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

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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Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition

Cells ◽

10.3390/cells8060517 ◽

2019 ◽

Vol 8 (6) ◽

pp. 517 ◽

Cited By ~ 12

Author(s):

Claudia Burrello ◽

Maria Rita Giuffrè ◽

Angeli Dominique Macandog ◽

Angelica Diaz-Basabe ◽

Fulvia Milena Cribiù ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Immune Cells ◽

Intestinal Inflammation ◽

Fecal Microbiota Transplantation ◽

Experimental Colitis ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Chronic Intestinal Inflammation ◽

Gut Microbiota Composition

Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients.

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

Animal Microbiome ◽

10.1186/s42523-021-00138-9 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Yuliaxis Ramayo-Caldas ◽

Laura M. Zingaretti ◽

David Pérez-Pascual ◽

Pamela A. Alexandre ◽

Antonio Reverter ◽

...

Keyword(s):

Gut Microbiota ◽

Association Studies ◽

Host Genome ◽

Phenotypic Variance ◽

Microbiota Composition ◽

Microbial Composition ◽

Phagocytic Capacity ◽

Host Genetics ◽

Gut Microbiota Composition ◽

Variance Explained

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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Gut microbiota determines the social behavior of mice and induces metabolic and inflammatory changes in their adipose tissue

npj Biofilms and Microbiomes ◽

10.1038/s41522-021-00193-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Oryan Agranyoni ◽

Sapir Meninger-Mordechay ◽

Atara Uzan ◽

Oren Ziv ◽

Mali Salmon-Divon ◽

...

Keyword(s):

Adipose Tissue ◽

Social Behavior ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Critical Role ◽

Fecal Microbiota ◽

Rrna Gene ◽

Microbiota Composition ◽

The Social ◽

Inflammatory Profile

AbstractThe link between the gut microbiota and social behavior has been demonstrated, however the translational impact of a certain microbiota composition on stable behavioral patterns is yet to be elucidated. Here we employed an established social behavior mouse model of dominance (Dom) or submissiveness (Sub). A comprehensive 16S rRNA gene sequence analysis of Dom and Sub mice revealed a significantly different gut microbiota composition that clearly distinguishes between the two behavioral modes. Sub mice gut microbiota is significantly less diverse than that of Dom mice, and their taxa composition uniquely comprised the genera Mycoplasma and Anaeroplasma of the Tenericutes phylum, in addition to the Rikenellaceae and Clostridiaceae families. Conversely, the gut microbiota of Dom mice includes the genus Prevotella of the Bacteriodetes phylum, significantly less abundant in Sub mice. In addition, Sub mice show lower body weight from the age of 2 weeks and throughout their life span, accompanied with lower epididymis white adipose tissue (eWAT) mass and smaller adipocytes together with substantially elevated expression of inflammation and metabolic-related eWAT adipokines. Finally, fecal microbiota transplantation into germ-free mice show that Sub-transplanted mice acquired Sub microbiota and adopted their behavioral and physiological features, including depressive-like and anti-social behaviors alongside reduced eWAT mass, smaller adipocytes, and a Sub-like eWAT adipokine profile. Our findings demonstrate the critical role of the gut microbiome in determining dominance vs. submissiveness and suggest an association between gut microbiota, the eWAT metabolic and inflammatory profile, and the social behavior mode.

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Longitudinal evaluation of fecal microbiota transplantation for ameliorating calf diarrhea and improving growth performance

Nature Communications ◽

10.1038/s41467-020-20389-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hyun Sik Kim ◽

Tae Woong Whon ◽

Hojun Sung ◽

Yun-Seok Jeong ◽

Eun Sung Jung ◽

...

Keyword(s):

Gut Microbiota ◽

Growth Performance ◽

Potential Role ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Microbial Composition ◽

Calf Diarrhea ◽

The Family ◽

Enteric Infections

AbstractCalf diarrhea is associated with enteric infections, and also provokes the overuse of antibiotics. Therefore, proper treatment of diarrhea represents a therapeutic challenge in livestock production and public health concerns. Here, we describe the ability of a fecal microbiota transplantation (FMT), to ameliorate diarrhea and restore gut microbial composition in 57 growing calves. We conduct multi-omics analysis of 450 longitudinally collected fecal samples and find that FMT-induced alterations in the gut microbiota (an increase in the family Porphyromonadaceae) and metabolomic profile (a reduction in fecal amino acid concentration) strongly correlate with the remission of diarrhea. During the continuous follow-up study over 24 months, we find that FMT improves the growth performance of the cattle. This first FMT trial in ruminants suggest that FMT is capable of ameliorating diarrhea in pre-weaning calves with alterations in their gut microbiota, and that FMT may have a potential role in the improvement of growth performance.

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The effect of Sennoside A on the improvement of lipopolysaccharide -associated encephalopathy through gut microbiota

10.21203/rs.3.rs-201567/v1 ◽

2021 ◽

Author(s):

Suyan Li ◽

Fenyan Zhang ◽

Yiguang Lin ◽

Xiaoli Niu ◽

Jian Lv ◽

...

Keyword(s):

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Intestinal Flora ◽

Fecal Microbiota ◽

Protective Effects ◽

Sprague Dawley ◽

Microbial Composition ◽

Germ Free ◽

Sd Rats ◽

Tnf Α

Abstract Background Accumulating evidence suggests that the intestinal flora is involved in many neurodegenerative diseases. Sepsis can lead to severe intestinal flora imbalance and brain dysfunction. In this study, we investigated Sennoside A may relieve lipopolysaccharide(LPS)-associated encephalopathy via its effect on the gut microbiota in rats. Methods Adult male Sprague-Dawley (SD) rats and germ free (GF) rats were used. The ordinary and germ free SD rats were adopted as a LPS-associated encephalopathy model with or without Sennoside A administration. We investigated gut microbiota diversity and structure, conducted electroencephalograms (EEG) and measured the levels of TNF-α, IL-1β and IL-6 in the cortexes of Sprague Dawley (SD) rats with or without Sennoside A administration. Horizontal fecal microbiota transplantation (FMT) and germ-free rats were used to confirm the important roles of gut microbiota in the mitigation of LPS-associated encephalopathy in rats after Sennoside A supplementation. Results We found that Sennoside A treatment markedly improved brain function in septic rats including decreased ratios of abnormal EEG and lowered levels of TNF-α, IL-1β, and IL-6 in the rat cortexes. While the gut microbiota changed in septic SD rats, Sennoside A improved gut microbial composition, which might mediate its brain protective effects in sepsis. Sennoside A also reduced inflammation in the cortexes of septic rats via gut microbiota improvement. In germ-free rats that received lipopolysaccharide(LPS),Sennoside A could not lower the ratios of abnormal EEG, and could not alleviate TNF-α, IL-1β, and IL-6 levels in the rats’ cortexes. FMT lowered the ratios of abnormal EEG and alleviate TNF-α, IL-1β, and IL-6 levels in rats’ cortexes, which confirmed our hypothesis that the effect of Sennoside A on the improvement of LPS-associated encephalopathy through gut microbiota. Conclusion Our data confirm our hypothesis that Sennoside A likely exerts its brain protective effects through gut microbiota alteration.

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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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Modification of gut microbiota as a method of treatment of irritable bowel syndrome (literature review and own data)

Modern Gastroenterology ◽

10.30978/mg-2021-1-38 ◽

2021 ◽

Author(s):

S. M. Tkach ◽

A. E. Dorofeev ◽

Y. G. Kuzenko

Keyword(s):

Irritable Bowel Syndrome ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Sufficient Evidence ◽

Clinical Effects ◽

Time Treatment ◽

Probiotic Strains ◽

Irritable Bowel ◽

Specific Symptoms

Recently, our knowledge of gut microbiota (GM) disorders in various pathologies has significantly increased. In particular, to date, there is sufficient evidence that various disorders of GM may play a pathogenetic role in irritable bowel syndrome (IBS). Therefore, various methods of GM modification are now considered as a new promising strategy for the treatment of patients with IBS. The use of probiotics, prebiotics, synbiotics, antibiotics and fecal microbiota transplantation (FMT) are considered as methods of GM modification. Many clinical trials have been conducted to examine the therapeutic effect of probiotics on general or specific symptoms of IBS, but most of these studies have been very heterogeneous. Although some meta‑analyzes or systematic reviews show that probiotics may be useful in treating the symptoms of IBS, their findings in the studies differ due to insufficient sample size, poor study design, and the use of different probiotic strains. Currently, only one selective intestinal antibiotic with eubiotic properties is known — rifaximin, the effectiveness and safety of which have been proven in large randomized trials. The authors presented their own experience of rifaximin use at IBS that confirmed its efficiency. Own experience of the FMT conduction in patients with IBS is also presented. It has been revealed that even one‑time treatment significantly affected the GM by reducing the frequency and severity of dysbiotic disorders; it was accompanied by significant clinical effects in most patients that lasted up to 3 months of follow‑up.

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Effect of Fecal Microbiota Transplantation on Primary Hypertension and the Underlying Mechanism of Gut Microbiome Restoration: Protocol of a Randomized, Double-Blinded, Placebo-Controlled Study

10.21203/rs.3.rs-706375/v1 ◽

2021 ◽

Author(s):

Luyun Fan ◽

Jie Ren ◽

Youren Chen ◽

Yang Wang ◽

Zihong Guo ◽

...

Keyword(s):

Blood Pressure ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Blood Pressure Monitoring ◽

Fecal Microbiota ◽

Controlled Study ◽

Metagenomic Sequencing ◽

Microbial Composition ◽

Blood Pressure Elevation ◽

Double Blinded

Abstract BackgroundHypertension is in current the leading modifiable cause of global morbidity and mortality, contributing to substantial health and financial burdens. Although multiple explorations on management models and innovative therapeutic strategies of hypertension, vacancy still occur in the field with poor control rate reflected and lacking of novel, effectively clinical-translated medication or intervention options. Recent animal and human studies repeatedly confirmed a link between microbiota and hypertension. Of note is our previous study establishing a cause-and-effect relationship between gut microbiota and blood pressure elevation. A hypothesis of gut microbiota intervention on treating hypertension is thus postulated with fecal microbiota transplantation(FMT) from healthy donors performed. MethodsA multi-center, central randomized, placebo-controlled, double-blinded clinical trial is performed in 120 grade 1 hypertensive patients for overall three months. All recruited patients will be randomly assigned in a 1:1 ratio into orally-taken FMT capsules or placebo capsules with three interventions on day 1, day 7 and day 14 in separate, and followed up on day 30, day 60 and day 90. The primary outcome is the change for office systolic blood pressure from baseline to day 30 follow-up. Main secondary outcomes are BP indicators including changes in systolic and diastolic blood pressure from office, home, and 24-hour ambulatory blood pressure monitoring, assessments of ankle-branchial index and pulse wave velocity, profiling of fecal microbial composition and function, profiling of fecal and serum metabolome, changes in levels of blood glucose, blood lipids and body mass index, assessment of adverse events as a measure of safety. DiscussionStretching from our previous research on the role of gut microbiota in the pathogenesis of hypertension, this study serves as a clinical translation advancement and firstly explores the potential of fecal microbiota transplantation on treating hypertension. Underlying mechanisms particularly on anchoring specific microorganisms or their postbiotics contributing to blood pressure amelioration will also be investigated via multiple approaches such as metagenomic sequencing and metabolomic profiling.Trial registrationClinicalTrials.gov Identifier: NCT04406129, registried on May 28th, 2020, https://clinicaltrials.gov/ct2/show/NCT04406129

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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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Murine Genetic Background Has a Stronger Impact on the Composition of the Gut Microbiota than Maternal Inoculation or Exposure to Unlike Exogenous Microbiota

Applied and Environmental Microbiology ◽

10.1128/aem.00826-19 ◽

2019 ◽

Vol 85 (18) ◽

Cited By ~ 9

Author(s):

Hila Korach-Rechtman ◽

Shay Freilich ◽

Shiran Gerassy-Vainberg ◽

Keren Buhnik-Rosenblau ◽

Yael Danin-Poleg ◽

...

Keyword(s):

Gut Microbiota ◽

Inbred Lines ◽

Mouse Genetics ◽

Rrna Gene ◽

Continuous Exposure ◽

Microbiota Composition ◽

Microbial Composition ◽

Cross Model ◽

Host Genetics ◽

Reciprocal Hybrids

ABSTRACT The gut microbiota is a complex ecosystem, affected by both environmental factors and host genetics. Here, we aim at uncovering the bacterial taxa whose gut persistence is controlled by host genetic variation. We used a murine model based on inbred lines BALB/c and C57BL/6J and their F1 reciprocal hybrids (♀C57BL/6J × ♂BALB/c; ♀BALB/c × ♂C57BL/6J). To guarantee genetic similarity of F1 offspring, including the sex chromosomes, we used only female mice. Based on 16S rRNA gene sequencing, we found that the genetically different inbred lines present different microbiota, whereas their genetically identical F1 reciprocal hybrids presented similar microbiota. Moreover, the F1 microbial composition differed from that of both parental lines. Twelve taxa were shown to have genetically controlled gut persistence, while none were found to show maternal effects. Nine of these taxa were dominantly inherited by the C57BL/6J line. Cohousing of the parental inbred lines resulted in a temporary and minor shift in microbiota composition, which returned back to the former microbial composition following separation, indicating that each line tends to maintain a unique bacterial signature reflecting the line. Taken together, our findings indicate that mouse genetics has an effect on the microbial composition in the gut, which is greater than maternal effect and continuous exposure to different microbiota of the alternative line. Uncovering the bacterial taxa associated with host genetics and understanding their role in the gut ecosystem could lead to the development of genetically oriented probiotic products, as part of the personalized medicine approach. IMPORTANCE The gut microbiota play important roles for their host. The link between host genetics and their microbial composition has received increasing interest. Using a unique reciprocal cross model, generating genetically similar F1 hybrids with different maternal inoculation, we demonstrate the inheritance of gut persistence of 12 bacterial taxa. No taxa identified as maternally transmitted. Moreover, cohabitation of two genetically different inbred lines did not dramatically affect the microbiota composition. Taken together, our results demonstrate the importance of the genetic effect over maternal inoculation or effect of exposure to unlike exogenous microbiota. These findings may lead to the development of personalized probiotic products, specifically designed according to the genetic makeup.

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