Due to continued technological development, people increasingly come in contact with engineered nanomaterials (ENMs) that are now used in foods and many industrial applications. Many ENMs have historically been shown to possess antimicrobial properties, which has sparked concern for how dietary nanomaterials impact gastrointestinal health via microbial dysbiosis. We employed an in vitro Human Gut Simulator system to examine interactions of dietary nano titanium dioxide (TiO2) with human gut microbiota. Electron microscopy indicated a close association of TiO2 particles with bacterial cells. Addition of TiO2 to microbial communities led to a modest reduction in community density but had no impact on community diversity and evenness. In contrast, administration of known antimicrobial silver nanoparticles (NPs) in a control experiment resulted in a drastic reduction of population density. In both cases, communities recovered once the addition of nanomaterials was ceased. Constrained ordination analysis of community profiles revealed that simulated colonic region was the primary determinant of microbiota composition. Accordingly, predicted community functional capacity and measured production of short-chain fatty acids were not changed significantly upon microbiota exposure to TiO2. We conclude that tested TiO2 NPs have limited direct effect on human gut microbiota.
Inflammatory diseases of the gastrointestinal tract are often associated with microbial dysbiosis. Thus, dietary interactions with intestinal microbiota, to maintain homeostasis, play a crucial role in regulation of clinical disorders such as colitis. In the current study, we investigated if resveratrol, a polyphenol found in a variety of foods and beverages, would reverse microbial dysbiosis induced during colitis. Administration of resveratrol attenuated colonic inflammation and clinical symptoms in the murine model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Resveratrol treatment in mice with colitis led to an increase in CD4+FOXP3+ and CD4+IL-10+ T cells, and a decrease in CD4+IFN-γ+ and CD4+IL-17+ T cells. 16S rRNA gene sequencing to investigate alterations in the gut microbiota revealed that TNBS caused significant dysbiosis, which was reversed following resveratrol treatment. Analysis of cecal flush revealed that TNBS administration led to an increase in species such as Bacteroides acidifaciens, but decrease in species such as Ruminococcus gnavus and Akkermansia mucinphilia, as well as a decrease in SCFA i-butyric acid. However, resveratrol treatment restored the gut bacteria back to homeostatic levels, and increased production of i-butyric acid. Fecal transfer experiments confirmed the protective role of resveratrol-induced microbiota against colitis inasmuch as such recipient mice were more resistant to TNBS-colitis and exhibited polarization toward CD4+FOXP3+ T cells and decreases in CD4+IFN-γ+ and CD4+IL-17+ T cells. Collectively, these data demonstrate that resveratrol-mediated attenuation of colitis results from reversal of microbial dysbiosis induced during colitis and such microbiota protect the host from colonic inflammation by inducing Tregs while suppressing inflammatory Th1/Th17 cells.
more » « less- NSF-PAR ID:
- 10394151
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Journal of Leukocyte Biology
- Volume:
- 106
- Issue:
- 2
- ISSN:
- 0741-5400
- Page Range / eLocation ID:
- p. 467-480
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract -
more » « less
Abstract The intestinal microbiota has several effects on host physiology. Previous work from our laboratory demonstrated that the microbiota influences systemic iron homeostasis in mouse colitis models by altering inflammation-induced expression of the iron-regulating hormone hepcidin. In the present study, we examined the impact of the gut commensal bacterium Bacteroides fragilis on the expression of the iron exporter ferroportin, the target of hepcidin action, in macrophages, the cell type that plays a pivotal role in iron recycling. Mouse bone marrow-derived macrophages were exposed to B. fragilis and were analyzed by quantitative real-time polymerase chain reaction and Western blotting. We found that B. fragilis down-regulated ferroportin transcription independently of bacterial viability. Medium conditioned by the bacteria also reduced ferroportin expression, indicating the involvement of soluble factors, possibly Toll-like receptor ligands. Consistent with this idea, several of these ligands were able to down-regulate ferroportin. The B. fragilis-induced decrease in ferroportin was functionally important since it produced a significant increase in intracellular iron concentrations that prevented the effects of the iron chelator deferoxamine on Salmonella-induced IL-6 and IL-1β production. Our results thus reveal that B. fragilis can influence macrophage iron handling and inflammatory responses by modulating ferroportin expression.
-
more » « less
Abstract ADAM23 is a member of the brain macrophage-derived chemokine family. Structural homology of ADAM proteins suggests their function as integrin receptors. Previous studies have linked ADAM23 as a dominant contributor to brain development and cancer metastasis. The present studies now show that ADAM23 expression on DCs partially governs antigen-presentation capacities to responder CD4+ T cells. With the use of RNAi approaches, knockdown of ADAM23 in murine BMDCs resulted in impaired T cell activation, proliferation, and cytokine production. Knockdown did not alter the maturation profile of DCs (i.e., costimulatory molecule expression or production of proinflammatory cytokines) but markedly impaired cognate T cell responses. There was a significant decrease in antigen-specific clonal expansion coupled with a global decrease in Th cytokine production. Impaired early activation and proliferation did not alter/skew the balance of Th polarization but significantly depressed total levels of IL-2, IFN-γ, IL-4, and IL-17 cytokine production in CD4+ T cells primed by ADAM23 knockdown versus control DCs. Finally, neutralizing antibodies targeting the α(v)β(3) integrin receptors resulted in similar phenotypes of impaired CD4+ T cell responses. Taken together, these studies show a novel role of ADAM23 in governing DC antigen presentation to cognate CD4+ T cells.
-
more » « less
Scope Two hydrogenated xanthohumol (XN) derivatives, α,β‐dihydro‐XN (DXN) and tetrahydro‐XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet‐induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation.
Methods and results To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high‐fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance—specifically Bacteroidetes and Tenericutes—alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro‐inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects changes in the microbiota to improvements in MetS in the host.
Conclusion Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives.
-
more » « less
Abstract Background The etiology of sporadic Parkinson’s disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention.
Methods We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)—an inhibitor of nuclear factor kappa B (NFκB)—to model enhanced NFκB activity, and mice in which CD8+T-cells were depleted.
Results High levels of inflammatory markers including
CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+T-cell infiltration and elevatedIfng expression in the brain. CD8+T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology.Conclusions This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+T-cells in this process in male mice.
Graphical abstract
