Leveraging host-genetics and gut microbiota to determine immunocompetence in pigs

Abstract Background The gut microbiota influences host performance playing a relevant role in homeostasis and function of the immune system. The aim of the present work was to identify microbial signatures linked to immunity traits and to characterize the contribution of host-genome and gut microbiota to the immunocompetence in healthy pigs. Results To achieve this goal, we undertook a combination of network, mixed model and microbial-wide association studies (MWAS) for 21 immunity traits and the relative abundance of gut bacterial communities in 389 pigs genotyped for 70K SNPs. The heritability (h2; proportion of phenotypic variance explained by the host genetics) and microbiability (m2; proportion of variance explained by the microbial composition) showed similar values for most of the analyzed immunity traits, except for both IgM and IgG in plasma that was dominated by the host genetics, and the haptoglobin in serum which was the trait with larger m2 (0.275) compared to h2 (0.138). Results from the MWAS suggested a polymicrobial nature of the immunocompetence in pigs and revealed associations between pigs gut microbiota composition and 15 of the analyzed traits. The lymphocytes phagocytic capacity (quantified as mean fluorescence) and the total number of monocytes in blood were the traits associated with the largest number of taxa (6 taxa). Among the associations identified by MWAS, 30% were confirmed by an information theory network approach. The strongest confirmed associations were between Fibrobacter and phagocytic capacity of lymphocytes (r = 0.37), followed by correlations between Streptococcus and the percentage of phagocytic lymphocytes (r = -0.34) and between Megasphaera and serum concentration of haptoglobin (r = 0.26). In the interaction network, Streptococcus and percentage of phagocytic lymphocytes were the keystone bacterial and immune-trait, respectively. Conclusions Overall, our findings reveal an important connection between gut microbiota composition and immunity traits in pigs, and highlight the need to consider both sources of information, host genome and microbial levels, to accurately characterize immunocompetence in pigs.

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Leveraging host-genetics and gut microbiota to determine immunocompetence in pigs

10.1101/2021.06.08.447584 ◽

2021 ◽

Author(s):

Yuliaxis Ramayo-Caldas ◽

Laura M. Zingaretti ◽

David Perez-Pascual ◽

Pamela A Alexandre ◽

Antonio Reverter-Gomez ◽

...

Keyword(s):

Gut Microbiota ◽

Mixed Model ◽

Association Studies ◽

Host Genome ◽

Phenotypic Variance ◽

Microbial Composition ◽

Phagocytic Capacity ◽

Host Genetics ◽

Microbial Biomarkers ◽

Variance Explained

The aim of the present work was to identify microbial biomarkers linked to immunity traits and to characterize the contribution of host-genome and gut microbiota to the immunocompetence in healthy pigs. To achieve this goal, we undertook a combination of network, mixed model and microbial-wide association studies (MWAS) for 21 immunity traits and the relative abundance of gut bacterial communities in 389 pigs genotyped for 70K SNPs. The heritability (h2; proportion of phenotypic variance explained by the host genetics) and microbiability (m2; proportion of variance explained by the microbial composition) showed similar values for most of the analyzed immunity traits, except for both IgM and IgG in plasma that were dominated by the host genetics, and the haptoglobin in serum which was the trait with larger m2 (0.275) compared to h2 (0.138). Results from the MWAS suggested a polymicrobial nature of the immunocompetence in pigs and revealed associations between pigs gut microbiota composition and 15 of the analyzed traits. The lymphocytes phagocytic capacity (quantified as mean fluorescence) and the total number of monocytes in blood were the traits associated with the largest number of taxa (6 taxa). Among the associations identified by MWAS, 30% were confirmed by an information theory network approach. The strongest confirmed associations were between Fibrobacter and phagocytic capacity of lymphocytes (r=0.37), followed by correlations between Streptococcus and the percentage of phagocytic lymphocytes (r=-0.34) and between Megasphaera and serum concentration of haptoglobin (r=0.26). In the interaction network, Streptococcus and percentage of phagocytic lymphocytes were the keystone bacterial and immune-trait, respectively. Overall, our findings reveal an important connection between immunity traits and gut microbiota in pigs and highlight the need to consider both sources of information, host genome and microbial levels, to accurately characterize immunocompetence in pigs.

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Hematopoietic Npc1 mutation shifts gut microbiota composition in Ldlr−/− mice on a high-fat, high-cholesterol diet

Scientific Reports ◽

10.1038/s41598-019-51525-x ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Tom Houben ◽

John Penders ◽

Yvonne Oligschlaeger ◽

Inês A. Magro dos Reis ◽

Marc-Jan Bonder ◽

...

Keyword(s):

Lipid Metabolism ◽

Gut Microbiota ◽

High Cholesterol Diet ◽

Microbiota Composition ◽

High Cholesterol ◽

High Fat ◽

Microbial Composition ◽

Host Genetics ◽

Gut Microbiota Composition

Abstract While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the contribution of host genetics is rather unexplored. As several findings suggested a role for the lysosomal lipid transporter Niemann-Pick type C1 (NPC1) in macrophages during MetS, we here explored whether a hematopoietic Npc1 mutation, induced via bone marrow transplantation, influences gut microbiota composition in low-density lipoprotein receptor knockout (Ldlr−/−) mice fed a high-fat, high-cholesterol (HFC) diet for 12 weeks. Ldlr−/− mice fed a HFC diet mimic a human plasma lipoprotein profile and show features of MetS, providing a model to explore the role of host genetics on gut microbiota under MetS conditions. Fecal samples were used to profile the microbial composition by 16 s ribosomal RNA gene sequencing. The hematopoietic Npc1 mutation shifted the gut microbiota composition and increased microbial richness and diversity. Variations in plasma lipid levels correlated with microbial diversity and richness as well as with several bacterial genera. This study suggests that host genetic influences on lipid metabolism affect the gut microbiome under MetS conditions. Future research investigating the role of host genetics on gut microbiota might therefore lead to identification of diagnostic and therapeutic targets for MetS.

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Genome-wide association studies and heritability analysis reveal the involvement of host genetics in the Japanese gut microbiota

Communications Biology ◽

10.1038/s42003-020-01416-z ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Sachiko Ishida ◽

Kumiko Kato ◽

Masami Tanaka ◽

Toshitaka Odamaki ◽

Ryuichi Kubo ◽

...

Keyword(s):

Gut Microbiota ◽

Japanese Population ◽

Genome Wide Association Study ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Microbiota Composition ◽

Intrinsic Factors ◽

Genome Wide ◽

Gut Microbiota Composition

AbstractNumerous host extrinsic and intrinsic factors affect the gut microbiota composition, but their cumulative effects do not sufficiently explain the variation in the microbiota, suggesting contributions of missing factors. The Japanese population possesses homogeneous genetic features suitable for genome-wide association study (GWAS). Here, we performed GWASs for human gut microbiota using 1068 healthy Japanese adults. To precisely evaluate genetic effects, we corrected for the impacts of numerous host extrinsic and demographic factors by introducing them as covariates, enabling us to discover five loci significantly associated with microbiome diversity measures: HS3ST4, C2CD2, 2p16.1, 10p15.1, and 18q12.2. Nevertheless, these five variants explain only a small fraction of the variation in the gut microbiota. We subsequently investigated the heritability of each of the 21 core genera and found that the abundances of six genera are heritable. We propose that the gut microbiota composition is affected by a highly polygenic architecture rather than several strongly associated variants in the Japanese population.

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The gut microbiota profile of adults with kidney disease: A systematic review of the literature

10.21203/rs.2.10470/v1 ◽

2019 ◽

Author(s):

Jordan Stanford ◽

Karen Charlton ◽

Anita Stefoska-Needham ◽

Rukayat Ibrahim ◽

Kelly Lambert

Keyword(s):

Systematic Review ◽

Kidney Disease ◽

Gut Microbiota ◽

Cochrane Library ◽

Uremic Toxin ◽

Healthy Controls ◽

Microbiota Composition ◽

Dietary Intakes ◽

Microbial Composition ◽

Gut Microbiota Composition

Abstract Background There is mounting evidence that individuals with kidney disease have an abnormal gut microbiota composition. No studies to date have summarised the evidence to categorise how the gut microbiota profile of individuals with kidney disease may differ from healthy controls. Synthesis of this evidence is important to inform future clinical trials. This systematic review aims to characterise differences of the gut microbiota composition in adults with kidney disease, as well as to describe the functional capacity of the gut microbiota and reporting of diet as a confounder in these studies. Methods Included studies were those that investigated the gut microbial community in adults with any type of kidney disease and compared this to the profile of healthy controls. Six scientific databases (CINHAL, Medline, PubMed, Scopus, Web of Science, Cochrane Library) as well as selected grey literature sources were searched up until August 2018. Quality assessment was undertaken independently by three authors. The system of evidence level criteria was employed to quantitatively evaluate the alteration of microbiota by strictly considering the number, methodological quality and consistency of the findings. Additional findings relating to altered functions of the gut microbiota, dietary intakes and dietary methodologies used were qualitatively summarised. Results Sixteen articles, reporting 15 studies met the eligibility criteria and included a total of 540 adults with kidney disease and 1117 healthy controls. Compared to healthy controls, individuals with kidney disease had increased abundances of Enterobacteriaceae, and decreased abundances of Coprococcus and Prevotella. Adults with kidney stones also had an altered microbial composition with variations to Bacteroides, Lachnospiraceae NK4A136 group, Ruminiclostridium 5 group, Dorea, Enterobacter, Christensenellaceae and its genus Christensenellaceae R7 group. Altered microbial functions in adults with kidney disease were reported, particularly in the context of metabolic pathways relating to urea and uremic toxin generation. Only three of the 16 articles accounted for diet, and of these studies only two used a valid dietary assessment method. Conclusions The gut microbiota profile of adults with kidney disease differs from healthy controls. Future study designs should include adequate reporting of important confounders such as dietary intakes to assist with interpretation of findings.

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Dietary trans-10, cis-12-conjugated linoleic acid alters fatty acid metabolism and microbiota composition in mice

British Journal Of Nutrition ◽

10.1017/s0007114514004206 ◽

2015 ◽

Vol 113 (5) ◽

pp. 728-738 ◽

Cited By ~ 50

Author(s):

Tatiana M. Marques ◽

Rebecca Wall ◽

Orla O'Sullivan ◽

Gerald F. Fitzgerald ◽

Fergus Shanahan ◽

...

Keyword(s):

Lipid Metabolism ◽

Linoleic Acid ◽

Gut Microbiota ◽

Conjugated Linoleic Acid ◽

Control Group ◽

Standard Diet ◽

Microbiota Composition ◽

Microbial Composition ◽

16S Rrna Pyrosequencing ◽

Gut Microbiota Composition

The main aim of the present study was to investigate the effects of dietary trans-10, cis-12-conjugated linoleic acid (t10c12-CLA) on intestinal microbiota composition and SCFA production. C57BL/6 mice (n 8 per group) were fed a standard diet either supplemented with t10c12-CLA (0·5 %, w/w) (intervention) or with no supplementation (control), daily for 8 weeks. Metabolic markers (serum glucose, leptin, insulin and TAG, and liver TAG) were assessed by ELISA commercial kits, tissue long-chain fatty acids and caecal SCFA by GC, and microbial composition by 16S rRNA pyrosequencing. Dietary t10c12-CLA significantly decreased visceral fat mass (P< 0·001), but did not affect body weight (intervention), when compared with no supplementation (control). Additionally, lipid mass and composition were affected by t10c12-CLA intake. Caecal acetate, propionate and isobutyrate concentrations were higher (P< 0·05) in the t10c12-CLA-supplemented group than in the control group. The analysis of the microbiota composition following 8 weeks of t10c12-CLA supplementation revealed lower proportions of Firmicutes (P= 0·003) and higher proportions of Bacteroidetes (P= 0·027) compared with no supplementation. Furthermore, t10c12-CLA supplementation for 8 weeks significantly altered the gut microbiota composition, harbouring higher proportions of Bacteroidetes, including Porphyromonadaceae bacteria previously linked with negative effects on lipid metabolism and induction of hepatic steatosis. These results indicate that the mechanism of dietary t10c12-CLA on lipid metabolism in mice may be, at least, partially mediated by alterations in gut microbiota composition and functionality.

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Differences in the Microbial Composition of Hemodialysis Patients Treated with and without β-Blockers

Journal of Personalized Medicine ◽

10.3390/jpm11030198 ◽

2021 ◽

Vol 11 (3) ◽

pp. 198

Author(s):

Yi-Ting Lin ◽

Ting-Yun Lin ◽

Szu-Chun Hung ◽

Po-Yu Liu ◽

Wei-Chun Hung ◽

...

Keyword(s):

Random Forest ◽

Gut Microbiota ◽

Hemodialysis Patients ◽

Microbiota Composition ◽

Microbial Composition ◽

Α Diversity ◽

Β Blocker ◽

Β Blockers ◽

The Impact ◽

Gut Microbiota Composition

β-blockers are commonly prescribed to treat cardiovascular disease in hemodialysis patients. Beyond the pharmacological effects, β-blockers have potential impacts on gut microbiota, but no study has investigated the effect in hemodialysis patients. Hence, we aim to investigate the gut microbiota composition difference between β-blocker users and nonusers in hemodialysis patients. Fecal samples collected from hemodialysis patients (83 β-blocker users and 110 nonusers) were determined by 16S ribosomal RNA amplification sequencing. Propensity score (PS) matching was performed to control confounders. The microbial composition differences were analyzed by the linear discriminant analysis effect size, random forest, and zero-inflated Gaussian fit model. The α-diversity (Simpson index) was greater in β-blocker users with a distinct β-diversity (Bray–Curtis Index) compared to nonusers in both full and PS-matched cohorts. There was a significant enrichment in the genus Flavonifractor in β-blocker users compared to nonusers in full and PS-matched cohorts. A similar finding was demonstrated in random forest analysis. In conclusion, hemodialysis patients using β-blockers had a different gut microbiota composition compared to nonusers. In particular, the Flavonifractor genus was increased with β-blocker treatment. Our findings highlight the impact of β-blockers on the gut microbiota in hemodialysis patients.

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Comprehensive analysis of gut microbiota of a healthy population and covariates affecting microbial variation in two large Japanese cohorts

BMC Microbiology ◽

10.1186/s12866-021-02215-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jonguk Park ◽

Kumiko Kato ◽

Haruka Murakami ◽

Koji Hosomi ◽

Kumpei Tanisawa ◽

...

Keyword(s):

Gut Microbiota ◽

Large Scale ◽

Univariate Analysis ◽

Comprehensive Analysis ◽

Dietary Habit ◽

Healthy Population ◽

Microbiota Composition ◽

Microbial Composition ◽

Factors Associated ◽

Gut Microbiota Composition

Abstract Background Inter-individual variations in gut microbiota composition are observed even among healthy populations. The gut microbiota may exhibit a unique composition depending on the country of origin and race of individuals. To comprehensively understand the link between healthy gut microbiota and host state, it is beneficial to conduct large-scale cohort studies. The aim of the present study was to elucidate the integrated and non-redundant factors associated with gut microbiota composition within the Japanese population by 16S rRNA sequencing of fecal samples and questionnaire-based covariate analysis. Results A total of 1596 healthy Japanese individuals participated in this study via two independent cohorts, NIBIOHN cohort (n = 954) and MORINAGA cohort (n = 642). Gut microbiota composition was described and the interaction of these microorganisms with metadata parameters such as anthropometric measurements, bowel habits, medical history, and lifestyle were obtained. Thirteen genera, including Alistipes, Anaerostipes, Bacteroides, Bifidobacterium, Blautia, Eubacterium halli group, Faecalibacterium, Fusicatenibacter, Lachnoclostridium, Parabacteroides, Prevotella_9, Roseburia, and Subdoligranulum were predominant among the two cohorts. On the basis of univariate analysis for overall microbiome variation, 18 matching variables exhibited significant association in both cohorts. A stepwise redundancy analysis revealed that there were four common covariates, Bristol Stool Scale (BSS) scores, gender, age, and defecation frequency, displaying non-redundant association with gut microbial variance. Conclusions We conducted a comprehensive analysis of gut microbiota in healthy Japanese individuals, based on two independent cohorts, and obtained reliable evidence that questionnaire-based covariates such as frequency of bowel movement and specific dietary habit affects the microbial composition of the gut. To our knowledge, this was the first study to investigate integrated and non-redundant factors associated with gut microbiota among Japanese populations.

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Genetic determinants of gut microbiota composition and bile acid profiles in mice

10.1101/571075 ◽

2019 ◽

Cited By ~ 1

Author(s):

Julia H. Kemis ◽

Vanessa Linke ◽

Kelsey L. Barrett ◽

Frederick J. Boehm ◽

Lindsay L. Traeger ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Host Genetics ◽

Host Genetic ◽

Insight Into ◽

Gut Microbiota Composition ◽

Validation Experiments

AbstractThe microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ∼22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL forTuricibacter sp.and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter,Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences inSlc10a2gene expression associated with the different strains influences levels of both traits and revealed novel interactions betweenTuricibacterand BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.Author summaryInter-individual variation in the composition of the intestinal microbiota can in part be attributed to host genetics. However, the specific genes and genetic variants underlying differences in the microbiota remain largely unknown. To address this, we profiled the fecal microbiota composition of 400 genetically distinct mice, for which genotypic data is available. We identified many loci of the mouse genome associated with changes in abundance of bacterial taxa. One of these loci is also associated with changes in the abundance of plasma bile acids—metabolites generated by the host that influence both microbiota composition and host physiology. Follow up validation experiments provide mechanistic insights linking host genetic differences, with changes in ileum gene expression, bile acid-bacteria interactions and bile acid homeostasis. Together, this work demonstrates how genetic approaches can be used to generate testable hypothesis to yield novel insight into how host genetics shape gut microbiota composition.

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Physical activity and gut microbiota: a cross-sectional study

European Journal of Public Health ◽

10.1093/eurpub/ckaa166.413 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

F Gallè ◽

F Valeriani ◽

M Antinozzi ◽

R Liguori ◽

G Gianfranceschi ◽

...

Keyword(s):

Physical Activity ◽

Gut Microbiota ◽

Amplicon Sequencing ◽

Cross Sectional Study ◽

Microbiota Composition ◽

Sectional Study ◽

Microbial Composition ◽

Cross Sectional ◽

Bacterial Phyla ◽

Gut Microbiota Composition

Abstract Background The composition of gut microbiota, and in particular the intestinal abundance of the two main bacterial phyla of Firmicutes and Bacteroidetes, are associated with human health and diseases and may be conditioned by host and environmental factors such as age, gender and diet. The role of Physical Activity (PA) in determining gut microbiota composition has not been yet completely clarified. A cross-sectional study involving undergraduates from two Italian cities is ongoing to explore this relationship. Methods Students were invited to provide a fecal sample and to complete the International Physical Activity Questionnaire (IPAQ) in order to define their habitual PA level (inactive, minimally active, health enhancing physical activity -HEPA- active). Demographic and anthropometric information were also collected. DNA from fecal samples was analyzed through the 16S amplicon sequencing. Microbial composition and variability of the samples were evaluated on the light of participants' PA levels. Results A total of 153 students (47.7% males, mean age 22.4±2.9, mean BMI 22.3±2.7) participated to the study so far. Firmicutes and Bacteroidetes were the main represented phyla. An increase in Firmicutes (58.3±16 to 61.4±13.3, p = 0.68) and a reduction in Bacteroidetes (32.6±14.8 to 30.3±11.4, p = 0.51) have been registered with the increase of PA level. A higher variability (expressed as Shannon α-index) has been detected in minimally active (3.39±0.03) and HEPA-active (3.41±0) individuals respect to inactive subjects (3.35±0.07) (p = 0.05). Conclusions Even if they are not significant, these preliminary results suggest a relationship between PA levels and gut microbiota composition. An active lifestyle seems to be associated with a greater microbial diversity in the gut. Further researches are needed to explain these findings. Key messages Physical activity seems to be associated with gut microbiota composition. A greater variability in gut microbiota was found in active people.

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Differences in Anxiety Levels of Various Murine Models in Relation to the Gut Microbiota Composition

Biomedicines ◽

10.3390/biomedicines6040113 ◽

2018 ◽

Vol 6 (4) ◽

pp. 113 ◽

Cited By ~ 1

Author(s):

Eunchong Huang ◽

Shinwon Kang ◽

Haryung Park ◽

Soyoung Park ◽

Yosep Ji ◽

...

Keyword(s):

Gut Microbiota ◽

Psychological Symptoms ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Anxiety Level ◽

Microbiota Composition ◽

Microbial Composition ◽

Host Genetics ◽

Probiotic Strains ◽

Anxiety Levels

Psychobiotics are probiotic strains that confer mental health benefits to the host through the modulation of the gut microbial population. Mounting evidence shows that the gut microbiota play an important role in communication within the gut–brain axis. However, the relationship between the host genetics and the gut microbiota and their influence on anxiety are still not fully understood. Hence, in our research, we attempted to draw a connection between host genetics, microbiota composition, and anxiety by performing an elevated plus maze (EPM) test on four genetically different mice. Four different breeds of 5-week-old mice were used in this experiment: Balb/c, Orient C57BL/6N, Taconic C57BL/6N, and Taconic C57BL/6J. After 1 week of adaptation, their initial anxiety level was monitored using the EPM test via an EthoVision XT, a standardized software used for behavorial testing. Significant differences in the initial anxiety level and microbial composition were detected. Subsequently, the microbiota of each group was modulated by the administration of either a probiotic, fecal microbiota transplantation, or antibiotics. Changes were observed in host anxiety levels in correlation to the shift of the gut microbiota. Our results suggest that the microbiota, host genetics, and psychological symptoms are strongly related, yet the deeper mechanistic links need further exploration.

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