Gut Microbiota-host Interactions Research Articles

Can fecal microbiota transplantations modulate autoimmune responses in type 1 diabetes?

Type 1 diabetes (T1D) is a chronic autoimmune disease targeting insulin-producing pancreatic beta cells. T1D is a multifactorial disease incorporating genetic and environmental factors. In recent years, the advances in high-throughput sequencing have allowed researchers to elucidate the changes in the gut microbiota taxonomy and functional capacity that accompany T1D development. An increasing number of studies have shown a role of the gut microbiota in mediating immune responses in health and disease, including autoimmunity. Fecal microbiota transplantations (FMT) have been largely used in murine models to prove a causal role of the gut microbiome in disease progression and have been shown to be a safe and effective treatment in inflammatory human diseases. In this review, we summarize and discuss recent research regarding the gut microbiota-host interactions in T1D, the current advancement in therapies for T1D, and the usefulness of FMT studies to explore microbiota-host immunity encounters in murine models and to shape the course of human type 1 diabetes.

An engineered bacterial symbiont allows noninvasive biosensing of the honey bee gut environment.

The honey bee is a powerful model system to probe host-gut microbiota interactions, and an important pollinator species for natural ecosystems and for agriculture. While bacterial biosensors can provide critical insight into the complex interplay occurring between a host and its associated microbiota, the lack of methods to noninvasively sample the gut content, and the limited genetic tools to engineer symbionts, have so far hindered their development in honey bees. Here, we built a versatile molecular tool kit to genetically modify symbionts and reported for the first time in the honey bee a technique to sample their feces. We reprogrammed the native bee gut bacterium Snodgrassella alvi as a biosensor for IPTG, with engineered cells that stably colonize the gut of honey bees and report exposure to the molecules in a dose-dependent manner through the expression of a fluorescent protein. We showed that fluorescence readout can be measured in the gut tissues or noninvasively in the feces. These tools and techniques will enable rapid building of engineered bacteria to answer fundamental questions in host-gut microbiota research.

Host-gut microbiota interactions shape parasite infections in farmed Atlantic salmon.

Animals and their associated microbiota share long evolutionary histories. However, it is not always clear how host genotype and microbiota interact to affect phenotype. We applied a hologenomic approach to explore how host-microbiota interactions shape lifetime growth and parasite infection in farmed Atlantic salmon (Salmo salar). Multi-omics data sets were generated from the guts of 460 salmon, 82% of which were naturally infected with an intestinal cestode. A single Mycoplasma bacterial strain, MAG01, dominated the gut metagenome of large, non-parasitized fish, consistent with previous studies showing high levels of Mycoplasma in the gut microbiota of healthy salmon. While small and/or parasitized salmon also had high abundance of MAG01, we observed increased alpha diversity in these individuals, driven by increased frequency of low-abundance Vibrionaceae and other Mycoplasma species that carried known virulence genes. Colonization by one of these cestode-associated Mycoplasma strains was associated with host individual genomic variation in long non-coding RNAs. Integrating the multi-omic data sets revealed coordinated changes in the salmon gut mRNA transcriptome and metabolome that correlated with shifts in the microbiota of smaller, parasitized fish. Our results suggest that the gut microbiota of small and/or parasitized fish is in a state of dysbiosis that partly depends on the host genotype, highlighting the value of using a hologenomic approach to incorporate the microbiota into the study of host-parasite dynamics.IMPORTANCEStudying host-microbiota interactions through the perspective of the hologenome is gaining interest across all life sciences. Intestinal parasite infections are a huge burden on human and animal health; however, there are few studies investigating the role of the hologenome during parasite infections. We address this gap in the largest multi-omics fish microbiota study to date using natural cestode infection of farmed Atlantic salmon. We find a clear association between cestode infection, salmon lifetime growth, and perturbation of the salmon gut microbiota. Furthermore, we provide the first evidence that the genetic background of the host may partly determine how the gut microbiota changes during parasite-associated dysbiosis. Our study therefore highlights the value of a hologenomic approach for gaining a more in-depth understanding of parasitism.

Meta-analysis reveals obesity associated gut microbial alteration patterns and reproducible contributors of functional shift

ABSTRACT The majority of cohort-specific studies associating gut microbiota with obesity are often contradictory; thus, the replicability of the signature remains questionable. Moreover, the species that drive obesity-associated functional shifts and their replicability remain unexplored. Thus, we aimed to address these questions by analyzing gut microbial metagenome sequencing data to develop an in-depth understanding of obese host-gut microbiota interactions using 3329 samples (Obese, n = 1494; Control, n = 1835) from 17 different countries, including both 16S rRNA gene and metagenomic sequence data. Fecal metagenomic data from diverse geographical locations were curated, profiled, and pooled using a machine learning-based approach to identify robust global signatures of obesity. Furthermore, gut microbial species and pathways were systematically integrated through the genomic content of the species to identify contributors to obesity-associated functional shifts. The community structure of the obese gut microbiome was evaluated, and a reproducible depletion of diversity was observed in the obese compared to the lean gut. From this, we infer that the loss of diversity in the obese gut is responsible for perturbations in the healthy microbial functional repertoire. We identified 25 highly predictive species and 37 pathway associations as signatures of obesity, which were validated with remarkably high accuracy (AUC, Species: 0.85, and pathway: 0.80) with an independent validation dataset. We observed a reduction in short-chain fatty acid (SCFA) producers (several Alistipes species, Odoribacter splanchnicus, etc.) and depletion of promoters of gut barrier integrity (Akkermansia muciniphila and Bifidobacterium longum) in obese guts. Our analysis underlines SCFAs and purine/pyrimidine biosynthesis, carbohydrate metabolism pathways in control individuals, and amino acid, enzyme cofactor, and peptidoglycan biosynthesis pathway enrichment in obese individuals. We also mapped the contributors to important obesity-associated functional shifts and observed that these are both dataset-specific and shared across the datasets. In summary, a comprehensive analysis of diverse datasets unveils species specifically contributing to functional shifts and consistent gut microbial patterns associated to obesity.

Nourishing the gut: the impact of diet on host-gut microbiota interaction.

Understanding the spectrum of drivers that influence the gut microbiome (GM) remains a crucial field of investigation. Among these factors, diet has received particular attention, as it could explain up to 20% of the variability in GM composition between individuals. This review focuses on the complex relationships between different dietary patterns and GM in humans, based on recent findings. Current evidence underscores the multifaceted impact of diet on GM richness, diversity, and overall composition. Key contributing factors encompass dietary habits, nutritional interventions, food quality and variety, macronutrient distribution, timing of feeding, and selective exclusion of certain foods. The intricate interplay between diet and GM is of fundamental importance in shaping the interaction between the host and the environment. Further understanding the causal impact of diet on GM has promising potential for the advancement of strategies to promote health and mitigate cardio-metabolic disease risks through dietary interventions. http://links.lww.com/COCN/A21.

Integrated multi-omics approach reveals novel associations in the rapeseed diet-microbiota-host axis in pigs.

Diet-mediated host-microbiota interplay is a key factor in optimizing the gut function and overall health of the host. Gaining insight into the biological mechanisms behind this relationship is fundamental to finding sustainable, environment-friendly feed solutions in livestock production systems. Here, we apply a multi-omics integration approach to elucidate sustainable diet-associated host-gut microbiota interactions in pigs and we demonstrate novel and biologically relevant host-microbe associations in the gut, driven by a rapeseed meal-based feed (RSF). Interestingly, RSF-diet promoted the abundance of segmented filamentous bacteria Candidatus Arthromitus that was associated with the maintenance of mucosal immunity in the ileum of pigs. In the colon, RSF diet affected host mRNA splicing functions, which may result in different host gene products, through host-microbiota associations, particularly with the Faecalibacterium population, and through the interaction of dietary components such as sinapic acid with the host cells. Moreover, telomere maintenance and organization functions that may determine the overall health of the host were upregulated and notably associated with Subdoligranulum population in the colon of RSF diet-fed pigs. This integrative multi-omics approach provides more insight into the diet-microbiota-host axis, and a better understanding of mechanisms and opportunities to find new strategies for modulating host health and potentially improving caloric and nutritional efficiency in animal production.

The difference and variation of gut bacterial community and host physiology can support adaptation during and after overwintering in frog population.

The hibernation of amphibians can offer a unique window into overwintering adaptation processes and host-gut microbiota interactions through changes in metabolic availability and homeostasis. We attempted to identify differences in the physiology and gut microbiome during and after hibernation in Japanese wrinkled frogs (Glandirana rugosa), an aquatic overwintering amphibian. After hibernation, the high alpha and beta diversity of the gut bacterial community appears to reflect the more diverse and complex environmental conditions. During winter, Proteobacteria dominated the majority of the gut bacterial community, likely due to high oxygen saturation. After hibernation, Firmicutes and Bacteroidetes increased, which are supportive of host metabolism by gut microbiota. Corticosterone also showed high values and variances after hibernation, presumably allowing the population to remain adaptable across a broad range of environmental gradients. Innate immunity was high after hibernation but exhibited low variation among populations, which supports the idea of a prioritized investment in immunity after hibernation. Blood biochemistry suggests that aquatic overwintering frogs have a mechanism to adapt through overhydration and regulate homeostasis through water excretion associated with the kidney and urine after hibernation. Frog populations exhibit variations and adaptability in gut microbiota and physiology during and after hibernation: Through this, they may demonstrate an adaptive response that regulates metabolic availability in preparation for unpredictable environmental changes. We also propose that the maintenance of Proteobacteria during hibernation can support the colonization of Firmicutes and Bacteroidetes after hibernation, underscoring the need to study the complex effects of gut microbiota across multiple life stages.

Host-gut microbiota interactions during pregnancy.

Mammalian pregnancy is characterized by a well-known suite of physiological changes that support fetal growth and development, thereby positively affecting both maternal and offspring fitness. However, mothers also experience trade-offs between current and future maternal reproductive success, and maternal responses to these trade-offs can result in mother-offspring fitness conflicts. Knowledge of the mechanisms through which these trade-offs operate, as well as the contexts in which they operate, is critical for understanding the evolution of reproduction. Historically, hormonal changes during pregnancy have been thought to play a pivotal role in these conflicts since they directly and indirectly influence maternal metabolism, immunity, fetal growth and other aspects of offspring development. However, recent research suggests that gut microbiota may also play an important role. Here, we create a foundation for exploring this role by constructing a mechanistic model linking changes in maternal hormones, immunity and metabolism during pregnancy to changes in the gut microbiota. We posit that marked changes in hormones alter maternal gut microbiome composition and function both directly and indirectly via impacts on the immune system. The gut microbiota then feeds back to influence maternal immunity and metabolism. We posit that these dynamics are likely to be involved in mediating maternal and offspring fitness as well as trade-offs in different aspects of maternal and offspring health and fitness during pregnancy. We also predict that the interactions we describe are likely to vary across populations in response to maternal environments. Moving forward, empirical studies that combine microbial functional data and maternal physiological data with health and fitness outcomes for both mothers and infants will allow us to test the evolutionary and fitness implications of the gestational microbiota, enriching our understanding of the ecology and evolution of reproductive physiology.

Melatonin as a Mediator of the Gut Microbiota-Host Interaction: Implications for Health and Disease.

In recent years, the role played by melatonin on the gut microbiota has gained increasingly greater attention. Additionally, the gut microbiota has been proposed as an alternative source of melatonin, suggesting that this antioxidant indoleamine could act as a sort of messenger between the gut microbiota and the host. This review analyses the available scientific literature about possible mechanisms involved in this mediating role, highlighting its antioxidant effects and influence on this interaction. In addition, we also review the available knowledge on the effects of melatonin on gut microbiota composition, as well as its ability to alleviate dysbiosis related to sleep deprivation or chronodisruptive conditions. The melatonin-gut microbiota relationship has also been discussed in terms of its role in the development of different disorders, from inflammatory or metabolic disorders to psychiatric and neurological conditions, also considering oxidative stress and the reactive oxygen species-scavenging properties of melatonin as the main factors mediating this relationship.

Human Intestinal Organoids and Microphysiological Systems for Modeling Radiotoxicity and Assessing Radioprotective Agents.

Radiotherapy is a commonly employed treatment for colorectal cancer, yet its radiotoxicity-related impact on healthy tissues raises significant health concerns. This highlights the need to use radioprotective agents to mitigate these side effects. This review presents the current landscape of human translational radiobiology, outlining the limitations of existing models and proposing engineering solutions. We delve into radiotherapy principles, encompassing mechanisms of radiation-induced cell death and its influence on normal and cancerous colorectal cells. Furthermore, we explore the engineering aspects of microphysiological systems to represent radiotherapy-induced gastrointestinal toxicity and how to include the gut microbiota to study its role in treatment failure and success. This review ultimately highlights the main challenges and future pathways in translational research for pelvic radiotherapy-induced toxicity. This is achieved by developing a humanized in vitro model that mimics radiotherapy treatment conditions. An in vitro model should provide in-depth analyses of host-gut microbiota interactions and a deeper understanding of the underlying biological mechanisms of radioprotective food supplements. Additionally, it would be of great value if these models could produce high-throughput data using patient-derived samples to address the lack of human representability to complete clinical trials and improve patients' quality of life.

Toxic effect of Cd burden on the gut microflora and immune responses of wolf spider Pardosa pseudoannulata

Spiders are dominant predators in the paddy ecosystem, but the immunotoxicity induced by environmental contaminants like heavy metals is still largely unknown. The gut microbiota-host interaction was the basic immune mechanism discovered in the arthropods. Here, we investigated the gut microflora and immune responses of wolf spider Pardosa pseudoannulata under Cd burden. Cd exposure was identified to shape the gut microbial community structure of spiders, with increased levels of Firmicutes and pathogens, and decreased levels of Proteobacteria and Bacteroidota. The alteration of microbiota-derived immune messengers like peptidoglycan (PGN) was also observed. ELISA and hemolymph metabolomic analysis showed that the activities of immune effectors phenoloxidase (PO) and lysozyme (LZM) and the abundance of tyrosine derivates were decreased, which indicated the suppression of Cd on the melanization immune response of spiders. Correlation analysis revealed a close relationship between the impaired immune system and the disordered microbiota. This study provides insight into the underlying mechanisms of the gut microflora-immune system interaction of P. pseudoannulata in response to Cd burden.

Targeting Desulfovibrio vulgaris flagellin-induced NAIP/NLRC4 inflammasome activation in macrophages attenuates ulcerative colitis

IntroductionThe perturbations of gut microbiota could interact with excessively activated immune responses and play key roles in the etiopathogenesis of ulcerative colitis (UC). Desulfovibrio, the most predominant sulfate reducing bacteria (SRB) resided in the human gut, was observed to overgrow in patients with UC. The interactions between specific gut microbiota and drugs and their impacts on UC treatment have not been demonstrated well. ObjectivesThis study aimed to elucidate whether Desulfovibrio vulgaris (D. vulgaris, DSV) and its flagellin could activate nucleotide-binding oligomerization domain-like receptors (NLR) family of apoptosis inhibitory proteins (NAIP) / NLR family caspase activation and recruitment domain-containing protein 4 (NLRC4) inflammasome and promote colitis, and further evaluate the efficacy of eugeniin targeting the interaction interface of D. vulgaris flagellin (DVF) and NAIP to attenuate UC. MethodsThe abundance of DSV and the occurrence of macrophage pyroptosis in human UC tissues were investigated. Colitis in mice was established by dextran sulfate sodium (DSS) and gavaged with DSV or its purified flagellin. NAIP/NLRC4 inflammasome activation and macrophage pyroptosis were evaluated in vivo and in vitro. The effects of eugeniin on blocking the interaction of DVF and NAIP/NLRC4 and relieving colitis were also assessed. ResultsThe abundance of DSV increased in the feces of patients with UC and was found to be associated with disease activity. DSV and its flagellin facilitated DSS-induced colitis in mice. Mechanistically, RNA sequencing showed that gene expression associated with inflammasome complex and pyroptosis was upregulated after DVF treatment in macrophages. DVF was further demonstrated to induce significant macrophage pyroptosis in vitro, depending on NAIP/NLRC4 inflammasome activation. Furthermore, eugeniin was screened as an inhibitor of the interface between DVF and NAIP and successfully alleviated the proinflammatory effect of DVF in colitis. ConclusionTargeting DVF-induced NAIP/NLRC4 inflammasome activation and macrophage pyroptosis ameliorates UC. This finding is of great significance for exploring the gut microbiota-host interactions in UC development and providing new insights for precise treatment.

NAD+ Precursors in Human Health and Disease: Current Status and Future Prospects.

Significance: Nicotinamide adenine dinucleotide (NAD+) acts as a cofactor in many important biological processes. The administration of NAD+ precursors increases the intracellular NAD+ pool and has beneficial effects on physiological changes and diseases associated with aging in various organisms, including rodents and humans. Recent Advances: Evidence from preclinical studies demonstrating the beneficial effects of NAD+ precursors has rapidly increased in the last decade. The results of these studies have prompted the development of clinical trials using NAD+ precursors, particularly nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). In addition, in vivo studies of NAD+ metabolism have rapidly progressed. Critical Issues: Several studies have demonstrated that the oral administration of NAD+ precursors, such as NR and NMN, is safe and significantly increases NAD+ levels in humans. However, the efficacy of these NAD+ precursors is lower than expected from the results of preclinical studies. In addition, the identification of the contribution of the host-gut microbiota interactions to NR and NMN metabolism has added to the complexity of NAD+ metabolism. Future Directions: Further studies are required to determine the efficacy of NAD+ precursors in humans. Further in vivo studies of NAD+ metabolism are required to optimize the effects of NAD+ supplementation. There is also a need for methods of delivering NAD+ precursors to target organs or tissues to increase the outcomes of clinical trials. Antioxid. Redox Signal. 39, 1133-1149.

High-fat diet-disturbed gut microbiota-colonocyte interactions contribute to dysregulating peripheral tryptophan-kynurenine metabolism

BackgroundAberrant tryptophan (Trp)-kynurenine (Kyn) metabolism has been implicated in the pathogenesis of human disease. In particular, populations with long-term western-style diets are characterized by an excess of Kyn in the plasma. Host-gut microbiota interactions are dominated by diet and are essential for maintaining host metabolic homeostasis. However, the role of western diet-disturbed gut microbiota-colonocyte interactions in Trp metabolism remains to be elucidated.ResultsHere, 4-week-old mice were fed with a high-fat diet (HFD), representing a typical western diet, for 4 weeks, and multi-omics approaches were adopted to determine the mechanism by which HFD disrupted gut microbiota-colonocyte interplay causing serum Trp-Kyn metabolism dysfunction. Our results showed that colonocyte-microbiota interactions dominated the peripheral Kyn pathway in HFD mice. Mechanistically, persistent HFD-impaired mitochondrial bioenergetics increased colonic epithelial oxygenation and caused metabolic reprogramming in colonites to support the expansion of Proteobacteria in the colon lumen. Phylum Proteobacteria-derived lipopolysaccharide (LPS) stimulated colonic immune responses to upregulate the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to Trp depletion and Kyn accumulation in the circulation, which was further confirmed by transplantation of Escherichia coli (E.coli) indicator strains and colonic IDO1 depletion. Butyrate supplementation promoted mitochondrial functions in colonocytes to remodel the gut microbiota in HFD mice, consequently ameliorating serum Kyn accumulation.ConclusionsOur results highlighted that HFD disrupted the peripheral Kyn pathway in a gut microbiota-dependent manner and that the continuous homeostasis of gut bacteria-colonocytes interplay played a central role in the regulation of host peripheral Trp metabolism. Meanwhile, this study provided new insights into therapies against western diet-related metabolic disorders.24aEGHfcpJRSeLcqMKL4VcVideo

Deletion of hepatic growth hormone receptor (GHR) alters the mouse gut microbiota by affecting bile acid metabolism

ABSTRACT Both growth hormone (GH) and gut microbiota play significant roles in diverse physiological processes, but the crosstalk between them is poorly understood. Despite the regulation of GH by gut microbiota, study on GH’s influence on gut microbiota is limited, especially on the impacts of tissue specific GH signaling and their feedback effects on the host. In this study, we profiled gut microbiota and metabolome in tissue-specific GHR knockout mice in the liver (LKO) and adipose tissue (AKO). We found that GHR disruption in the liver rather than adipose tissue affected gut microbiota. It changed the abundance of Bacteroidota and Firmicutes at phylum level as well as abundance of several genera, such as Lactobacillus, Muribaculaceae, and Parasutterella, without affecting α-diversity. Moreover, the impaired liver bile acid (BA) profile in LKO mice was strongly associated with the change of gut microbiota. The BA pools and 12-OH BAs/non-12-OH BAs ratio were increased in the LKO mice, which was due to the induction of CYP8B1 by hepatic Ghr knockout. Consequently, the impaired BA pool in cecal content interacted with gut bacteria, which in turn increased the production of bacteria derived acetic acid, propionic acid, and phenylacetic acid that were possible to participate in the impaired metabolic phenotype of the LKO mice. Collectively, our findings suggested that the liver GH signaling regulates BA metabolism by its direct regulation on CYP8B1, which is an important factor influencing gut microbiota. Our study is significant in exploring gut microbiota modification effects of tissue-specific GH signaling as well as its involvement in gut microbiota–host interaction.

Digested Cinnamon (Cinnamomum verum J. Presl) Bark Extract Modulates Claudin-2 Gene Expression and Protein Levels under TNFα/IL-1β Inflammatory Stimulus.

Epigenetic changes, host-gut microbiota interactions, and environmental factors contribute to inflammatory bowel disease (IBD) onset and progression. A healthy lifestyle may help to slow down the chronic or remitting/relapsing intestinal tract inflammation characteristic of IBD. In this scenario, the employment of a nutritional strategy to prevent the onset or supplement disease therapies included functional food consumption. Its formulation consists of the addition of a phytoextract enriched in bioactive molecules. A good candidate as an ingredient is the Cinnamon verum aqueous extract. Indeed, this extract, subjected to a process of gastrointestinal digestion simulation (INFOGEST), exhibits beneficial antioxidant and anti-inflammatory properties in an in vitro model of the inflamed intestinal barrier. Here, we deepen the study of the mechanisms related to the effect of digested cinnamon extract pre-treatment, showing a correlation between transepithelial electrical resistance (TEER) decrement and alterations in claudin-2 expression under Tumor necrosis factor-α/Interleukin-1β (TNF-α/IL-1) β cytokine administration. Our results show that pre-treatment with cinnamon extract prevents TEER loss by claudin-2 protein level regulation, influencing both gene transcription and autophagy-mediated degradation. Hence, cinnamon polyphenols and their metabolites probably work as mediators in gene regulation and receptor/pathway activation, leading to an adaptive response against renewed insults.

Gut Microbiota and Cardiovascular Disease: Evidence on the Metabolic and Inflammatory Background of a Complex Relationship.

Several studies in recent years have demonstrated that gut microbiota-host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematous, but also to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. The ways the microbiota is involved in modulating cardiovascular risk are multiple and not only related to inflammatory mechanisms. Indeed, human and the gut microbiome cooperate as a metabolically active superorganism, and this affects host physiology through metabolic pathways. In turn, congestion of the splanchnic circulation associated with heart failure, edema of the intestinal wall, and altered function and permeability of the intestinal barrier result in the translocation of bacteria and their products into the systemic circulation, further enhancing the pro-inflammatory conditions underlying cardiovascular disorders. The aim of the present review is to describe the complex interplay between gut microbiota, its metabolites, and the development and evolution of cardiovascular diseases. We also discuss the possible interventions intended to modulate the gut microbiota to reduce cardiovascular risk.

Integrative multi-omics deciphers the spatial characteristics of host-gut microbiota interactions in Crohn’s disease

Dysregulated host-microbial interactions play critical roles in initiation and perpetuation of gut inflammation in Crohn's disease (CD). However, the spatial distribution and interaction network across the intestine and its accessory tissues are still elusive. Here, we profile the host proteins and tissue microbes in 540 samples from the intestinal mucosa, submucosa-muscularis-serosa, mesenteric adipose tissues, mesentery, and mesenteric lymph nodes of 30 CD patients and spatially decipher the host-microbial interactions. We observe aberrant antimicrobial immunity and metabolic processes across multi-tissues during CD and determine bacterial transmission along with altered microbial communities and ecological patterns. Moreover, we identify several candidate interaction pairs between host proteins and microbes associated with perpetuation of gut inflammation and bacterial transmigration across multi-tissues in CD. Signature alterations in host proteins (e.g., SAA2 and GOLM1) and microbes (e.g., Alistipes and Streptococcus) are further imprinted in serum and fecal samples as potential diagnostic biomarkers, thus providing a rationale for precision diagnosis.

Interactions of Nanomaterials with Gut Microbiota and Their Applications in Cancer Therapy.

Cancer treatment is a challenge by its incredible complexity. As a key driver and player of cancer, gut microbiota influences the efficacy of cancer treatment. Modalities to manipulate gut microbiota have been reported to enhance antitumor efficacy in some cases. Nanomaterials (NMs) have been comprehensively applied in cancer diagnosis, imaging, and theranostics due to their unique and excellent properties, and their effectiveness is also influenced by gut microbiota. Nanotechnology is capable of targeting and manipulating gut microbiota, which offers massive opportunities to potentiate cancer treatment. Given the complexity of gut microbiota-host interactions, understanding NMs-gut interactions and NMs-gut microbiota interactions are important for applying nanotechnologies towards manipulating gut microbiota in cancer prevention and treatment. In this review, we provide an overview of NMs-gut interactions and NMs-gut microbiota interactions and highlight the influences of gut microbiota on the diagnosis and treatment effects of NMs, further illustrating the potential of nanotechnologies in cancer therapy. Investigation of the influences of NMs on cancer from the perspective of gut microbiota will boost the prospect of nanotechnology intervention of gut microbiota for cancer therapy.

Abstract 6224: Exploring the integration of CMS subtyping and other omics in colorectal cancer classification and its reflection in stool miRNome and metagenome for non-invasive precision medicine

Abstract Background: The Consensus Molecular Subtypes (CMS) is a subtyping system used for colorectal cancer (CRC) to facilitate traditional tumor classification and clinical translation. Relying on RNA-seq data, the system classifies patients into four molecular subtypes (CMS 1-4). Each subtype is enriched with several mutations, but no genetic aberrations are peculiar to a single CMS. A more in-depth characterization of each subtype's genomic and epigenomic background by integrating different omics may help in refining this classification, including the missing assignment of a subgroup of tumors. The possible translation of this improved classification to surrogate tissues, such as stool, has never been investigated. Aims: We aim to comprehensively characterize the CMS by the integrative analysis of target genomic sequencing, RNA-Seq, small RNA-Seq, and immune infiltrate profiling data of a cohort of CRC patients. These data will be used to identify integrative CMS-specific signatures and to characterize those tumors not assigned to any CMS. In addition, differences in stool miRNome and metagenomic profiles will be explored to identify potential specific signatures characterizing each subtype. Methods: Tumor tissue and adjacent mucosa were collected from 87 CRC patients and preserved in RNA later. mRNA and other non-coding RNA expression levels were evaluated with ribosomal depleted RNA-seq and small RNA-seq. Tumors were assigned to a CMS subtype using the CMScaller algorithm and genomically characterized with the TruSight Oncology 500 (TSO500) cancer panel. Differential expression analyses were performed using the DESeq2 package for the R software to identify CMS-specific expression signatures. Small RNA-seq and shotgun metagenomic analyses were performed on stool samples collected from the same patients. Preliminary Results: Tumors were assigned to CMS1 (n=9), CMS2 (n=24), CMS3 (n=26), and CMS4 (n=22), except for six samples. Differential expression analyses between paired tumor samples and adjacent mucosa within each CMS revealed 1096 differentially expressed genes in CMS1, 4218 in CMS2, 27 in CMS3 and 190 in CMS4. From the genomic point of view, CMS3 cases showed 384 unique missense variants, while CMS1 included almost all samples with microsatellite instability. Small RNA-seq on the same tissue sample identified 380 dysregulated miRNAs (215 up and 165 downregulated) in the tumor compared to adjacent mucosa. Conclusions: A more in-depth CMS subtyping by integrating different omics analyses could help refine this classification system. Moreover, the possible CMS reflection in stool miRNome and metagenomic could shed new light on the host gut-microbiota interactions and allow a non-invasive classification applicable for a routine personalized clinical management of CRC. Citation Format: Amedeo Gagliardi, Giulia Francesca, Giulio Ferrero, Sonia Tarallo, Giulia Piaggeschi, Antonio Francavilla, Carla Di Battista, Enrico Berrino, Caterina Marchiò, Francesca Cordero, Barbara Pardini, Alessio Naccarati. Exploring the integration of CMS subtyping and other omics in colorectal cancer classification and its reflection in stool miRNome and metagenome for non-invasive precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6224.