, this bone loss is IL-17-independent, suggesting that the establishment of oral mucosal homeostasis after birth and its maintenance in adult life involve distinct mechanisms., (© 2023. Springer Nature Limited.)

Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin. Colibactin-producing E. coli promote colorectal cancer (CRC) in preclinical models, and in vitro induce a specific mutational signature that is also detected in human CRC genomes. Yet, how colibactin exposure affects the mutational landscape of CRC in vivo remains unclear. Here we show that colibactin-producing E. coli-driven colonic tumors in mice have a significantly higher SBS burden and a larger percentage of these mutations can be attributed to a signature associated with mismatch repair deficiency (MMRd; SBS15), compared to tumors developed in the presence of colibactin-deficient E. coli. We found that the synthetic colibactin 742 but not an inactive analog 746 causes DNA damage and induces transcriptional activation of p53 and senescence signaling pathways in non-transformed human colonic epithelial cells. In MMRd colon cancer cells (HCT 116), chronic exposure to 742 resulted in the upregulation of BRCA1, Fanconi anemia, and MMR signaling pathways as revealed by global transcriptomic analysis. This was accompanied by increased T>N single-base substitutions (SBS) attributed to the proposed pks + E. coli signature (SBS88), reactive oxygen species (SBS17), and mismatch-repair deficiency (SBS44). A significant co-occurrence between MMRd SBS44 and pks-associated SBS88 signature was observed in a large cohort of human CRC patients (n=2,945), and significantly more SBS44 mutations were found when SBS88 was also detected. Collectively, these findings reveal the host response mechanisms underlying colibactin genotoxic activity and suggest that colibactin may exacerbate MMRd-associated mutations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4 + T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4 + T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4 + T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection., (© 2023. The Author(s).)

Modernization of society from a rural, hunter-gatherer setting into an urban and industrial habitat, with the associated dietary changes, has led to an increased prevalence of cardiometabolic and additional noncommunicable diseases, such as cancer, inflammatory bowel disease, and neurodegenerative and autoimmune disorders. However, while dietary sciences have been rapidly evolving to meet these challenges, validation and translation of experimental results into clinical practice remain limited for multiple reasons, including inherent ethnic, gender, and cultural interindividual variability, among other methodological, dietary reporting-related, and analytical issues. Recently, large clinical cohorts with artificial intelligence analytics have introduced new precision and personalized nutrition concepts that enable one to successfully bridge these gaps in a real-life setting. In this review, we highlight selected examples of case studies at the intersection between diet-disease research and artificial intelligence. We discuss their potential and challenges and offer an outlook toward the transformation of dietary sciences into individualized clinical translation.

Background & Aims: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC., Methods: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans., Results: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis., Conclusions: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH., Impact and Implications: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood. Here we show that ablation of TET2/3 in intestinal epithelial cells results in a murine phenotype characterized by a severe homeostasis imbalance in the small intestine. Tet2/3-deleted mice show a pronounced loss of mature Paneth cells as well as fewer Tuft and more Enteroendocrine cells. Further results show major changes in DNA methylation at putative enhancers, which are associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescues the methylation and cellular defects. TET2/3 loss also alters the microbiome, predisposing the intestine to inflammation under homeostatic conditions and acute inflammation-induced death. Together, our results uncover previously unrecognized critical roles for DNA demethylation, possibly occurring subsequently to chromatin opening during intestinal development, culminating in the establishment of normal intestinal crypts., (© 2023. The Author(s).)

The intestinal epithelial barrier facilitates homeostatic host-microbiota interactions and immunological tolerance. However, mechanistic dissections of barrier dynamics following luminal stimulation pose a substantial challenge. Here, we describe an ex vivo intestinal permeability assay, X-IPA, for quantitative analysis of gut permeability dynamics at the whole-tissue level. We demonstrate that specific gut microbes and metabolites induce rapid, dose-dependent increases to gut permeability, thus providing a powerful approach for precise investigation of barrier functions., (© 2023. The Author(s).)

The microbial community of the gut, collectively termed the gut microbiota, modulates both host metabolism and disease development in a variety of clinical contexts. The microbiota can have detrimental effects and be involved in disease development and progression, but it can also offer benefits to the host. This has led in the last years to the development of different therapeutic strategies targeting the microbiota. In this review, we will focus on one of these strategies that involve the use of engineered bacteria to modulate gut microbiota in the treatment of metabolic disorders. We will discuss the recent developments and challenges in the use of these bacterial strains with an emphasis on their use for the treatment of metabolic diseases., (© 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

The microbiome may impact cancer development, progression and treatment responsiveness, but its fungal components remain insufficiently studied in this context. In this review, we highlight accumulating evidence suggesting a possible involvement of commensal and pathogenic fungi in modulation of cancer-related processes. We discuss the mechanisms by which fungi can influence tumour biology, locally by activity exerted within the tumour microenvironment, or remotely through secretion of bioactive metabolites, modulation of host immunity and communications with neighbouring bacterial commensals. We examine prospects of utilising fungi-related molecular signatures in cancer diagnosis, patient stratification and assessment of treatment responsiveness, while highlighting challenges and limitations faced in performing such research. In all, we demonstrate that fungi likely constitute important members of mucosal and tumour-residing microbiomes. Exploration of fungal inter-kingdom interactions with the bacterial microbiome and the host and decoding of their causal impacts on tumour biology may enable their harnessing into cancer diagnosis and treatment., Competing Interests: Competing interests: EE is a scientific co-founder of DayTwo and BiomX, and an advisor to Hello Inside, Igen and Aposense in topics unrelated to this work. The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Caloric restriction (CR) and related time-restricted diets have been popularized as means of preventing metabolic disease while improving general well-being. However, evidence as to their long-term efficacy, adverse effects, and mechanisms of activity remains incompletely understood. The gut microbiota is modulated by such dietary approaches, yet causal evidence to its possible downstream impacts on host metabolism remains elusive. Herein, we discuss the positive and adverse influences of restrictive dietary interventions on gut microbiota composition and function, and their collective impacts on host health and disease risk. We highlight known mechanisms of microbiota influences on the host, such as modulation of bioactive metabolites, while discussing challenges in achieving mechanistic dietary-microbiota insights, including interindividual variability in dietary responses as well as other methodological and conceptual challenges. In all, causally understanding the impact of CR approaches on the gut microbiota may enable to better decode their overall influences on human physiology and disease., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Inflammatory bowel disease (IBD) constitutes a group of auto-inflammatory disorders that impact the gastrointestinal tract and other systemic organs. The gut microbiome contributes to IBD pathology through multiple mechanisms. Bacteriophages (hereafter termed phages) are viruses that are able to specifically infect bacteria. Considered as part of the gut microbiome, phages may impact the bacterial community structure in various clinical contexts. Additionally, exogenous phage administration may represent a means of suppressing IBD-associated pathobionts; however, the utilization of phage therapy remains at an early developmental phase., Objectives: Herein, we summarize the latest advances in understanding endogenous phage impacts on the gut microbiome in a healthy gut and in IBD. We highlight the prospect of phage utilization as a targeted mode of pathobiont eradication, for preventing and treating IBD manifestations and complications., Sources: Selected peer-reviewed publications regarding the role of phages in a healthy gut and in IBD, published between 2013 and 2022., Content: The human gut microbiome is increasingly suggested to play a significant role in the onset and progression of multiple non-communicable diseases such as IBD. Several studies suggest that this effect may be mediated by discrete disease-contributing commensals. However, the eradication of such pathogenic bacteria remains a daunting unmet task. Altered community structure in IBD may be influenced by blooms of phages within the gut bacterial ecosystem. Moreover, combinations of phages specifically targeting disease-contributing pathobiont strain clades may be harnessed as potential eradication treatment preventing and treating IBD, while bearing minimal adverse impacts on the surrounding bacterial microbiome., Implications: Understanding the endogenous phage-gut commensal interactions in a healthy gut and in IBD may enable phage utilization in precision gut microbiome editing, towards treating IBD and other non-communicable microbiome-associated diseases. Nevertheless, developing phage combination-mediated IBD pathobiont eradication treatment modalities will likely necessitate better strain-level bacterial target identification and resolution of treatment-related challenges, such as phage delivery, off-target effects, and bacterial resistance., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Immunotherapy revolutionized treatment options in cancer, yet the mechanisms underlying resistance in many patients remain poorly understood. Cellular proteasomes have been implicated in modulating antitumor immunity by regulating antigen processing, antigen presentation, inflammatory signaling and immune cell activation. However, whether and how proteasome complex heterogeneity may affect tumor progression and the response to immunotherapy has not been systematically examined. Here, we show that proteasome complex composition varies substantially across cancers and impacts tumor-immune interactions and the tumor microenvironment. Through profiling of the degradation landscape of patient-derived non-small-cell lung carcinoma samples, we find that the proteasome regulator PSME4 is upregulated in tumors, alters proteasome activity, attenuates presented antigenic diversity and associates with lack of response to immunotherapy. Collectively, our approach affords a paradigm by which proteasome composition heterogeneity and function should be examined across cancer types and targeted in the context of precision oncology., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1β and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Human microbiome research is evolving from describing associations to understanding the impact of bioactive strains on humans. Despite challenges, progress is being made to apply data-driven microbiome diagnostics and interventions, potentially leading to precision medicine breakthroughs in the next decade., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:E.E. is a scientific cofounder of DayTwo and BiomX, and an advisor to Hello Inside, Igen, and Aposense. J.P. declares no competing interests., (Copyright: © 2023 Puschhof, Elinav. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In a recent report in Nature, Dohnalová et al., describe a gut-brain axis mechanism in highlighting the importance of the gut microbiota and its derived metabolites in long-term exercise engagement and performance., Competing Interests: Declaration of interests E.E. is a scientific cofounder of Daytwo and Biomx and an advisor to Hello Inside, Igen, and Aposense in topics unrelated to this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

While saliva regulates the interplay between the microbiota and the oral immune system, the mechanisms establishing postnatal salivary immunity are ill-defined. Here, we show that high levels of neutrophils and neonatal Fc receptor (FcRn)-transferred maternal IgG are temporarily present in the neonatal murine salivary glands in a microbiota-independent manner. During weaning, neutrophils, FcRn, and IgG decrease in the salivary glands, while the polymeric immunoglobulin receptor (pIgR) is upregulated in a growth arrest-specific 6 (GAS6)-dependent manner independent of the microbiota. Production of salivary IgA begins following weaning and relies on CD4-help, IL-17, and the microbiota. The weaning phase is characterized by a transient accumulation of dendritic cells capable of migrating from the oral mucosa to the salivary glands upon exposure to microbial challenges and activating T cells. This study reveals the postnatal mechanisms developed in the salivary glands to induce immunity and proposes the salivary glands as an immune inductive site., Competing Interests: Declaration of interests The authors declare no financial competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) - T cell cancer therapy has yielded promising results in treating hematologic malignancies in clinical studies, and a growing number of CAR-T regimens are approved for clinical usage. While the therapy is considered of great potential in expanding the cancer immunotherapy arsenal, more than half of patients receiving CAR-T infusions do not respond, while others develop significant adverse effects, collectively indicating a need for optimization of CAR-T treatment to the individual. The microbiota is increasingly suggested as a major modulator of immunotherapy responsiveness. Studying causal microbiota roles possibly contributing to CAR-T therapy efficacy, adverse effects reduction, and prediction of patient responsiveness constitutes an exciting area of active research. Herein, we discuss the latest developments implicating human microbiota involvement in CAR-T therapy, while highlighting challenges and promises in harnessing the microbiota as a predictor and modifier of CAR-T treatment towards optimized efficacy and minimization of treatment-related adverse effects.