Numerous studies have accelerated the knowledge expansion on the role of gut microbiota in inflammatory bowel disease (IBD). However, the precise mechanisms behind host-microbe cross-talk remain largely undefined, due to the complexity of the human intestinal ecosystem and multiple external factors. In this review, we introduce the interactome concept to systematically summarize how intestinal dysbiosis is involved in IBD pathogenesis in terms of microbial composition, functionality, genomic structure, transcriptional activity, and downstream proteins and metabolites. Meanwhile, this review also aims to present an updated overview of the relevant mechanisms, high-throughput multi-omics methodologies, different types of multi-omics cohort resources, and computational methods used to understand host-microbiota interactions in the context of IBD. Finally, we discuss the challenges pertaining to the integration of multi-omics data in order to reveal host-microbiota cross-talk and offer insights into relevant future research directions.

The gut microbiota undergoes continuous variations among individuals and across their lifespan, shaped by diverse factors encompassing diet, age, lifestyle choices, medication intake, and disease states. These microbial inhabitants play a pivotal role in orchestrating physiological metabolic pathways through the production of metabolites like bile acids, choline, short-chain fatty acids, and neurotransmitters, thereby establishing a dynamic "gut-organ axis" with the host. The intricate interplay between the gut microbiota and the host is indispensable for gut health, and RNA N6-methyladenosine modification, a pivotal epigenetic mark on RNA, emerges as a key player in this process. M6A modification, the most prevalent internal modification of eukaryotic RNA, has garnered significant attention in the realm of RNA epigenetics. Recent findings underscore its potential to influence gut microbiota diversity and intestinal barrier function by modulating host gene expression patterns. Conversely, the gut microbiota, through its impact on the epigenetic landscape of host cells, may indirectly regulate the recruitment and activity of RNA m6A-modifying enzymes. This review endeavors to delve into the biological functions of m6A modification and its consequences on intestinal injury and disease pathogenesis, elucidating the partial possible mechanisms by which the gut microbiota and its metabolites maintain host intestinal health and homeostasis. Furthermore, it also explores the intricate crosstalk between them in intestinal injury, offering a novel perspective that deepens our understanding of the mechanisms underlying intestinal diseases.

Microbial genome-wide association studies (GWAS) have uncovered numerous host genetic variants associated with gut microbiota. However, links between host genetics, the gut microbiome and specific cellular contexts remain unclear. Here we use a computational framework, scBPS (single-cell Bacteria Polygenic Score), to integrate existing microbial GWAS and single-cell RNA-sequencing profiles of 24 human organs, including the liver, pancreas, lung and intestine, to identify host tissues and cell types relevant to gut microbes. Analysing 207 microbial taxa and 254 host cell types, scBPS-inferred cellular enrichments confirmed known biology such as dominant communications between gut microbes and the digestive tissue module and liver epithelial cell compartment. scBPS also identified a robust association between Collinsella and the central-veinal hepatocyte subpopulation. We experimentally validated the causal effects of Collinsella on cholesterol metabolism in mice through single-nuclei RNA sequencing on liver tissue to identify relevant cell subpopulations. Mechanistically, oral gavage of Collinsella modulated cholesterol pathway gene expression in central-veinal hepatocytes. We further validated our approach using independent microbial GWAS data, alongside single-cell and bulk transcriptomic analyses, demonstrating its robustness and reproducibility. Together, scBPS enables a systematic mapping of the host-microbe crosstalk by linking cell populations to their interacting gut microbes.

This article provides an overview of the advancements in the application of fecal microbiota transplantation (FMT) in treating diseases related to intestinal dysbiosis. FMT involves the transfer of healthy donor fecal microbiota into the patient's body, aiming to restore the balance of intestinal microbiota and thereby treat a variety of intestinal diseases such as recurrent Clostridioides difficile infection (rCDI), inflammatory bowel disease (IBD), constipation, short bowel syndrome (SBS), and irritable bowel syndrome (IBS). While FMT has shown high efficacy in the treatment of rCDI, further research is needed for its application in other chronic conditions. This article elaborates on the application of FMT in intestinal diseases and the mechanisms of intestinal dysbiosis, as well as discusses key factors influencing the effectiveness of FMT, including donor selection, recipient characteristics, treatment protocols, and methods for assessing microbiota. Additionally, it emphasizes the key to successful FMT. Future research should focus on optimizing the FMT process to ensure long-term safety and explore the potential application of FMT in a broader range of medical conditions.

The intestinal microbiota is important for the health of the host and recent studies have shown that some genes of the host regulated the composition of the intestinal microbiota. Group 10 phospholipase A2 (PLA2G10) is a member of the lipolytic enzyme family PLA2, which hydrolyze the ester bond at the sn-2 position of phospholipids to produce free fatty acids and lysophospholipids. PLA2G10 is secreted into the intestinal lumen, but its impact on the gut microbiota remains unclear. In this study, we generated intestine-specific Pla2g10 knock-in mice, and used 16S RNA sequencing to compare their gut microbiota with that of their wild-type (WT) littermates. Results showed that gut-specific Pla2g10 knock-in induced both PLA2G10 mRNA and protein levels in the colon. Moreover, intestinal Pla2g10 overexpression reduced the α-diversity of the gut microbiota relative to that of WT mice. The abundance of Bacteroidetes was lower in the Pla2g10 knock-in mice than that in the control mice, while the ratio of Firmicutes/Bacteroidetes was higher. Furthermore, the abundance of the genus Allobaculum was reduced, whereas the abundance of beneficial bacteria genera, including Enterorhabdus, Dubosiella, and Lactobacillus, was increased by host intestinal Pla2g10 overexpression. In summary, intestinal Pla2g10 overexpression increased the proportions of beneficial bacterial in the colonic chyme of mice, providing a potential therapeutic target for future improvement of the gut microbiota.

The gut microbiota actually shares the host's physical space and affects the host's physiological functions and health indicators through a complex network of interactions with the host. However, its role as a determinant of host health and disease is often underestimated. With the emergence of new technologies including next-generation sequencing (NGS) and advanced techniques such as microbial community sequencing, people have begun to explore the interaction mechanisms between microorganisms and hosts at various omics levels such as genomics, transcriptomics, metabolomics, and proteomics. With the enrichment of multi-omics integrated analysis methods based on the microbiome, an increasing number of complex statistical analysis methods have also been proposed. In this review, we summarized the multi-omics research analysis methods currently used to study the interaction between the microbiome and the host. We analyzed the advantages and limitations of various methods and briefly introduced their application progress.

Central precocious puberty (CPP) is an endocrine disease in children, characterized by rapid genital development and secondary sexual characteristics before the age of eight in girls and nine in boys. The premature activation of the hypothalamic-pituitary-gonadal axis (HPGA) limits the height of patients in adulthood and is associated with a higher risk of breast cancer. How to prevent and improve the prognosis of CPP is an important problem. Vitamin D receptor (VDR) is widely expressed in the reproductive system, participates in the synthesis and function of regulatory sex hormones, and affects the development and function of gonads. In addition, gut microbiota plays an important role in human health by mainly regulating metabolites, energy homeostasis, and hormone regulation. This review aims to clarify the effect of vitamin D deficiency on the occurrence and development of CPP and explore the role of gut microbiota in it. Although evidence on the interaction between vitamin D deficiency, gut microbiota, and sexual development remains limited, vitamin D supplementation and gut microbiota interventions offer a promising, non-invasive strategy for managing CPP.

Colorectal cancer (CRC) is a major public health problem worldwide, currently ranking third in cancer incidence and second in mortality. Multiple genes and environmental factors have been involved in the complex and multifactorial process of CRC carcinogenesis. VDR is an intracellular hormone receptor expressed in both normal epithelial and cancer colon cells at various levels. Several VDR gene polymorphisms, including FokI and BsmI, have been evaluated for their possible association with CRC susceptibility. The aim of our study was to investigate these two SNPs for the first time in Romanian CRC patients. FokI (rs228570 C>T) and BsmI (rs1544410 A>G) were genotyped by real-time polymerase chain reaction (RT-PCR) in 384-well plates using specific TaqMan predesigned probes on a ViiA™ 7 RT-PCR System. A total of 441 subjects (166 CRC patients and 275 healthy controls) were included. No statistically significant difference was observed between CRC patients and controls when we compared the wild-type genotype with heterozygous and mutant genotypes for both FokI (OR 0.85, 95% CI: 0.56-1.28; OR 0.95, 95% CI: 0.51-1.79, respectively) and BsmI (OR 0.97, 95% CI: 0.63-1.49; OR 1.10, 95% CI: 0.65-1.87, respectively) or in the dominant and recessive models. Also, we compared allele frequencies, and no correlation was found. Moreover, the association between these SNPs and the tumor site, TNM stage, and histological type was examined separately, and there was no statistically significant difference. In conclusion, our study did not show any association between FokI and BsmI SNPs and CRC susceptibility in a Romanian population. Further studies including a larger number of samples are needed to improve our knowledge regarding the influence of VDR polymorphism on CRC susceptibility.

Evidence indicates that both vitamin D and the gut microbiome are involved in the process of colon carcinogenesis. However, it is unclear what effects supplemental vitamin D3 has on the gut microbiome and its metabolites in healthy adults. We conducted a double-blind, randomized, placebo-controlled trial to identify the acute and long-term microbiota structural and metabolite changes that occur in response to a moderate dose (4,000 IU) of vitamin D3 for 12 weeks in healthy adults. Our results demonstrated a significant increase in serum 25-hydroxy-vitamin D (25(OH)D) in the treatment group compared to placebo (P < 0.0001). Vitamin D3 significantly increased compositional similarity (P < 0.0001) in the treatment group, and enriched members of the Bifidobacteriaceae family. We also identified a significant inverse relationship between the percent change in serum 25(OH)D and microbial stability in the treatment group (R = -0.52, P < 0.019). Furthermore, vitamin D3 supplementation resulted in notable metabolic shifts, in addition to resulting in a drastic rewiring of key gut microbial-metabolic associations. In conclusion, we show that a moderate dose of vitamin D3 among healthy adults has unique acute and persistent effects on the fecal microbiota, and suggest novel mechanisms by which vitamin D may affect the host-microbiota relationship.

Preventative measures to reduce the rise in early-onset colorectal cancer are of critical need. Both vitamin D, dietary and serum levels, and the gut microbiome are implicated in the etiology of colorectal cancer. By understanding the intimate relationship between vitamin D, the gut microbiome, and its metabolites, we may be able to identify key mechanisms that can be targeted for intervention, including inflammation and metabolic dysfunction. Furthermore, the similarity of vitamin D to cholesterol, which is metabolized by the gut microbiome, gives precedence to its ability to produce metabolites that can be further studied and leveraged for controlling colorectal cancer incidence and mortality.

Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.

Background: The aim is to assess the association between the level of vitamin D, maternal diseases, and macrosomia in newborns. Methods: This study included 258 full-term newborns (86 newborns with macrosomia; and 172 newborns with normal weight). Enzyme immunoassays for the determination of vitamin D were performed. Results: Newborns with macrosomia were statistically significantly more likely to have severe vitamin D deficiency compared with control (13.5 ± 6.7 ng/mL vs. 21.3 ± 12.1 ng/mL; p < 0.05). In the main group, severe deficiency was found in 40.7% of newborns, in the control group this rate was 5.8% (χ2 = 71,788, df = 3, p < 0.001). Multiple regression analysis shows that statistically significant risk factors for the development of macrosomia were vitamin D deficiency in the cord blood (OR = 2.29), maternal age over 36 years old (OR = 19.54), and hypothyroidism (OR = 9.35). Conclusion: the results of our study demonstrate relationship between macrosomia in newborns and vitamin D deficiency in the cord blood, maternal overweight and obesity, maternal age and thyroid disease.

The VDR gene is identified as a crucial host factor, influencing the gut microbiota. The current research focuses on an observational study that compares gut microbiota composition among individuals with different VDR gene TaqI polymorphisms in a Caucasian Spanish population. This study aims to elucidate the interplay between genetic variations in the VDR gene and the gut microbial composition.

87 healthy participants (57 men, 30 women), aged 18 to 48 years, were examined. Anthropometric measures, body composition, and dietary habits were assessed. VDR gene polymorphism TaqI rs731236 was determined using TaqMan assays. The V3 and V4 regions of the 16S rRNA gene were sequenced to study bacterial composition, which was analyzed using QIIME2, DADA2 plugin, and PICRUSt2. Statistical analyses included tests for normal distribution, alpha/beta diversity, ADONIS, LEfSe, and DESeq2, with established significance thresholds.

No significant differences in body composition or dietary habits were observed based on VDR genotypes. Dietary intake analysis revealed no variations in energy, macronutrients, or fiber among the different VDR genotypes. Fecal microbiota analysis indicated significant differences in alpha diversity as measured by Faith's Phylogenetic Diversity index. Differential abundance analysis identified taxonomic disparities, notably in the genera Parabacteroides and Butyricimonas.

Overall, this study suggests potential associations between genetic variations in the VDR gene and the composition and function of gut microbiota.

Anorexia nervosa has the highest mortality rate among psychiatric illnesses. Current treatments remain ineffective for a large fraction of patients. This may be due to unclear mechanisms behind its development and maintenance. Studies exploring the role of the gut microbiome have revealed inconsistent evidence of dysbiosis. This article aims to investigate changes in the gut microbiome, particularly, mean differences in the Firmicutes to Bacteroidetes ratio, in adolescent and adult individuals with anorexia nervosa following inpatient treatment.

Longitudinal studies investigating gut microbiome composition in inpatient populations of anorexia nervosa before and after treatment were systematically reviewed. Additionally, gut microbiome compositions were characterized in three acute anorexia nervosa inpatients early after admission and after 4-12 weeks of treatment.

Review results indicated an increase in the Firmicutes to Bacteroidetes ratio in individuals with anorexia nervosa after treatment. These however did not match values of their healthy counterparts. In the case-series samples, the reverse occurred with samples taken 4 weeks after treatment. In the patient who provided an extra sample 12 weeks after treatment, similar results to the studies included in the review were observed. Furthermore, Firmicutes to Bacteroidetes ratio values in the case-series samples were notably higher in the two patients who had chronic anorexia nervosa.

Differences in methodologies, small sample sizes, and insufficient data limited the generalizability of the outcomes of the reviewed studies. Results suggest a potentially unique microbiome signature in individuals with chronic anorexia nervosa, which may explain different outcomes in this group of patients.

Classically, vitamin D is known to regulate skeletal and mineral ion homeostasis [...].

Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk factors for social anxiety exist, it is currently unknown how social fear sensitivity manifests biologically. Furthermore, since some individuals are resilient and others are susceptible to social fear, it is important to interrogate the mechanisms underpinning individual response to social fear situations. The microbiota-gut-brain axis has been associated with social behaviour, has recently been linked with social anxiety disorder, and may serve as a therapeutic target for modulation. Here, we assess the potential of this axis to be linked with social fear extinction processes in a murine model of social anxiety disorder. To this end, we correlated differential social fear responses with microbiota composition, central gene expression, and immune responses. Our data provide evidence that microbiota variability is strongly correlated with alterations in social fear behaviour. Moreover, we identified altered gene candidates by amygdalar transcriptomics that are linked with social fear sensitivity. These include genes associated with social behaviour (Armcx1, Fam69b, Kcnj9, Maoa, Serinc5, Slc6a17, Spata2, and Syngr1), inflammation and immunity (Cars, Ckmt1, Klf5, Maoa, Map3k12, Pex5, Serinc5, Sidt1, Spata2), and microbe-host interaction (Klf5, Map3k12, Serinc5, Sidt1). Together, these data provide further evidence for a role of the microbiota-gut-brain axis in social fear responses.

Colorectal cancer (CRC) is one of the most significant forms of human cancer. It is characterized by its heterogeneity because several molecular factors are involved in contiguity and can link it to others without having a linear correlation. Among the factors influencing tumor transformation in CRC, transforming growth factor-beta (TGF-β) plays a key promoter role. This factor is associated with human colorectal tumors with a very high prognosis: it increases the survival, invasion, and metastasis of CRC cells, thus functioning as an oncogene. The inhibition of this factor can constitute a major therapeutic route for CRC treatment. Various chemical drugs including synthetic molecules and biotherapies have been developed as TGF-β inhibitors. Moreover, the scientific community has recently shown a major interest in screening natural drugs inhibiting TGF-β in CRC. In this context, we carried out this review article using computerized databases, such as PubMed, Google Scholar, Springer Link, Science Direct, Cochrane Library, Embase, Web of Science, and Scopus, to highlight the molecular mechanism of TGF-β in CRC induction and progression and current advances in the pharmacodynamic effects of natural bioactive substances targeting TGF-β in CRC.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, affecting nearly 2 million people worldwide. The etiology of MS is multifactorial: Approximately 30% of the MS risk is genetic, which implies that the remaining ~70% is environmental, with a number of factors proposed. One recently implicated risk factor for MS is the composition of the gut microbiome. Numerous case-control studies have identified changes in gut microbiota composition of people with MS (pwMS) compared with healthy control individuals, and more recent studies in animal models have begun to identify the causative microbes and underlying mechanisms. Here, we review some of these mechanisms, with a specific focus on the role of host genetic variation, dietary inputs, and gut microbial metabolism, with a particular emphasis on short-chain fatty acid and tryptophan metabolism. We put forward a model where, in an individual genetically susceptible to MS, the gut microbiota and diet can synergize as potent environmental modifiers of disease risk and possibly progression, with diet-dependent gut microbial metabolites serving as a key mechanism. We also propose that specific microbial taxa may have divergent effects in individuals carrying distinct variants of MS risk alleles or other polymorphisms, as a consequence of host gene-by-gut microbiota interactions. Finally, we also propose that the effects of specific microbial taxa, especially those that exert their effects through metabolites, are highly dependent on the host dietary intake. What emerges is a complex multifaceted interaction that has been challenging to disentangle in human studies, contributing to the divergence of findings across heterogeneous cohorts with differing geography, dietary preferences, and genetics. Nonetheless, this provides a complex and individualized, yet tractable, model of how the gut microbiota regulate susceptibility to MS, and potentially progression of this disease. Thus, we conclude that prophylactic or therapeutic modulation of the gut microbiome to prevent or treat MS will require a careful and personalized consideration of host genetics, baseline gut microbiota composition, and dietary inputs.

The gut microbiota significantly influences the onset and progression of juvenile idiopathic arthritis (JIA) and associated uveitis (JIAU); however, the causality remains unclear. This study aims to establish a causal link between gut microbiota and JIA or JIAU.

Using publicly available genome-wide association studies (GAWS) summary data, we conducted a two-sample Mendelian randomisation (MR) analysis employing various methods, namely inverse variance weighted (IVW), simple mode, weighted mode, weighted median and MR-Egger regression methods, to assess the causal association between JIA or JIAU and gut microbiota. Sensitivity analyses, including Cochrane's Q test, MR-Egger intercept test, leave-one-out analysis and MR-PRESSO, were performed to evaluate the robustness of the MR results. Subsequently, reverse MR analysis was conducted to determine causality between gene-predicted gut microbiota abundance and JIA or JIAU.

The MR analysis revealed a causal association between gut microbiota abundance variations and JIA or JIAU risk. Specifically, the increased abundance of genus Ruminococcaceae UCG013 (OR: 0.055, 95%CI: 0.006-0.103, p = 0.026) and genus Ruminococcaceae UCG003 (β: 0.06, 95%CI: 0.003-0.117, p = 0.041) correlated with an increased risk of JIA, while genus Lachnospiraceae UCG001 (OR: 0.833, 95%CI: 0.699~0.993, p = 0.042) was associated with a reduced risk of JIA, among others. Sensitivity analysis confirmed MR analysis robustness.

This study provides substantial evidence supporting a causal association between genetically predicted gut microbiota and JIA or JIAU. It highlights the significant role of intestinal flora in JIA or JIAU development, suggesting their potential as novel biomarkers for diagnosis and prevention. These findings offer valuable insights to mitigate the impact of JIA or JIAU.

Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown.

Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements.

During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-users, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality.

Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Immunoglobulins (Ig) reactive with α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, are present in humans and were previously associated with eating disorders. In this longitudinal study involving patients with anorexia nervosa (AN), we determined whether α-MSH in serum is bound to IgG and analyzed long-term dynamics of both α-MSH peptide and α-MSH-reactive Ig in relation to changes in BMI and gut microbiota composition.

The study included 64 adolescents with a restrictive form of AN, whose serum samples were collected at hospital admission, discharge, and during a 1-year follow-up visit and 41 healthy controls, all females.

We found that in both study groups, approximately 40% of serum α-MSH was reversibly bound to IgG and that levels of α-MSH-reactive IgG but not of α-MSH peptide in patients with AN were low at hospital admission but recovered 1 year later. Total IgG levels were also low at admission. Moreover, BMI-standard deviation score correlated positively with α-MSH IgG in both groups studied but negatively with α-MSH peptide only in controls. Significant correlations between the abundance of specific bacterial taxa in the gut microbiota and α-MSH peptide and IgG levels were found in both study groups, but they were more frequent in controls.

We conclude that IgG in the blood plays a role as an α-MSH-binding protein, whose characteristics are associated with BMI in both patients with AN and controls. Furthermore, the study suggests that low production of α-MSH-reactive IgG during the starvation phase in patients with AN may be related to altered gut microbiota composition.

The number of smokers worldwide increased greatly during the past decades and reached 1.14 billion in 2019, becoming a leading risk factor for human health. Tobacco smoking has wide effects on human genetics, epigenetics, transcriptome, and gut microbiome. Although many studies have revealed effects of smoking on host transcriptome, research on the relationship between smoking, host gene expression, and the gut microbiome is limited.

We first explored transcriptome and metagenome profile differences between smokers and nonsmokers. To evaluate the relationship between host gene expression and gut microbiome, we then applied bidirectional mediation analysis to infer causal relationships between smoking, gene expression, and gut microbes.

Metagenome and transcriptome analyses revealed 71 differential species and 324 differential expressed genes between smokers and nonsmokers. With smoking as an exposure variable, we identified 272 significant causal relationships between gene expression and gut microbes, among which there were 247 genes that mediate the effect of smoking on gut microbes. Pathway-based enrichment analysis showed that these genes were significantly enriched in heme metabolic pathway, which mainly mediated the changes of Bacteroides finegoldii and Lachnospiraceae bacterium 9_1_43BFAA. Additionally, by performing metabolome data analysis in the Integrated Human Microbiome Project (iHMP) database, we verified the correlation between the intermediate products of the heme metabolism pathway (porphobilinogen, bilirubin, and biliverdin) and gut microbiome.

By investigating the bidirectional interaction between smoking-related host gene expression and gut microbes, this study provided evidence for the mediation of smoking on gut microbes through co-involvement or interaction of heme metabolism.

By comparing the metagenome and transcriptome sequencing profiles between 34 smokers and 33 age- and gender-matched nonsmokers, we are the first to reveal causal relationships among tobacco smoking, host gene expression, and gut microbes. These findings offer insight into how smoking affects gut microbes through host gene expression and metabolism, which highlights the importance of heme metabolism in modulating the effects of smoking on gut microbiome.

The gut microbiome affects the health status of the host through complex interactions with the host's intestinal wall. These host-microbiome interactions may spatially vary along the physical and chemical environment of the intestine, but these changes remain unknown. This study investigated these intricate relationships through a gene co-expression network analysis based on dual transcriptome profiling of different intestinal sites-cecum, transverse colon, and rectum-of the primate common marmoset. We proposed a gene module extraction algorithm based on the graph theory to find tightly interacting gene modules of the host and the microbiome from a vast co-expression network. The 27 gene modules identified by this method, which include both host and microbiome genes, not only produced results consistent with previous studies regarding the host-microbiome relationships, but also provided new insights into microbiome genes acting as potential mediators in host-microbiome interplays. Specifically, we discovered associations between the host gene FBP1, a cancer marker, and polysaccharide degradation-related genes (pfkA and fucI) coded by Bacteroides vulgatus, as well as relationships between host B cell-specific genes (CD19, CD22, CD79B, and PTPN6) and a tryptophan synthesis gene (trpB) coded by Parabacteroides distasonis. Furthermore, our proposed module extraction algorithm surpassed existing approaches by successfully defining more functionally related gene modules, providing insights for understanding the complex relationship between the host and the microbiome.IMPORTANCEWe unveiled the intricate dynamics of the host-microbiome interactions along the colon by identifying closely interacting gene modules from a vast gene co-expression network, constructed based on simultaneous profiling of both host and microbiome transcriptomes. Our proposed gene module extraction algorithm, designed to interpret inter-species interactions, enabled the identification of functionally related gene modules encompassing both host and microbiome genes, which was challenging with conventional modularity maximization algorithms. Through these identified gene modules, we discerned previously unrecognized bacterial genes that potentially mediate in known relationships between host genes and specific bacterial species. Our findings underscore the spatial variations in host-microbiome interactions along the colon, rather than displaying a uniform pattern throughout the colon.

Millions of years of co-evolution between animals and their associated microbial communities have shaped and diversified the nature of their relationship. Studies continue to reveal new layers of complexity in host-microbe interactions, the fate of which depends on a variety of different factors, ranging from neutral processes and environmental factors to local dynamics. Research is increasingly integrating ecosystem-based approaches, metagenomics and mathematical modelling to disentangle the individual contribution of ecological factors to microbiome evolution. Within this framework, host factors are known to be among the dominant drivers of microbiome composition in different animal species. However, the extent to which they shape microbiome assembly and evolution remains unclear. In this review, we summarize our understanding of how host factors drive microbial communities and how these dynamics are conserved and vary across taxa. We conclude by outlining key avenues for research and highlight the need for implementation of and key modifications to existing theory to fully capture the dynamics of host-associated microbiomes. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.

Among all non-communicable diseases, Cardiovascular Diseases (CVDs) stand as the leading global cause of mortality. Within this spectrum, Myocardial Infarction (MI) strikingly accounts for over 15 % of all deaths. The intricate web of risk factors for MI, comprising family history, tobacco use, oral health, hypertension, nutritional pattern, and microbial infections, is firmly influenced by the human gut and oral microbiota, their diversity, richness, and dysbiosis, along with their respective metabolites. Host genetic factors, especially allelic variations in signaling and inflammatory markers, greatly affect the progression or severity of the disease. Despite the established significance of the human microbiome-nutrient-metabolite interplay in associations with CVDs, the unexplored terrain of the gut-heart-oral axis has risen as a critical knowledge gap. Moreover, the pivotal role of the microbiome and the complex interplay with host genetics, compounded by age-related changes, emerges as an area of vital importance in the development of MI. In addition, a distinctive disease susceptibility and severity influenced by gender-based or ancestral differences, adds a crucial insights to the association with increased mortality. Here, we aimed to provide an overview on interactions of microbiome (oral and gut) with major risk factors (tobacco use, alcohol consumption, diet, hypertension host genetics, gender, and aging) in the development of MI and therapeutic regulation.

Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

Little is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals. Host genetic variation was the most significant factor associated with the microbiome except for geography and disease status, with its top 5 principal components accounting for 12.11% of the microbiome variability. Within COPD individuals, 113 SNPs mapped to candidate genes reported as genetically associated with COPD exhibited associations with 29 microbial species and 48 functional modules (P < 1 × 10-5), where Streptococcus salivarius exhibits the strongest association to SNP rs6917641 in TBC1D32 (P = 9.54 × 10-8). Integration of concurrent host transcriptomic data identified correlations between the expression of host genes and their genetically-linked microbiome features, including NUDT1, MAD1L1 and Veillonella parvula, TTLL9 and Stenotrophomonas maltophilia, and LTA4H and Haemophilus influenzae. Mendelian randomization analyses revealed a potential causal link between PARK7 expression and microbial type III secretion system, and a genetically-mediated association between COPD and increased relative abundance of airway Streptococcus intermedius. These results suggest a previously underappreciated role of host genetics in shaping the airway microbiome and provide fresh hypotheses for genetic-based host-microbiome interactions in COPD.

Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the bowel. On the flip side, functions also arise from its role as an interface with the environment. Indeed, the gut houses microorganisms, collectively known as the gut microbiota, which interact with the host, and is the site of complex immune activities. Its role in human pathology is complex and scientific evidence is progressively elucidating the functions of the gut, especially regarding the pathogenesis of chronic intestinal diseases and inflammatory conditions affecting various organs and systems. This editorial aims to highlight and relate the factors involved in the pathogenesis of intestinal and systemic inflammation.

Plant phenotype is a complex entity largely controlled by the genotype and various environmental factors. Importantly, co-evolution has allowed plants to coexist with the biotic factors in their surroundings. Recently, plant endophytes as an external plant phenotype, forming part of the complex plethora of the plant microbial assemblage, have gained immense attention from plant scientists. Functionally, endophytes impact the plant in many ways, including increasing nutrient availability, enhancing the ability of plants to cope with both abiotic and biotic stress, and enhancing the accumulation of important plant secondary metabolites. The current state of research has been devoted to evaluating the phenotypic impacts of endophytes on host plants, including their direct influence on plant metabolite accumulation and stress response. However, there is a knowledge gap in how genetic factors influence the interaction of endophytes with host plants, pathogens, and other plant microbial communities, eventually controlling the extended microbial plant phenotype. This review will summarize how host genetic factors can impact the abundance and functional diversity of the endophytic microbial community, how endophytes influence host gene expression, and the host-endophyte-pathogen disease triangle. This information will provide novel insights into how breeders could specifically target the plant-endophyte extended phenotype for crop improvement.

Some observational studies have shown that gut microbiome is significantly changed in patients with schizophrenia. We aim to identify the genetic causal link between gut microbiome and schizophrenia.

A two-sample Mendelian randomization (MR) study was used to evaluate the causal link between gut microbiome and schizophrenia with 28 gut microbiome-associated genetic instrumental variants chosen from recent MR reports and the largest schizophrenia genome-wide association studies (8-Apr-22 release).

Inverse variance weighted method showed that genetically increased Bacteroidales_S24-7 (per SD) resulted in increased risk of schizophrenia (OR = 1.110, 95% CI: [1.012-1.217], P  = 0.027). Similarly, genetically increased Prevotellaceae promoted schizophrenia risk (OR = 1.124, 95% CI: [1.030-1.228], P  = 0.009). However, genetically increased Lachnospiraceae reduced schizophrenia risk (OR = 0.878, 95% CI: [0.785-0.983], P  = 0.023). In addition, schizophrenia risk was also suppressed by genetically increased Lactobacillaceae (OR = 0.878, 95% CI: [0.776-0.994], P  = 0.040) and Verrucomicrobiaceae (OR = 0.860, 95% CI: [0.749-0.987], P  = 0.032). Finally, we did not find any significant results in the causal association of other 23 gut microbiome with schizophrenia.

Our analysis suggests that genetically increased Bacteroidales_S24-7 and Prevotellaceae promotes schizophrenia risk, whereas genetically increased Lachnospiraceae, Lactobacillaceae, and Verrucomicrobiaceae reduces schizophrenia risk. Thus, regulation of the disturbed intestinal microbiota may represent a new therapeutic strategy for patients with schizophrenia.

Vitamin D3 regulates a variety of biological processes irrespective of its well-known importance for calcium metabolism. Epidemiological and animal studies indicate a role in immune regulation, intestinal barrier function and microbiome diversity. Here, we analyzed the impact of different vitamin D3- containing diets on C57BL/6 and BALB/c mice, with a particular focus on gut homeostasis and also investigated effects on immune cells in vitro. Weak regulatory effects were detected on murine T cells. By trend, the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 suppressed IFN, GM-CSF and IL-10 cytokine secretion in T cells of C57BL/6 but not BALB/c mice, respectively. Using different vitamin D3-fortified diets, we found a tissue-specific enrichment of mainly CD11b+ myeloid cells but not T cells in both mouse strains e.g. in spleen and Peyer's Patches. Mucin Reg3γ and Batf expression, as well as important proteins for gut homeostasis, were significantly suppressed in the small intestine of C57BL76 but not BALB/c mice fed with a high-vitamin D3 containing diet. Differences between both mouse stains were not completely explained by differences in vitamin D3 receptor expression which was strongly expressed in epithelial cells of both strains. Finally, we analyzed gut microbiome and again an impact of vitamin D3 was detected in C57BL76 but not BALB/c. Our data suggest strain-specific differences in vitamin D3 responsiveness under steady state conditions which may have important implications when choosing a murine disease model to study vitamin D3 effects.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that results from dysfunction in innate and/or adaptive immune responses. Impaired innate immunity, which leads to lack of control of an altered intestinal microbiota and to activation of the adaptive immune system, promotes a secondary inflammatory response that is responsible for tissue damage. Neutrophils are key players in innate immunity in IBD, but their roles have been neglected compared with those of other immune cells. The latest studies on neutrophils in IBD have revealed unexpected complexities, with heterogeneous populations and dual functions, both deleterious and protective, for the host. In parallel, interconnections between disease development, intestinal microbiota and neutrophils have been highlighted. Numerous IBD susceptibility genes (such as NOD2, NCF4, LRRK2, CARD9) are involved in neutrophil functions related to defence against microorganisms. Moreover, severe monogenic diseases involving dysfunctional neutrophils, including chronic granulomatous disease, are characterized by intestinal inflammation that mimics IBD and by alterations in the intestinal microbiota. This observation demonstrates the dialogue between neutrophils, gut inflammation and the microbiota. Neutrophils affect microbiota composition and function in several ways. In return, microbial factors, including metabolites, regulate neutrophil production and function directly and indirectly. It is crucial to further investigate the diverse roles played by neutrophils in host-microbiota interactions, both at steady state and in inflammatory conditions, to develop new IBD therapies. In this Review, we discuss the roles of neutrophils in IBD, in light of emerging evidence proving strong interconnections between neutrophils and the gut microbiota, especially in an inflammatory context.

This paper addresses the topic of determinism in contemporary microbiome research. I distinguish two types of deterministic claims about the microbiome, and I show evidence that both types of claims are present in the contemporary literature. First, the idea that the host genetics determines the composition of the microbiome which I call "host-microbiome determinism". Second, the idea that the genetics of the holobiont (the individual unit composed by a host plus its microbiome) determines the expression of certain phenotypic traits, which I call "microbiome-phenotype determinism". Drawing on the stability of traits conception of individuality (Suárez in Hist Philos Life Sci 42:11, 2020) I argue that none of these deterministic hypotheses is grounded on our current knowledge of how the holobiont is transgenerationally assembled, nor how it expresses its phenotypic traits.