The gut microbiota regulates intestinal immunity, but whether immune activation reciprocally alters gut commensals is unknown. In this issue of Cell Host & Microbe, Becattini et al. used a ...reductionist approach, incorporating gnotobiotic mouse models and multi-omics analyses, to address how gut commensals respond and adapt to acute immune activation.
The gut microbiota regulates intestinal immunity, but whether immune activation reciprocally alters gut commensals is unknown. In this issue of Cell Host & Microbe, Becattini et al. used a reductionist approach, incorporating gnotobiotic mouse models and multi-omics analyses, to address how gut commensals respond and adapt to acute immune activation.
A new genetic tool enables mechanistic dissection of microbiome–host interactions
Decades of microbiome studies, using a combination of multiomics approaches, have revealed strong associations ...between microbiota and human health. The next step is to identify the causal molecular mechanisms behind this association: Which microbes, genes, and their metabolites, if any, are responsible for a host phenotype? And if these molecules do affect us, how can we modulate their concentrations in the host to promote gut health?
Nutrition profoundly shapes immunity and inflammation across the lifespan of mammals, from pre- and post-natal periods to later life. Emerging insights into diet-microbiota interactions indicate that ...nutrition has a dominant influence on the composition-and metabolic output-of the intestinal microbiota, which in turn has major consequences for host immunity and inflammation. Here, we discuss recent findings that support the concept that dietary effects on microbiota-derived metabolites potently alter immune responses in health and disease. We discuss how specific dietary components and metabolites can be either pro-inflammatory or anti-inflammatory in a context- and tissue-dependent manner during infection, chronic inflammation, and cancer. Together, these studies emphasize the influence of diet-microbiota crosstalk on immune regulation that will have a significant impact on precision nutrition approaches and therapeutic interventions for managing inflammation, infection, and cancer immunotherapy.
Intestinal health relies on the immunosuppressive activity of CD4
regulatory T (T
) cells
. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by ...dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)
. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced T
(pT
) cells
, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids
with a range of physiological functions
. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pT
cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of T
cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing T
cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.
Hundreds of microbiota genes are associated with host biology/disease. Unraveling the causal contribution of a microbiota gene to host biology remains difficult because many are encoded by nonmodel ...gut commensals and not genetically targetable. A general approach to identify their gene transfer methodology and build their gene manipulation tools would enable mechanistic dissections of their impact on host physiology. We developed a pipeline that identifies the gene transfer methods for multiple nonmodel microbes spanning five phyla, and we demonstrated the utility of their genetic tools by modulating microbiome-derived short-chain fatty acids and bile acids in vitro and in the host. In a proof-of-principle study, by deleting a commensal gene for bile acid synthesis in a complex microbiome, we discovered an intriguing role of this gene in regulating colon inflammation. This technology will enable genetically engineering the nonmodel gut microbiome and facilitate mechanistic dissection of microbiota-host interactions.
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•Identify gene transfer methods for nonmodel gut Firmicutes/Clostridia•Develop gene manipulation tools for nonmodel gut Firmicutes/Clostridia•Functional analysis of a microbiota gene baiH in the host with a complex microbiome•baiH mediates host bile acid pool, gut microbiome composition, and colon inflammation
A pipeline for the genetic manipulation of nonmodel gut microbes enables single-gene, functional interrogation of bacteria in a complex microbial system.
Fecal microbiota transplantation (FMT) is an emerging treatment modality for ulcerative colitis (UC). Several randomized controlled trials have shown efficacy for FMT in the treatment of UC, but a ...better understanding of the transferable microbiota and their immune impact is needed to develop more efficient microbiome-based therapies for UC.
Metagenomic analysis and strain tracking was performed on 60 donor and recipient samples receiving FMT for active UC. Sorting and sequencing of immunoglobulin (Ig) A–coated microbiota (called IgA-seq) was used to define immune-reactive microbiota. Colonization of germ-free or genetically engineered mice with patient-derived strains was performed to determine the mechanism of microbial impact on intestinal immunity.
Metagenomic analysis defined a core set of donor-derived transferable bacterial strains in UC subjects achieving clinical response, which predicted response in an independent trial of FMT for UC. IgA-seq of FMT recipient samples and gnotobiotic mice colonized with donor microbiota identified Odoribacter splanchnicus as a transferable strain shaping mucosal immunity, which correlated with clinical response and the induction of mucosal regulatory T cells. Colonization of mice with O splanchnicus led to an increase in Foxp3+/RORγt+ regulatory T cells, induction of interleukin (IL) 10, and production of short chain fatty acids, all of which were required for O splanchnicus to limit colitis in mouse models.
This work provides the first evidence of transferable, donor-derived strains that correlate with clinical response to FMT in UC and reveals O splanchnicus as a key component promoting both metabolic and immune cell protection from colitis. These mechanistic features will help enable strategies to enhance the efficacy of microbial therapy for UC. Clinicaltrials.gov ID NCT02516384.
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Fecal microbiota transplantation is an emerging therapy to treat ulcerative colitis. These findings define strain transferability associated with clinical response and highlight the mechanisms of their immune impact.
Meroterpenoids are a class of fungal natural products that are produced from polyketide and terpenoid precursors. An understanding of meroterpenoid biosynthesis at the genetic level should facilitate ...engineering of second-generation molecules and increasing production of first-generation compounds. The filamentous fungus Aspergillus nidulans has previously been found to produce two meroterpenoids, austinol and dehydroaustinol. Using targeted deletions that we created, we have determined that, surprisingly, two separate gene clusters are required for meroterpenoid biosynthesis. One is a cluster of four genes including a polyketide synthase gene, ausA. The second is a cluster of 10 additional genes including a prenyltransferase gene, ausN, located on a separate chromosome. Chemical analysis of mutant extracts enabled us to isolate 3,5-dimethylorsellinic acid and 10 additional meroterpenoids that are either intermediates or shunt products from the biosynthetic pathway. Six of them were identified as novel meroterpenoids in this study. Our data, in aggregate, allow us to propose a complete biosynthetic pathway for the A. nidulans meroterpenoids.
Adherent-invasive E. coli (AIEC) are enriched in the intestinal microbiota of patients with Crohn’s disease (CD) and promote intestinal inflammation. Yet, how AIEC metabolism of nutrients impacts ...intestinal homeostasis is poorly defined. Here, we show that AIEC encoding the large subunit of propanediol dehydratase (PduC), which facilitates the utilization of fucose fermentation product 1,2-propanediol, are increased in the microbiome of CD patients and drive AIEC-induced intestinal T cell inflammation. In murine models, CX3CR1+ mononuclear phagocytes (MNP) are required for PduC-dependent induction of T helper 17 (Th17) cells and interleukin-1β (IL-1β) production that leads to AIEC-induced inflammatory colitis. Activation of this inflammatory cascade requires the catalytic activity of PduC to generate propionate, which synergizes with lipopolysaccharide (LPS) to induce IL-1β by MNPs. Disrupting fucose availability limits AIEC-induced propionate production and intestinal inflammation. These findings identify MNPs as metabolic sensors linking AIEC metabolism with intestinal inflammation and identify microbial metabolism as a potential therapeutic target in Crohn’s disease treatment.
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•pduC is enriched in Crohn’s disease-associated E. coli•AIEC induction of IL-1β and T cell-dependent colitis requires PduC•PduC-dependent propionate triggers IL-1β from CX3CR1+ MNPs and promotes Th17 cells•Limiting fucose availability reduces AIEC propionate production and inflammation
Viladomiu and Metz et al., show that propanediol metabolism by Crohn’s disease adherent-invasive E. coli is critical for promoting intestinal T cell inflammation. They identify a central role for CX3CR1+ mononuclear phagocytes in sensing AIEC-derived propionate to trigger interleukin-1β (IL-1β) and establish a link between AIEC metabolism and tissue inflammation.
The gut microbiota produce hundreds of molecules that are present at high concentrations in the host circulation. Unraveling the contribution of each molecule to host biology remains difficult. We ...developed a system for constructing clean deletions in
spp., the source of many molecules from the gut microbiome. By applying this method to the model commensal organism
, we knocked out genes for 10
-derived molecules that accumulate in host tissues. In mice colonized by a
for which the production of branched short-chain fatty acids was knocked out, we discovered that these microbial products have immunoglobulin A-modulatory activity.
Aim
Glucagon‐like peptide‐1 receptor agonists (GLP‐1Ras) have been reported to prevent non‐alcoholic fatty liver disease (NAFLD), but the potential mechanisms are still debated. MicroRNAs (miRNAs) ...play a prominent role in the field of metabolic disorders, including NAFLD. Our study was designed to further evaluate the effect of GLP‐1Ra liraglutide on NAFLD in terms of miRNAs.
Methods
MicroRNA expression was evaluated by clustering analysis of microRNA arrays in high fat diet‐fed mice. The luciferase reporter assay was carried out to validate the cross‐talk between adipose triglyceride lipase (ATGL) and miR‐124a. MicroRNA‐124a mimics and inhibitor plasmids were transfected to study the role of miR‐124a in palmitate‐treated normal human liver cell line (HL‐7702). Liraglutide treatment was used to observe the effect of GLP‐1Ra on the miR‐124a/ATGL pathway.
Results
Expression of ATGL decreased and miR‐124a expression increased in hepatosteatosis in vivo and in vitro. Mechanistically, miR‐124a interacted with the 3′‐untranslated region of ATGL mRNA and induced its degradation. MicroRNA‐124a overexpression antagonized the effect of liraglutide on NAFLD by inhibiting ATGL expression, whereas miR‐124a knockdown led to elevated ATGL and sirtuin 1 (Sirt1) expression, and subsequently decreased lipid accumulation and inflammation in cells.
Conclusions
MicroRNA‐124a overexpression contributes to the progression of NAFLD through reduction of ATGL expression, whereas miR‐124a knockdown can reverse this trend, suggesting that miR‐124a and its downstream target ATGL can be novel therapeutic targets of NAFLD. We reveal a novel mechanism by which liraglutide attenuates NAFLD by the miR‐124a/ATGL/Sirt1 pathway.
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