Biology subjects

Nemet, I.

Publications and source records attributed to Nemet, I..

7 recordsLinked to original sources

bioRxiv2026

Gut microbially produced phenolic acids have differential and sex-dependent effects on host metabolic health

Gut microbiota-derived metabolites are increasingly recognized as important regulators of host metabolism, but the specific functions of individual metabolites remain poorly understood. We therefore investigated the metabolic effects of two structurally related, phenylalanine-derived microbial metabolites phenylacetic acid (PAA) and phenylpropionic acid (PPA) in a mouse model of diet-induced obesity. Although clinical studies have linked PAA and its downstream product phenylacetylglutamine to metabolic disease, PAA did not alter body mass or adiposity in this model. Instead, it improved glucose tolerance selectively in male mice and markedly remodeled lipid metabolism in both sexes, reducing circulating triglycerides and acylcarnitines and activating hepatic PPAR--associated transcriptional programs associated with fatty acid {omega}-hydroxylation and peroxisomal lipid metabolism. Despite this extensive metabolic remodeling, PAA did not worsen hepatic steatosis, fibrosis, or markers of liver injury. By contrast, PPA had minimal effects on hepatic metabolic pathways but produced pronounced sex-dependent physiological responses, increasing adiposity in female mice and improving glucose tolerance in male mice. These findings show that structurally related microbial metabolites can have distinct, sex-dependent metabolic effects and highlight the need to define the actions of individual microbiome-derived metabolites when developing targeted therapies for metabolic disease.

systems biology↗

bioRxiv2025

The antimicrobial metabolite nisin Z reduces intestinal tumorigenesis and modulates the cecal microbiome in ApcMin/+ mice

Nisin Z, an antimicrobial metabolite produced by Lactococcus lactis spp., has been safely used as a food preservative for many years. Nisin Z also showed promising activity against various cancer types in vitro, and significantly reduced tumor size in an ectopic head and neck cancer model. Here, we investigate the activity of nisin Z for colorectal cancer treatment and observed an in vitro reduction in cellular proliferation, and a moderate enhancement in cell death. We next analyzed the effect of oral nisin Z administration in the Apcmin/+ intestinal adenoma mouse model. We measured tumor burden along the gastrointestinal tract and observed a decrease in tumor burden in the middle region of the small intestine, but not in the lower region or colon. Since tumor progression in the Apcmin/+ model is exacerbated by an inflammatory environment, we next determined whether nisin Z impacts this in a direct or indirect manner. We show that nisin Z can directly reduce NF-{kappa}B activation in a dose-dependent manner. In addition, nisin Z impacted the cecal microbiome composition as well as microbiota-associated plasma metabolites, causing an overall shift towards a more health-associated profile. Interestingly, the Apcmin/+ genotype differentially impacted the nisin Z-mediated differences in cecal microbiome composition and plasma metabolites compared to wildtype animals. In summary, our data suggest that the reduction in small intestinal tumor burden could be due to nisin Zs contribution to a reduced pro-inflammatory environment. Future studies will reveal whether nisins localized effect is due to degradation of the peptidic compound in more distal regions of the gastrointestinal tract and focus on development of delivery systems to increase efficacy. ImportanceWith the increased incidence of colorectal cancer, especially among younger individuals, it is critical to study approaches that help with the prevention and treatment of this debilitating disease. Our study indicates that nisin Z, a bacterially produced peptide antibiotic, decreases the growth of colorectal cancer cells and moderately increases cell death in vitro. Oral administration of nisin Z in an intestinal adenoma mouse model revealed a reduction of tumor burden in the middle region of the small intestine. This decreased tumor burden might in part be attributed to a direct anti-inflammatory effect, as well as an indirect effect on the gut microbiota and their metabolites due to nisin Zs antibacterial activity. Overall, we demonstrate a potential activity for nisin Z in the prevention or amelioration of inflammation-associated colorectal cancer, underscoring the significance of investigating the properties of bacterial natural products in human health.

microbiology↗

bioRxiv2025

Gut microbial conversion of dietary elderberry extract to hydrocinnamic acid improves obesity-associated metabolic disorders

Obesity-associated metabolic disorders such as type 2 diabetes mellitus and metabolic dysfunction associated fatty liver disease are major global health concerns, yet current pharmacological treatments often present with major side-effects. Dietary interventions including polyphenol-rich foods offer a promising complementary option for obesity amelioration, but their efficacy is dependent on specific gut microbial metabolism and the underlying molecular mechanisms mostly remain elusive. Here, we demonstrated that dietary elderberry (Eld) extract abrogates the effects of an obesogenic diet in a gut microbiota-dependent manner, by preventing insulin resistance and reducing hepatic steatosis in mice. We developed a targeted, quantitative liquid chromatography-tandem mass spectrometry method for detection of gut bacterial polyphenol catabolites and identified hydrocinnamic acid as a key microbial metabolite, enriched in the portal vein plasma of Eld supplemented animals. Next, we showed that hydrocinnamic acid potently activates hepatic AMP-activated protein kinase , explaining its role in improved liver lipid homeostasis. Furthermore, we uncovered the metabolic pathway cumulating in hydrocinnamic acid production in the common gut commensal Clostridium sporogenes. Our characterization of hydrocinnamic acid as a diet-derived, and microbiota-dependent metabolite with insulin-sensitizing and anti-steatotic activities will contribute to microbiome-targeted dietary interventions to prevent and treat obesity-associated metabolic diseases.

microbiology↗

bioRxiv2024

Identification of strain-specific cues that regulate biofilm formation in Bacteroides thetaiotaomicron

Members of the gut microbiome encounter a barrage of host- and microbe-derived microbiocidal factors that must be overcome to maintain fitness in the intestine. The long-term stability of many gut microbiome strains within the microbiome suggests the existence of strain-specific strategies that have evolved to foster resilience to such insults. Despite this, little is known about the mechanisms that mediate this resistance. Biofilm formation represents one commonly employed defense strategy against stressors like those found in the intestine. Here, we demonstrate strain-level variation in the capacity of the gut symbiont Bacteroides thetaiotaomicron to form biofilms. Despite the potent induction of biofilm formation by purified bile in most strains, we show that the specific bile acid species driving biofilm formation differ among strains, and uncover that a secondary bile-acid, lithocholic acid, and its conjugated forms, potently induce biofilm formation in a strain-specific manner. Additionally, we found that the short-chain fatty acid, acetic acid, could suppress biofilm formation. Thus, our data defines the molecular components of bile that promote biofilm formation in B. thetaiotaomicron and reveals that distinct molecular cues trigger the induction or inhibition of this process. Moreover, we uncover strain-level variation in these responses, thus identifying that both shared and strain-specific determinants govern biofilm formation in this species. ImportanceIn order to thrive within the intestine, it is imperative that gut microbes resist the multitude of insults derived from the host immune system and other microbiome members. As such, they have evolved strategies that ensure their survival within the intestine. We investigated one such strategy, biofilm formation, in Bacteroides thetaiotaomicron, a common member of the human microbiome. We uncovered significant variation in natural biofilm formation in the absence of an overt stimulus among different Bacteroides thetaiotaomicron strains, and revealed that different strains adopted a biofilm lifestyle in response to distinct molecular stimuli. Thus our studies provide novel insights into factors mediating gut symbiont resiliency, revealing strain-specific and shared strategies in these responses. Collectively, our findings underscore the prevalence of strain-level differences that should be factored into our understanding of gut microbiome functions.

microbiology↗

bioRxiv2021

A gut microbial metabolite of dietary polyphenols reverses obesity-driven hepatic steatosis

The molecular mechanisms by which dietary fruits and vegetables confer cardiometabolic benefits remain poorly understood. Historically, these beneficial properties have been attributed to the antioxidant activity of flavonoids. Here, we reveal that the host metabolic benefits associated with flavonoid consumption actually hinge on gut microbial metabolism. We show that a single gut microbial flavonoid catabolite is sufficient to reduce diet-induced cardiometabolic disease burden in mice. Dietary supplementation with elderberry extract attenuated obesity and continuous delivery of the catabolite 4-hydroxphenylacetic acid was sufficient to reverse hepatic steatosis. Analysis of human gut metagenomes revealed that under one percent contains a flavonol catabolic pathway, underscoring the rarity of this process. Our study will impact the design of dietary and probiotic interventions to complement traditional cardiometabolic treatment strategies. One-Sentence SummarySelect gut microbes can metabolize flavonoids from a fruit and vegetable diet to monophenolic acids, which improve fatty liver disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/460661v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1c4f56borg.highwire.dtl.DTLVardef@1cc4be3org.highwire.dtl.DTLVardef@18a4af5org.highwire.dtl.DTLVardef@3f44a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2021

CRISPR screens for host factors critical for infection by SARS-CoV-2 variants of concern identify GATA6 as a central modulator of ACE2.

The global spread of SARS-CoV-2 led to the most challenging pandemic in this century, posing major economic and health challenges worldwide. Revealing host genes essential for infection by multiple variants of SASR-CoV-2 can provide insights into the virus pathogenesis, and facilitates the development of novel broad-spectrum host-directed therapeutics. Here, employing genome-scale CRISPR screens, we provide a comprehensive data-set of cellular factors that are exploited by WT-SARS-CoV-2 as well as two additional recently emerged variants of concerns (VOCs), Alpha and Beta. These screens identified known and novel host factors critical for SARS-CoV-2 infection, including various components belonging to the Clathrin-dependent transport pathway, ubiquitination and Heparan sulfate biogenesis. In addition, the host phosphatidylglycerol biosynthesis processes appeared to have major anti-viral functions. Comparative analysis of the different VOCs revealed the host factors KREMEN2 and SETDB1 as potential unique candidates required only to the Alpha variant, providing a possible explanation for the increased infectivity of this variant. Furthermore, the analysis identified GATA6, a zinc finger transcription factor, as an essential pro-viral gene for all variants inspected. We revealed that GATA6 directly regulates ACE2 transcription and accordingly, is critical for SARS-CoV-2 cell entry. Analysis of clinical samples collected from SARS-CoV-2 infected individuals showed an elevated level of GATA6, indicating the important role GATA6 may be playing in COVID-19 pathogenesis. Finally, pharmacological inhibition of GATA6 resulted in down-modulation of ACE2 and consequently to inhibition of the viral infectivity. Overall, we show GATA6 represents a target for the development of anti-SARS-CoV-2 therapeutic strategies and reaffirm the value of the CRISPR loss-of-function screens in providing a list of potential new targets for therapeutic interventions.

microbiology↗

bioRxiv2021

The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against novel viral variants

A wide range of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) were reported to date, most of which target the spike glycoprotein and in particular its receptor binding domain (RBD) and N-terminal domain (NTD) of the S1 subunit. The therapeutic implementation of these antibodies has been recently challenged by emerging SARS-CoV-2 variants that harbor extensively mutated spike versions. Consequently, the re-assessment of mAbs, previously reported to neutralize the original early-version of the virus, is of high priority. Four previously selected mAbs targeting non-overlapping epitopes, were evaluated for their binding potency to RBD versions harboring individual mutations at spike positions 417, 439, 453, 477, 484 and 501. Mutations at these positions represent the prevailing worldwide distributed modifications of the RBD, previously reported to mediate escape from antibody neutralization. Additionally, the in vitro neutralization potencies of the four RBD-specific mAbs, as well as two NTD-specific mAbs, were evaluated against two frequent SARS-CoV-2 variants of concern (VOCs): (i) the B.1.1.7 variant, emerged in the UK and (ii) the B.1.351 variant, emerged in South Africa. Variant B.1.351 was previously suggested to escape many therapeutic mAbs, including those authorized for clinical use. The possible impact of RBD mutations on recognition by mAbs is addressed by comparative structural modelling. Finally, we demonstrate the therapeutic potential of three selected mAbs by treatment of K18-hACE2 transgenic mice two days post infection with each of the virus strains. Our results clearly indicate that despite the accumulation of spike mutations, some neutralizing mAbs preserve their potency against SARS-CoV-2. In particular, the highly potent MD65 and BL6 mAbs are shown to retain their ability to bind the prevalent novel viral mutations and to effectively protect against B.1.1.7 and B.1.351 variants of high clinical concern.

immunology↗