scholarly journals Trem-2 modulation of gut microbiota is blunted during hepatotoxic injury and uncoupled from liver repair responses

2019 ◽  
Author(s):  
Inês Coelho ◽  
Nádia Duarte ◽  
Maria Paula Macedo ◽  
Carlos Penha-Gonçalves

AbstractThe involvement of gut microbiota in liver disease has been addressed in the context of the “leaky gut hypothesis” postulating that dysbiosis allow microbial components to elicit liver inflammatory responses and hepatic tissue damage. Conversely, commensal gut microbiota acting on innate immune receptors protect against hepatotoxic insults. Given that mice deficient for the triggering receptor expressed on myeloid cells-2 (Trem-2) show increased vulnerability to experimental drug-induced hepatic damage we explored the possibility that Trem-2 is a modulator of gut microbiota composition.We found that microbiota composition in untreated Trem-2 KO mice differs from the wild-type showing overall decrease in microbiota diversity and increased representation of Verrucomicrobia. Interestingly, induction of liver damage with hepatotoxic drugs blunted this microbiota diversity difference and altered phyla composition with increased representation of Verrucomicrobia during acute hepatic injury and Proteobacteria during chronic challenge. Furthermore, co-housing experiments that homogenized microbiota diversity showed that the increased liver tissue vulnerability to hepatotoxic insults in Trem-2 KO mice was not dependent on microbiota composition. This work uncouples Trem-2 dependent alterations in gut commensal microbiota from Trem-2 pro-recovery effects in the damaged liver tissue. These findings support the possibility that unlinked actions of innate immune receptors contribute to disease association with microbiota alterations, particularly with the Verrucomicrobia phylum.ImportanceTrem-2 is a mammalian innate immunity receptor involved in development and resolution of tissue damage, namely in the brain and in the liver. Nevertheless, it is not known whether gut microbiota is contributing to these Trem-2 mediated phenotypes. We found that Trem-2 KO mice spontaneously display different gut microbiota composition as compared to wild-type mice, namely with increased abundance of the phylum Verrucomicrobia. Notably these differences do not impact the control of Trem-2 on liver tissue vulnerability to hepatotoxic insults. This work uncouples Trem-2 modulation of gut microbiota and the role of Trem-2 on responses to liver damage. This work brings new insights on role of innate immune receptors on the association of organic and systemic diseases with gut microbiota.

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Alexander Koliada ◽  
Vladislav Moseiko ◽  
Mariana Romanenko ◽  
Oleh Lushchak ◽  
Nadiia Kryzhanovska ◽  
...  

Abstract Background Evidence was previously provided for sex-related differences in the human gut microbiota composition, and sex-specific discrepancy in hormonal profiles was proposed as a main determinant of these differences. On the basis of these findings, the assumption was made on the role of microbiota in the sexual dimorphism of human diseases. To date, sex differences in fecal microbiota were demonstrated primarily at lower taxonomic levels, whereas phylum-level differences between sexes were reported in few studies only. In the present population-based cross-sectional research, sex differences in the phylum-level human gut microbiota composition were identified in a large (total n = 2301) sample of relatively healthy individuals from Ukraine. Results Relative abundances of Firmicutes and Actinobacteria, as determined by qRT-PCR, were found to be significantly increased, while that of Bacteroidetes was significantly decreased in females compared to males. The Firmicutes to Bacteroidetes (F/B) ratio was significantly increased in females compared to males. Females had 31 % higher odds of having F/B ratio more than 1 than males. This trend was evident in all age groups. The difference between sexes was even more pronounced in the elder individuals (50+): in this age group, female participants had 56 % higher odds of having F/B ratio > 1 than the male ones. Conclusions In conclusion, sex-specific differences in the phylum-level intestinal microbiota composition were observed in the Ukraine population. The F/B ratio was significantly increased in females compared to males. Further investigation is needed to draw strong conclusions regarding the mechanistic basis for sex-specific differences in the gut microbiota composition and regarding the role of these differences in the initiation and progression of human chronic diseases.


2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Angie Jefferson ◽  
Katie Adolphus

AbstractThe influence on health of the human gut microbiota is increasingly recognised, however wheat fibre, consumed frequently in Western diets has traditionally been considered inert with regard to gut microbiota composition and metabolic activity. We undertook a systematic review (PRISMA methodology) of human intervention studies examining the effects of intact cereal fibres on gut microbiota composition among healthy adults.(1) Studies published in the past 20 years were identified on PubMed and Cochrane electronic databases. Inclusion criteria were: healthy adult participants, at least one intact cereal fibre (or its sub-fraction) and measurement of faecal microbiota related outcomes. Out of forty studies meeting inclusion criteria, seventeen manipulated wheat fibre/bran or its key constituent arabinoxylans (AXOS), and ten used a whole diet approach with predominantly wheat fibre. Results from these twenty seven wheat fibre papers are presented here. Eight studies provided wheat bran/fibre (ranging from 5.7g-21g/day wheat fibre or 13g-28g/day wheat bran). Three reported significant effects on gut microbiota abundance and/or diversity (both at phyla and species level) and one showed no effect. Six reported significant increases in fermentation metabolites and one reported no significant change. Ten studies manipulated whole day fibre intake (predominantly wheat but also permitting some oats, rye and rice). Wholegrain intake ranged from 80g-150 g per day and fibre from 13.7g–40 g per day. Six found significant increases in bacterial diversity and/or abundance and five showed significant increases in fermentation metabolites. Two identified that response to high fibre intervention is dependent on baseline gut microbiota richness - those with limited richness exhibiting greater microbiota change over time in response to fibre increase. Two reported no significant effects. Nine studies utilised manipulation of AXOS (2.2g–18.8 g per day) with five demonstrating significant increases in target bacterial species and six significant increases in fermentation metabolites. One reported no significant effect to faecal metabolites. This review supports a role for the wheat fibre found in everyday foods (such as bran breakfast cereal of high fibre breads) promoting both microbiota diversity and abundance. While the healthy microbiome is yet to be defined, consumption of a single daily serving of wheat bran fibre appears sufficient to effect gut microbiota fermentation (with demonstrable effects arising from as low as 6g/day), and promote species diversity, with potential benefit to health.However exploration of stability over longer time frames (> 12 weeks) is now required.


2020 ◽  
Vol 71 (1) ◽  
pp. 149-161 ◽  
Author(s):  
Ilias Attaye ◽  
Sara-Joan Pinto-Sietsma ◽  
Hilde Herrema ◽  
Max Nieuwdorp

Cardiometabolic disease (CMD), such as type 2 diabetes mellitus and cardiovascular disease, contributes significantly to morbidity and mortality on a global scale. The gut microbiota has emerged as a potential target to beneficially modulate CMD risk, possibly via dietary interventions. Dietary interventions have been shown to considerably alter gut microbiota composition and function. Moreover, several diet-derived microbial metabolites are able to modulate human metabolism and thereby alter CMD risk. Dietary interventions that affect gut microbiota composition and function are therefore a promising, novel, and cost-efficient method to reduce CMD risk. Studies suggest that fermentable carbohydrates can beneficially alter gut microbiota composition and function, whereas high animal protein and high fat intake negatively impact gut microbiota function and composition. This review focuses on the role of macronutrients (i.e., carbohydrate, protein, and fat) and dietary patterns (e.g., vegetarian/vegan and Mediterranean diet) in gut microbiota composition and function in the context of CMD.


2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Caroline Le Roy ◽  
Ruth Bowyer ◽  
Claire Steves ◽  
Tim Spector ◽  
Bell Jordana

Abstract Objectives Accumulation of visceral fat mass (VFM) is a major risk factor for cardiovascular and metabolic disease. Both gut microbiota and diet have been shown to impact host adiposity in an interdependent manner, but the exact nature of their joint contributions has not been characterised. Here, we aimed to estimate and separate the effect of gut microbiota composition from that of nutrient intake on host VFM in of 1760 older female twins. Methods The gut microbiome profile was assessed by 16S sequencing. VFM was measured by DEXA whole body scan and nutrient intake was assessed through food frequency questionnaires. We used a combination of pair-wise associations, random forest modelling and mediation analysis to separate the effect of the gut microbiota and nutrients on VFM. Results Pairwise analyses revealed that 93 OTUs and 10 nutrients were significantly linked to VFM. Five of the 10 nutrients (fibre, trans fatty acids, magnesium, vitamin E and biotin) were also associated with 23% of the 93 VFM-associated OTUs. To separate the effects of the gut microbiota from nutrients on VFM we carried out conditional analyses. We observed that the majority (87%) of the 93 OTUs remained significantly associated with VFM irrespective of nutrient intake correction. In contrast, we observed that fibre, magnesium, biotin and vitamin E were no longer significantly associated with VFM when adjusting models for OTUs (P > 0.05), implying a role of the gut microbiota in mediating these nutrient effects on VFM. Formal mediation analysis revealed that the individual effect of fibre, biotin, magnesium and vitamin E on VFM were mediated at 69, 43, 41 and 31% respectively by OTUs. Moreover, we estimated that accumulated effect of OTUs on VFM (R2 = 0.19) was twice the one of nutrients (R2 = 0.11) and so were their prediction potential determined using random forest classification. Conclusions Our results suggest that while the role of certain nutrients on VFM appears to depend on gut microbiota composition, specific gut microbes may affect host adiposity regardless of dietary intake. The findings imply that the gut microbiota may have a greater contribution towards shaping host adiposity and VFM, compared to diet alone. Funding Sources We gratefully acknowledge support provided by the JPI HDHL funded DINAMIC consortium (administered by the MRC UK, MR/N030125/1). Supporting Tables, Images and/or Graphs


2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Mei Wang ◽  
Brooke Smith ◽  
Brock Adams ◽  
Miller Tran ◽  
Ryan Dilger ◽  
...  

Abstract Objectives Enterotoxigenic Escherichia coli (ETEC) are an important cause of diarrhea in human infants and young farm animals. Osteopontin (OPN), a glycoprotein present in high concentration in human milk, has immunomodulatory functions, which could indirectly impact the microbiota. Furthermore, a previous study has shown fecal microbiota composition differs between wild-type and OPN knockout mice. Herein, the effects of OPN-enriched algae on the gut microbiota composition and volatile fatty acid (VFA) concentrations of ETEC-infected piglets were assessed. Methods Naturally-farrowed piglets were sow-reared for 21 days and then randomized to two weaning diets: WT (formula + 1% wild-type algae) or OPN (formula + 1% OPN-enriched algae). On postnatal day (PND) 31, all piglets were infected orally with a live culture of ETEC (1010 colony-forming unit/3 mL dose) daily for three consecutive days. On PND 41, ascending colon (AC) contents were collected. Gut microbiota was assessed by sequencing V3-V4 regions of 16S rRNA gene and VFAs were determined by gas chromatography. Alpha-diversity and VFAs were analyzed using PROC MIXED procedure of SAS. Beta-diversity was evaluated by permutational multivariate analysis of variance (PERMANOVA) and differential abundance analysis on the bacterial genera was performed using DESeq2 package of R. Results Shannon indices were lower in the AC contents of OPN piglets compared to WT piglets. The overall colonic microbiota of OPN piglets differed from that of WT piglets (PERMANOVA P = 0.015). At genus level, OPN-enriched algae increased the abundance of Streptococcus, decreased the abundances of Sutterella, Candidatus Soleaferrea, dga-11 gut group, Rikenellaceae RC9 gut group, Ruminococcaceae UCG-010, unculturedRuminococcaceae, Prevotella 2 and 7 compared to piglets consuming wild-type algae (P < 0. 05). OPN piglets also had higher (P < 0.05) concentrations of acetate, propionate, butyrate and valerate compared to WT. Conclusions In ETEC infected piglets, 1% OPN-enriched algae decreased alpha-diversity and modulated the microbiota composition and VFA profiles compared to 1% WT algae. Other studies have shown that OPN inhibits biofilm formation in vitro, but future research is needed to assess in vivo microbiome-modulation mechanisms. Funding Sources Triton Algae Innovations.


2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Jessica C. Ralston ◽  
Kathleen A.J. Mitchelson ◽  
Gina M. Lynch ◽  
Tam T.T. Tran ◽  
Conall R. Strain ◽  
...  

AbstractReduced inflammatory signaling (IL-1RI-/-) alters metabolic responses to dietary challenges (1). Inflammasome deficiency (e.g. IL-18-/-, Asc-/-) can modify gut microbiota concomitant with hepatosteatosis; an effect that was transferable to wild-type (WT) mice by co-housing (2). Taken together, this evidence suggests that links between diet, microbiota and IL-1RI-signaling can influence metabolic health. Our aim was to determine whether IL-1RI-mediated signaling interacted with the gut microbiome to impact metabolic tissue functionality in a diet-specific fashion. Male WT (C57BL/J6) and IL-1RI-/- mice were fed either high-fat diet (HFD; 45% kcal) or low-fat diet (LFD; 10% kcal) for 24 weeks and were housed i) separately by genotype or ii) with genotypes co-housed together (i.e. isolated vs shared microbial environment; n = 8–10 mice per group). Glucose tolerance and insulin secretion response (1.5 g/kg i.p.), gut microbiota composition and caecal short-chain fatty acids (SCFA) were assessed. Liver and adipose tissue were harvested and examined for triacylglycerol (TAG) formation, cholesterol and metabolic markers (Fasn, Cpt1α, Pparg, Scd1, Dgat1/2), using histology, gas-chromatography and RT-PCR, respectively. Statistical analysis included 1-way or 2-way ANOVA, where appropriate, with Bonferroni post-hoc correction. Co-housing significantly affected gut microbiota composition, illustrated by clustering in PCoA (unweighted UniFrac distance) of co-housed mice but not their single-housed counterparts, on both HFD and LFD. The taxa driving these differences were primarily from Lachnospiraceae and Ruminococcaceae families. Single-housed WT had lower hepatic weight, TAG, cholesterol levels and Fasn despite HFD, an effect lost in their co-housed counterparts, who aligned more to IL-1RI-/- hepatic lipid status. Hepatic Cpt1α was lowest in co-housed WT. Adipose from IL-1RI-/- groups on HFD displayed increased adipocyte size and reduced adipocyte number compared to WT groups, but greater lipogenic potential (Pparg, Scd1, Dgat2) alongside a blunted IL-6 response to pro-inflammatory stimuli (~32%, P = 0.025). Whilst caecal SCFA concentrations were not different between groups, single-housed IL-1RI-/- adipocytes showed greatest sensitivity to SCFA-induced lipogenesis. Interestingly, differences in tissue functionality and gut microbiome occurred despite unaltered glucose tolerance; although there was a trend for phenotypic transfer of body weight via co-housing. For all endpoints examined, similar genotype/co-housing effects were observed for both HFD and LFD with the greatest impacts seen in HFD-fed mice. In conclusion, while the gut microbiome may be an important consideration in dietary interventions, these results question the magnitude of its impact in relation to the IL-1RI-dependent immunometabolism-glucose homeostasis axis.


2010 ◽  
Vol 104 (S2) ◽  
pp. S1-S63 ◽  
Author(s):  
Marcel Roberfroid ◽  
Glenn R. Gibson ◽  
Lesley Hoyles ◽  
Anne L. McCartney ◽  
Robert Rastall ◽  
...  

The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, ‘normobiosis’ characterises a composition of the gut ‘ecosystem’ in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to ‘dysbiosis’, in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in ‘prebiotic effects’), defined as: ‘The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.’ Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.


Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 270 ◽  
Author(s):  
Ce Yuan ◽  
Clifford J. Steer ◽  
Subbaya Subramanian

Changes in gut microbiota composition have consistently been observed in patients with colorectal cancer (CRC). Yet, it is not entirely clear how the gut microbiota interacts with tumor cells. We know that tumor cells undergo a drastic change in energy metabolism, mediated by microRNAs (miRNAs), and that tumor-derived miRNAs affect the stromal and immune cell fractions of the tumor microenvironment. Recent studies suggest that host intestinal miRNAs can also affect the growth and composition of the gut microbiota. Our previous CRC studies showed a high-level of interconnectedness between host miRNAs and their microbiota. Considering all the evidence to date, we postulate that the altered nutrient composition and miRNA expression in the CRC microenvironment selectively exerts pressure on the surrounding microbiota, leading to alterations in its composition. In this review article, we present our current understanding of the role of miRNAs in mediating host–microbiota interactions in CRC.


Microbiome ◽  
2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Jordi Mayneris-Perxachs ◽  
María Arnoriaga-Rodríguez ◽  
Diego Luque-Córdoba ◽  
Feliciano Priego-Capote ◽  
Vicente Pérez-Brocal ◽  
...  

Abstract Background Gonadal steroid hormones have been suggested as the underlying mechanism responsible for the sexual dimorphism observed in metabolic diseases. Animal studies have also evidenced a causal role of the gut microbiome and metabolic health. However, the role of sexual dimorphism in the gut microbiota and the potential role of the microbiome in influencing sex steroid hormones and shaping sexually dimorphic susceptibility to disease have been largely overlooked. Although there is some evidence of sex-specific differences in the gut microbiota diversity, composition, and functionality, the results are inconsistent. Importantly, most of these studies have not taken into account the gonadal steroid status. Therefore, we investigated the gut microbiome composition and functionality in relation to sex, menopausal status, and circulating sex steroids. Results No significant differences were found in alpha diversity indices among pre- and post-menopausal women and men, but beta diversity differed among groups. The gut microbiota from post-menopausal women was more similar to men than to pre-menopausal women. Metagenome functional analyses revealed no significant differences between post-menopausal women and men. Gonadal steroids were specifically associated with these differences. Hence, the gut microbiota of pre-menopausal women was more enriched in genes from the steroid biosynthesis and degradation pathways, with the former having the strongest fold change among all associated pathways. Microbial steroid pathways also had significant associations with the plasma levels of testosterone and progesterone. In addition, a specific microbiome signature was able to predict the circulating testosterone levels at baseline and after 1-year follow-up. In addition, this microbiome signature could be transmitted from humans to antibiotic-induced microbiome-depleted male mice, being able to predict donor’s testosterone levels 4 weeks later, implying that the microbiota profile of the recipient mouse was influenced by the donor’s gender. Finally, obesity eliminated most of the differences observed among non-obese pre-menopausal women, post-menopausal women, and men in the gut microbiota composition (Bray-Curtis and weighted unifrac beta diversity), functionality, and the gonadal steroid status. Conclusions The present findings evidence clear differences in the gut microbial composition and functionality between men and women, which is eliminated by both menopausal and obesity status. We also reveal a tight link between the gut microbiota composition and the circulating levels of gonadal steroids, particularly testosterone.


Gut ◽  
2021 ◽  
pp. gutjnl-2020-322599
Author(s):  
Hsin-Chih Lai ◽  
Tzu-Lung Lin ◽  
Ting-Wen Chen ◽  
Yu-Lun Kuo ◽  
Chih-Jung Chang ◽  
...  

ObjectiveChronic obstructive pulmonary disease (COPD) is a global disease characterised by chronic obstruction of lung airflow interfering with normal breathing. Although the microbiota of respiratory tract is established to be associated with COPD, the causality of gut microbiota in COPD development is not yet established. We aimed to address the connection between gut microbiota composition and lung COPD development, and characterise bacteria and their derived active components for COPD amelioration.DesignA murine cigarette smoking (CS)-based model of COPD and strategies evaluating causal effects of microbiota were performed. Gut microbiota structure was analysed, followed by isolation of target bacterium. Single cell RNA sequencing, together with sera metabolomics analyses were performed to identify host responsive molecules. Bacteria derived active component was isolated, followed by functional assays.ResultsGut microbiota composition significantly affects CS-induced COPD development, and faecal microbiota transplantation restores COPD pathogenesis. A commensal bacterium Parabacteroides goldsteinii was isolated and shown to ameliorate COPD. Reduction of intestinal inflammation and enhancement of cellular mitochondrial and ribosomal activities in colon, systematic restoration of aberrant host amino acids metabolism in sera, and inhibition of lung inflammations act as the important COPD ameliorative mechanisms. Besides, the lipopolysaccharide derived from P. goldsteinii is anti-inflammatory, and significantly ameliorates COPD by acting as an antagonist of toll-like receptor 4 signalling pathway.ConclusionThe gut microbiota–lung COPD axis was connected. A potentially benefial bacterial strain and its functional component may be developed and used as alternative agents for COPD prevention or treatment.


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