Zinc Status Elicits Age-Dependent Effects in the Gut Microbiome

Abstract Objectives Zinc is an essential micronutrient critical for a variety of cellular processes, including immune function. In US, 12% of the population do not consume the EAR for zinc. In older populations the prevalence of inadequate zinc intake increases to ∼40%. Moreover, zinc levels are also often depressed in aged individuals, even when consuming a zinc-adequate diet. Thus, older populations can be highly susceptible to zinc deficiency. Both zinc deficiency and aging are associated with progressive immune dysfunction and chronic inflammation that could be correlated with the promotion of many age-related diseases. Increasing evidence indicates that the interaction among gut microbiota, the immune system, and diet contributes to age-related inflammation. Objectives: The goal of this study is to determine the importance of zinc status and age with respect to composition of the gut microbiome. We hypothesize that age and zinc status are correlated with specific taxa in the gut microbiome. Further, we expect to see additional correlations, both positive and negative, between these significant taxa and markers of host inflammation. Methods We studied the effects of dietary zinc supplementation and marginal zinc deficiency on changes in microbial communities in young and old mice. Young (2 mo) and old (24 mo) C57Bl/6 mice were fed a zinc adequate (30ppm Zn), zinc supplemented (300ppm Zn), or marginal zinc deficient (6 ppm Zn) diet for six weeks. 16S rRNA amplicon sequencing was performed on fecal samples at study start and end; cecal and colon samples at study end. Results Age correlated with overall microbial composition in the gut, according to a PERMANOVA test and a permutation test, regardless of zinc status. Gut microbiome content of young mice had significant overall correlation with zinc status, while the gut microbiome of old mice was not significantly affected by zinc status. Conclusions Age effects on the microbiome are significant and must be considered when studying effects of diet on the host gut microbiome. Zinc status, especially deficiency, elicits a varied effect on the microbiome that is dependent upon host age. Sampling site (i.e., colon, cecum, feces) had a small but significant effect on specific microbial taxa. Funding Sources NIFA, USDA.

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Effects of Zinc Status and Aging on Age-Related Immune Dysfunction and Chronic Inflammation

Current Developments in Nutrition ◽

10.1093/cdn/nzaa067_081 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1854-1854

Author(s):

Carmen Wong ◽

Kendra Braun ◽

John Bouranis ◽

Edward Davis ◽

Thomas Sharpton ◽

...

Keyword(s):

Inflammatory Response ◽

Chronic Inflammation ◽

Zinc Deficiency ◽

Serum Zinc ◽

Immune Dysfunction ◽

Zinc Status ◽

Aged Mice ◽

Age Related ◽

Marginal Zinc Deficiency ◽

Old Mice

Abstract Objectives Aging is associated with progressive immune dysfunction, including impaired adaptive response, increased susceptibility to infection, and reduced vaccination efficacy. Aging is also associated with chronic inflammation that correlated with the promotion of many age-related diseases. Zinc is an essential micronutrient critical for immune function. In US, 12% of the population do not consume the estimated average requirement for zinc. The prevalence of inadequate zinc intake is even higher among older populations, and are at increased risk for marginal zinc deficiency. Effects of zinc deficiency share similarities to age-related immune dysfunction, including impaired adaptive immunity and increased in proinflammatory response. The goal of this study is to understand the effects of zinc status and aging on age-related immune dysfunction and chronic inflammation. We hypothesize that age-related decline in zinc status contributes to immune dysregulation and chronic inflammation in the elderly. Methods We studied the effects of dietary zinc supplementation and marginal zinc deficiency on changes in mucosal immunity and inflammatory response in young and old mice. Young (2 mo) and old (24 mo) C57Bl/6 mice were fed a zinc adequate (ZA, 30 ppm Zn), zinc supplemented (ZS, 300 ppm Zn), or marginal zinc deficient (MZD, 6 ppm Zn) diets for 6 wks. Serum zinc status, cytokines, and naïve/memory T-cell phenotypes, were determined at the end of the study. Results Old mice had reduced zinc and increased proinflammatory cytokines MCP1 and IL6 in the serum, increased Th1/Th17/inflammatory cytokines (IFNγ, IL17, TNFα, respectively) and decreased naïve CD4 T-cells in the mesenteric lymph nodes (MLN). ZS significantly increased serum zinc levels, decreased TNFα, IFNγ, IL17 in MLN, and increased naïve T-cell populations in aged mice. MZD further reduced serum zinc and increased serum IL6 levels in aged mice. Conclusions ZS improved the immune function of aged mice and reduced inflammatory response, and MZD further increased age-related inflammation. Our data suggest that zinc status is an important contributing factor in age-related immune dysfunction and chronic inflammation. Funding Sources NIFA, USDA.

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Marginal Zinc Deficiency and Environmentally Relevant Concentrations of Arsenic Elicit Combined Effects on the Gut Microbiome

mSphere ◽

10.1128/msphere.00521-18 ◽

2018 ◽

Vol 3 (6) ◽

Cited By ~ 14

Author(s):

Christopher A. Gaulke ◽

John Rolshoven ◽

Carmen P. Wong ◽

Laurie G. Hudson ◽

Emily Ho ◽

...

Keyword(s):

Dna Damage ◽

Zinc Deficiency ◽

Relative Abundance ◽

Gut Microbiome ◽

Zinc Concentration ◽

Arsenic Exposure ◽

Physiological Changes ◽

Plasma Zinc ◽

Marginal Zinc Deficiency ◽

Dietary Variation

ABSTRACT Extensive research shows that dietary variation and toxicant exposure impact the gut microbiome, yielding effects on host physiology. However, prior work has mostly considered such exposure-microbiome interactions through the lens of single-factor exposures. In practice, humans exposed to toxicants vary in their dietary nutritional status, and this variation may impact subsequent exposure of the gut microbiome. For example, chronic arsenic exposure affects 200 million people globally and is often comorbid with zinc deficiency. Zinc deficiency can enhance arsenic toxicity, but it remains unknown how zinc status impacts the gut microbiome’s response to arsenic exposure and whether this response links to host toxicity. Using 16S amplicon sequencing, we examined the combinatorial effects of exposure to environmentally relevant concentrations of arsenic on the composition of the microbiome in C57BL/6 mice fed diets varying in zinc concentration. Arsenic exposure and marginal zinc deficiency independently altered microbiome diversity. When combined, their effects on microbiome community structure were amplified. Generalized linear models identified microbial taxa whose relative abundance in the gut was perturbed by zinc deficiency, arsenic, or their interaction. Further, we correlated taxonomic abundances with host DNA damage, adiponectin expression, and plasma zinc concentration to identify taxa that may mediate host physiological responses to arsenic exposure or zinc deficiency. Arsenic exposure and zinc restriction also result in increased DNA damage and decreased plasma zinc. These physiological changes are associated with the relative abundance of several gut taxa. These data indicate that marginal zinc deficiency sensitizes the microbiome to arsenic exposure and that the microbiome associates with some toxicological effects of arsenic. IMPORTANCE Xenobiotic compounds, such as arsenic, have the potential to alter the composition and functioning of the gut microbiome. The gut microbiome may also interact with these compounds to mediate their impact on the host. However, little is known about how dietary variation may reshape how the microbiome responds to xenobiotic exposures or how these modified responses may in turn impact host physiology. Here, we investigated the combinatorial effects of marginal zinc deficiency and physiologically relevant concentrations of arsenic on the microbiome. Both zinc deficiency and arsenic exposure were individually associated with altered microbial diversity and when combined elicited synergistic effects. Microbial abundance also covaried with host physiological changes, indicating that the microbiome may contribute to or be influenced by these pathologies. Collectively, this work demonstrates that dietary zinc intake influences the sensitivity of the microbiome to subsequent arsenic exposure.

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Long-Term Blackcurrant Supplementation Modified Gut Microbiome Profiles in Mice in an Age-Dependent Manner: An Exploratory Study

Nutrients ◽

10.3390/nu12020290 ◽

2020 ◽

Vol 12 (2) ◽

pp. 290 ◽

Cited By ~ 1

Author(s):

Lei Cao ◽

Sang Gil Lee ◽

Melissa M. Melough ◽

Junichi R. Sakaki ◽

Kendra R. Maas ◽

...

Keyword(s):

Gut Microbiome ◽

Beta Diversity ◽

Age Groups ◽

Dependent Manner ◽

16S Sequencing ◽

Microbiome Composition ◽

Age Related ◽

Regulatory Effects ◽

Old Mice ◽

Young Mice

Recent studies have suggested that blackcurrant (BC) anthocyanins have promising health benefits, possibly through regulating gut microbiome. Three- and eighteen-month old female mice were fed standard mouse diets for 4 months, each with or without BC (1% w/w) supplementation (n = 3 in each treatment group, 12 in total). We then assessed gut microbiome profiles using 16S sequencing of their feces. Old mice had a less diverse microbiome community compared to young mice and there was a remarkable age-related difference in microbiome composition in the beta diversity analysis. BC supplementation did not significantly affect alpha or beta diversity. The relative abundance of several phyla, including Firmicutes, Bacteroidetes, Proteobacteria and Tenericutes, was lower in old mice. BC downregulated Firmicutes abundance in young mice and upregulated Bacteroidetes in both age groups, leading to a decreased Firmicutes/Bacteroidetes ratio. There were age-specific differences in the effect of BC supplementation on the microbiome. Twenty-four operational taxonomic units showed a significant interaction between age and BC supplementation (p < 0.01), which suggests that the ecosystem and the host health status affect the functions and efficiency of BC intake. These results indicate that BC supplementation favorably modulates gut microbiome, but there are distinct age-specific differences. Studies with human hosts are needed to better understand BC’s regulatory effects on the gut microbiome.

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Marginal zinc deficiency in older adults: responsiveness of zinc status indicators.

Journal of the American College of Nutrition ◽

10.1080/07315724.1994.10718434 ◽

1994 ◽

Vol 13 (5) ◽

pp. 455-462 ◽

Cited By ~ 54

Author(s):

C W Bales ◽

R A DiSilvestro ◽

K L Currie ◽

C S Plaisted ◽

H Joung ◽

...

Keyword(s):

Older Adults ◽

Zinc Deficiency ◽

Zinc Status ◽

Marginal Zinc Deficiency

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Gut microbiome development in early childhood is affected by day care attendance

npj Biofilms and Microbiomes ◽

10.1038/s41522-021-00265-w ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Amnon Amir ◽

Ortal Erez-Granat ◽

Tzipi Braun ◽

Katya Sosnovski ◽

Rotem Hadar ◽

...

Keyword(s):

Early Childhood ◽

Home Care ◽

Gut Microbiome ◽

Day Care ◽

Critical Time ◽

Microbial Composition ◽

School Year ◽

Diverse Environment ◽

Microbial Development ◽

Older Populations

AbstractThe human gut microbiome develops during the first years of life, followed by a relatively stable adult microbiome. Day care attendance is a drastic change that exposes children to a large group of peers in a diverse environment for prolonged periods, at this critical time of microbial development, and therefore has the potential to affect microbial composition. We characterize the effect of day care on the gut microbial development throughout a single school year in 61 children from 4 different day care facilities, and in additional 24 age-matched home care children (n = 268 samples, median age of entering the study was 12 months). We show that day care attendance is a significant and impactful factor in shaping the microbial composition of the growing child, the specific daycare facility and class influence the gut microbiome, and each child becomes more similar to others in their day care. Furthermore, in comparison to home care children, day care children have a different gut microbial composition, with enrichment of taxa more frequently observed in older populations. Our results provide evidence that daycare may be an external factor that contributes to gut microbiome maturation and make-up in early childhood.

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Postoperative Complications Are Associated with Long-Term Changes in the Gut Microbiota Following Colorectal Cancer Surgery

Life ◽

10.3390/life11030246 ◽

2021 ◽

Vol 11 (3) ◽

pp. 246

Author(s):

Felix C.F. Schmitt ◽

Martin Schneider ◽

William Mathejczyk ◽

Markus A. Weigand ◽

Jane C. Figueiredo ◽

...

Keyword(s):

Colorectal Cancer ◽

Postoperative Complications ◽

Gut Microbiota ◽

Gut Microbiome ◽

Tumor Resection ◽

Microbial Composition ◽

Colorectal Cancer Surgery ◽

Long Term Changes ◽

Stool Samples

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups—patients who suffered from postoperative complications (n = 30) and those without complication (n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications (p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans. The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

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Transcriptional regulation of ZIP genes is independent of local zinc status in Brachypodium shoots upon zinc deficiency and resupply

Plant Cell & Environment ◽

10.1111/pce.14151 ◽

2021 ◽

Author(s):

Sahand Amini ◽

Borjana Arsova ◽

Sylvie Gobert ◽

Monique Carnol ◽

Bernard Bosman ◽

...

Keyword(s):

Transcriptional Regulation ◽

Zinc Deficiency ◽

Zinc Status ◽

Zip Genes

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Xylitol enhances synthesis of propionate in the colon via cross-feeding of gut microbiota

Microbiome ◽

10.1186/s40168-021-01029-6 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Shasha Xiang ◽

Kun Ye ◽

Mian Li ◽

Jian Ying ◽

Huanhuan Wang ◽

...

Keyword(s):

Gut Microbiome ◽

Lactobacillus Reuteri ◽

Carbon Sources ◽

Short Chain Fatty Acids ◽

Microbial Composition ◽

Key Enzymes ◽

Rrna Sequencing ◽

Phosphate Acetyltransferase

Abstract Background Xylitol, a white or transparent polyol or sugar alcohol, is digestible by colonic microorganisms and promotes the proliferation of beneficial bacteria and the production of short-chain fatty acids (SCFAs), but the mechanism underlying these effects remains unknown. We studied mice fed with 0%, 2% (2.17 g/kg/day), or 5% (5.42 g/kg/day) (weight/weight) xylitol in their chow for 3 months. In addition to the in vivo digestion experiments in mice, 3% (weight/volume) (0.27 g/kg/day for a human being) xylitol was added to a colon simulation system (CDMN) for 7 days. We performed 16S rRNA sequencing, beneficial metabolism biomarker quantification, metabolome, and metatranscriptome analyses to investigate the prebiotic mechanism of xylitol. The representative bacteria related to xylitol digestion were selected for single cultivation and co-culture of two and three bacteria to explore the microbial digestion and utilization of xylitol in media with glucose, xylitol, mixed carbon sources, or no-carbon sources. Besides, the mechanisms underlying the shift in the microbial composition and SCFAs were explored in molecular contexts. Results In both in vivo and in vitro experiments, we found that xylitol did not significantly influence the structure of the gut microbiome. However, it increased all SCFAs, especially propionate in the lumen and butyrate in the mucosa, with a shift in its corresponding bacteria in vitro. Cross-feeding, a relationship in which one organism consumes metabolites excreted by the other, was observed among Lactobacillus reuteri, Bacteroides fragilis, and Escherichia coli in the utilization of xylitol. At the molecular level, we revealed that xylitol dehydrogenase (EC 1.1.1.14), xylulokinase (EC 2.7.1.17), and xylulose phosphate isomerase (EC 5.1.3.1) were key enzymes in xylitol metabolism and were present in Bacteroides and Lachnospiraceae. Therefore, they are considered keystone bacteria in xylitol digestion. Also, xylitol affected the metabolic pathway of propionate, significantly promoting the transcription of phosphate acetyltransferase (EC 2.3.1.8) in Bifidobacterium and increasing the production of propionate. Conclusions Our results revealed that those key enzymes for xylitol digestion from different bacteria can together support the growth of micro-ecology, but they also enhanced the concentration of propionate, which lowered pH to restrict relative amounts of Escherichia and Staphylococcus. Based on the cross-feeding and competition among those bacteria, xylitol can dynamically balance proportions of the gut microbiome to promote enzymes related to xylitol metabolism and SCFAs.

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Distinct composition and metabolic functions of human gut microbiota are associated with cachexia in lung cancer patients

The ISME Journal ◽

10.1038/s41396-021-00998-8 ◽

2021 ◽

Author(s):

Yueqiong Ni ◽

Zoltan Lohinai ◽

Yoshitaro Heshiki ◽

Balazs Dome ◽

Judit Moldvay ◽

...

Keyword(s):

Lung Cancer ◽

Gut Microbiota ◽

Cancer Patients ◽

Gut Microbiome ◽

Human Gut ◽

Microbial Composition ◽

Shotgun Metagenomics ◽

Lung Cancer Patients ◽

Microbial Species ◽

Functional Pathways

AbstractCachexia is associated with decreased survival in cancer patients and has a prevalence of up to 80%. The etiology of cachexia is poorly understood, and limited treatment options exist. Here, we investigated the role of the human gut microbiome in cachexia by integrating shotgun metagenomics and plasma metabolomics of 31 lung cancer patients. The cachexia group showed significant differences in the gut microbial composition, functional pathways of the metagenome, and the related plasma metabolites compared to non-cachectic patients. Branched-chain amino acids (BCAAs), methylhistamine, and vitamins were significantly depleted in the plasma of cachexia patients, which was also reflected in the depletion of relevant gut microbiota functional pathways. The enrichment of BCAAs and 3-oxocholic acid in non-cachectic patients were positively correlated with gut microbial species Prevotella copri and Lactobacillus gasseri, respectively. Furthermore, the gut microbiota capacity for lipopolysaccharides biosynthesis was significantly enriched in cachectic patients. The involvement of the gut microbiome in cachexia was further observed in a high-performance machine learning model using solely gut microbial features. Our study demonstrates the links between cachectic host metabolism and specific gut microbial species and functions in a clinical setting, suggesting that the gut microbiota could have an influence on cachexia with possible therapeutic applications.

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Impact of the gut microbiome on the atorvastatin-dependent modulation of the serum lipidome

European Heart Journal ◽

10.1093/ehjci/ehaa946.3823 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J Roessler ◽

F Zimmermann ◽

D Schmidt ◽

U Escher ◽

A Jasina ◽

...

Keyword(s):

Gut Microbiota ◽

Relative Abundance ◽

Gut Microbiome ◽

Interindividual Variation ◽

Funding Source ◽

Microbial Composition ◽

Atorvastatin Treatment ◽

Qrt Pcr ◽

16S Rna ◽

Regulatory Properties

Abstract Background and aims The modulation of serum lipids, in particular of the low-density lipoprotein cholesterol (LDL-C), by statins varies between individuals. The mechanisms regulating this interindividual variation are only poorly understood. Here, we investigated the relation between the gut microbiome and the regulatory properties of atorvastatin on the serum lipidome using mice with depleted gut microbiome. Methods Over a period of 6 weeks, mice (C57BL/6) with either an intact (conventional mice, CONV, n=24) or antibiotic-based depleted gut microbiome (antibiotic treated mice, ABS, n=16) were put on standard chow diet (SCD) or high fat diet (HFD), respectively. During the last 4 weeks of treatment atorvastatin (Ator, 10mg/kg body weight/day) or control vehicle was administered via daily oral gavage. Blood lipids (total cholesterol, VLDL, LDL-C, HDL-C) and serum sphingolipids were compared among the groups. The expressions of hepatic and intestinal genes involved in cholesterol metabolism were analyzed by qRT-PCR. Alterations in the gut microbiota profile of mice with intact gut microbiome were examined using 16S RNA qRT-PCR. Results In CONV mice, HFD led to significantly increased blood LDL-C levels as compared with SCD (HFD: 36.8±1.4 mg/dl vs. SCD: 22.0±1.8 mg/dl; P<0.01). In CONV mice atorvastatin treatment significantly reduced blood LDL-C levels after HFD, whereas in ABS mice the LDL-C lowering effect of atorvastatin was markedly attenuated (CONV+HFD+Ator: 31.0±1.8 mg/dl vs. ABS+HFD+Ator: 46.4±3 mg/dl; P<0.01). A significant reduction in the abundance of several plasma lipids, in particular sphingolipids and glycerophospholipids upon atorvastatin treatment was observed in CONV mice, but not in ABS mice. The expressions of distinct hepatic and intestinal cholesterol-regulating genes (ldlr, srebp2, pcsk9 and npc1l1) upon atorvastatin treatment were significantly altered in gut microbiota depleted mice. In response to HFD a decrease in the relative abundance of the bacterial phyla Bacteroides and an increase in the relative abundance of Firmicutes was observed. The altered ratio between Bacteroides and Firmicutes in HFD fed mice was partly reversed upon atorvastatin treatment. Conclusions Our findings indicate a crucial role of the gut microbiome for the regulatory properties of atorvastatin on the serum lipidome and, in turn, support a critical impact of atorvastatin on the gut microbial composition. The results provide novel insights into potential microbiota related mechanisms underlying interindividual variation in modulation of the serum lipidome by statins, given interindividual differences in microbiome composition and function. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Heart Research Foundation

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