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The Microbiota and Its Association with Cellular Transformation and Metabolic Changes

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 32256

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Dr. Davide Zella

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Guest Editor

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Interests: human microbiota; cancer biology; p53; DNA repair; DnaK; cellular transformation
Special Issues, Collections and Topics in MDPI journals

Dr. Francesca Benedetti

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Guest Editor

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Interests: microbiota; cancer biology; p53; DnaK
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, scientists have made remarkable discoveries as regards elucidating the association between the human microbiota and both human cancers and metabolic changes. New data point to modified immunological activation, altered metabolism, and dysregulated kinase activation with consequent impaired cellular signal transduction. In vitro studies have also shown that several bacteria are able to promote epigenetic changes, alter host cell cycles, affect apoptotic pathways, and stimulate the production of inflammatory substances that can lead to DNA damage, thus potentially promoting abnormal cell growth and transformation. In addition, in vivo experiments have shown that the treatment of germ-free animals with cancer-inducing agents has resulted in a reduction of tumor formation, compared to non-germ-free mice. Finally, studies in human subjects have further highlighted the association between certain bacteria, such as H. pylori, F. nucleatum, and some mycoplasmas, and the origin of some cancers. However, the precise mechanisms of cellular transformation are still largely unknown. This Special Issue will collect original research articles and review papers related to any aspect of the crosstalk between the human microbiota and the host cell, aimed at describing and elucidating potential molecular mechanisms promoting cellular transformation and metabolic changes.

Dr. Davide Zella
Dr. Francesca Benedetti
Guest Editors

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Keywords

Microbiota–host cell interaction;
Cancer biology;
Cellular transformation;
Molecular pathways

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Published Papers (8 papers)

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Research

Jump to: Review

15 pages, 3190 KiB

Open AccessArticle

Irradiation-Induced Dysbiosis: The Compounding Effect of High-Fat Diet on Metabolic and Immune Functions in Mice

by Briana K. Clifford, Nadia M. L. Amorim, Nadeem O. Kaakoush, Lykke Boysen, Nicodemus Tedla, David Goldstein, Edna C. Hardeman and David Simar

Int. J. Mol. Sci. 2023, 24(6), 5631; https://doi.org/10.3390/ijms24065631 - 15 Mar 2023

Viewed by 2222

Abstract

The negative impact of irradiation or diet on the metabolic and immune profiles of cancer survivors have been previously demonstrated. The gut microbiota plays a critical role in regulating these functions and is highly sensitive to cancer therapies. The aim of this study was to investigate the effect of irradiation and diet on the gut microbiota and metabolic or immune functions. We exposed C57Bl/6J mice to a single dose of 6 Gy radiation and after 5 weeks, fed them a chow or high-fat diet (HFD) for 12 weeks. We characterised their faecal microbiota, metabolic (whole body and adipose tissue) functions, and systemic (multiplex cytokine, chemokine assay, and immune cell profiling) and adipose tissue inflammatory profiles (immune cell profiling). At the end of the study, we observed a compounding effect of irradiation and diet on the metabolic and immune profiles of adipose tissue, with exposed mice fed a HFD displaying a greater inflammatory signature and impaired metabolism. Mice fed a HFD also showed altered microbiota, irrespective of irradiation status. An altered diet may exacerbate the detrimental effects of irradiation on both the metabolic and inflammatory profiles. This could have implications for the diagnosis and prevention of metabolic complications in cancer survivors exposed to radiation. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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18 pages, 5017 KiB

Open AccessArticle

Microbiome Dysbiosis Shows Strong Association of Gut-Derived Altered Metabolomic Profile in Gulf War Chronic Multisymptom Illness Symptom Persistence Following Western Diet Feeding and Development of Obesity

by Dipro Bose, Vitalli Stebliankin, Trevor Cickovski, Punnag Saha, Ayushi Trivedi, Subhajit Roy, Madhura More, Ashok Tuteja, Kalai Mathee, Giri Narasimhan and Saurabh Chatterjee

Int. J. Mol. Sci. 2023, 24(4), 4245; https://doi.org/10.3390/ijms24044245 - 20 Feb 2023

Cited by 1 | Viewed by 4897

Abstract

The pathophysiology of Gulf War Illness (GWI) remains elusive even after three decades. The persistence of multiple complex symptoms along with metabolic disorders such as obesity worsens the health of present Gulf War (GW) Veterans often by the interactions of the host gut microbiome and inflammatory mediators. In this study, we hypothesized that the administration of a Western diet might alter the host metabolomic profile, which is likely associated with the altered bacterial species. Using a five-month symptom persistence GWI model in mice and whole-genome sequencing, we characterized the species-level dysbiosis and global metabolomics, along with heterogenous co-occurrence network analysis, to study the bacteriome–metabolomic association. Microbial analysis at the species level showed a significant alteration of beneficial bacterial species. The beta diversity of the global metabolomic profile showed distinct clustering due to the Western diet, along with the alteration of metabolites associated with lipid, amino acid, nucleotide, vitamin, and xenobiotic metabolism pathways. Network analysis showed novel associations of gut bacterial species with metabolites and biochemical pathways that could be used as biomarkers or therapeutic targets to ameliorate symptom persistence in GW Veterans. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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17 pages, 6129 KiB

Open AccessArticle

Pathogenesis of Tobacco-Associated Lung Adenocarcinoma Is Closely Coupled with Changes in the Gut and Lung Microbiomes

by Casey T. Finnicum, Zahraa Rahal, Maya Hassane, Warapen Treekitkarnmongkol, Ansam Sinjab, Rhiannon Morris, Yuejiang Liu, Elizabeth L. Tang, Sarah Viet, Jason L. Petersen, Philip L. Lorenzi, Lin Tan, Joseph Petrosino, Kristi L. Hoffman, Junya Fujimoto, Seyed Javad Moghaddam and Humam Kadara

Int. J. Mol. Sci. 2022, 23(18), 10930; https://doi.org/10.3390/ijms231810930 - 18 Sep 2022

Cited by 4 | Viewed by 3581

Abstract

Microbial dysbiosis has emerged as a modulator of oncogenesis and response to therapy, particularly in lung cancer. Here, we investigate the evolution of the gut and lung microbiomes following exposure to a tobacco carcinogen. We performed 16S rRNA-Seq of fecal and lung samples collected prior to and at several timepoints following (nicotine-specific nitrosamine ketone/NNK) exposure in Gprc5a^−/− mice that were previously shown to exhibit accelerated lung adenocarcinoma (LUAD) development following NNK exposure. We found significant progressive changes in human-relevant gut and lung microbiome members (e.g., Odoribacter, Alistipes, Akkermansia, and Ruminococus) that are closely associated with the phenotypic development of LUAD and immunotherapeutic response in human lung cancer patients. These changes were associated with decreased short-chain fatty acids (propionic acid and butyric acid) following exposure to NNK. We next sought to study the impact of Lcn2 expression, a bacterial growth inhibitor, given our previous findings on its protective role in LUAD development. Indeed, we found that the loss of Lcn2 was associated with widespread gut and lung microbiome changes at all timepoints, distinct from those observed in our Gprc5a^−/− mouse model, including a decrease in abundance and diversity. Our overall findings apprise novel cues implicating microbial phenotypes in the development of tobacco-associated LUAD. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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29 pages, 2867 KiB

Open AccessArticle

The Effect of Intensity-Modulated Radiotherapy to the Head and Neck Region on the Oral Innate Immune Response and Oral Microbiome: A Prospective Cohort Study of Head and Neck Tumour Patients

by Zahra Dorna Mojdami, Abdelahhad Barbour, Morvarid Oveisi, Chunxiang Sun, Noah Fine, Sourav Saha, Cara Marks, Omnia Elebyary, Erin Watson, Howard Tenenbaum, Amir Azarpazhooh and Michael Glogauer

Int. J. Mol. Sci. 2022, 23(17), 9594; https://doi.org/10.3390/ijms23179594 - 24 Aug 2022

Cited by 6 | Viewed by 2759

Abstract

Neutrophils, also known as polymorphonuclear leukocytes (PMNs), form a significant component of the innate host response, and the consequence of the interaction between the oral microbiota and PMNs is a crucial determinant of oral health status. The impact of radiation therapy (RT) for head and neck tumour (HNT) treatment on the oral innate immune system, neutrophils in particular, and the oral microbiome has not been thoroughly investigated. Therefore, the objective of this study was to characterize RT-mediated changes in oral neutrophils (oPMNs) and the oral microbiome in patients undergoing RT to treat HNTs. Oral rinse samples were collected prior to, during and post-RT from HNT patients receiving RT at Dental Oncology at Princess Margaret Cancer Centre. The oPMNs counts and activation states were analysed using flow cytometry, and the oral microbiome was analysed using 16S rRNA gene sequencing. Statistically significant (p < 0.05) drops in oPMN counts and the activation states of the CD11b, CD16, CD18, CD64 and H3Cit markers from pre-RT to post-RT were observed. Moreover, exposure to RT caused a significant reduction in the relative abundance of commensal Gram-negative bacteria and increased the commensal Gram-positive microbes. Ionizing radiation for the treatment of HNTs simultaneously decreased the recruitment of oPMNs into the oral cavity and suppressed their activation state. The oral microbiome composition post-RT was altered significantly due to RT which may favour the colonization of specific microbial communities unfavourable for the long-term development of a balanced oral microbiome. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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17 pages, 4677 KiB

Open AccessArticle

ZIP8-Mediated Intestinal Dysbiosis Impairs Pulmonary Host Defense against Bacterial Pneumonia

by Derrick R. Samuelson, Deandra R. Smith, Kelly C. Cunningham, Todd A. Wyatt, Sannette C. Hall, Daryl J. Murry, Yashpal S. Chhonker and Daren L. Knoell

Int. J. Mol. Sci. 2022, 23(3), 1022; https://doi.org/10.3390/ijms23031022 - 18 Jan 2022

Cited by 8 | Viewed by 2672

Abstract

Pneumococcal pneumonia is a leading cause of morbidity and mortality worldwide. An increased susceptibility is due, in part, to compromised immune function. Zinc is required for proper immune function, and an insufficient dietary intake increases the risk of pneumonia. Our group was the first to reveal that the Zn transporter, ZIP8, is required for host defense. Furthermore, the gut microbiota that is essential for lung immunity is adversely impacted by a commonly occurring defective ZIP8 allele in humans. Taken together, we hypothesized that loss of the ZIP8 function would lead to intestinal dysbiosis and impaired host defense against pneumonia. To test this, we utilized a novel myeloid-specific Zip8KO mouse model in our studies. The comparison of the cecal microbial composition of wild-type and Zip8KO mice revealed significant differences in microbial community structure. Most strikingly, upon a S. pneumoniae lung infection, mice recolonized with Zip8KO-derived microbiota exhibited an increase in weight loss, bacterial dissemination, and lung inflammation compared to mice recolonized with WT microbiota. For the first time, we reveal the critical role of myeloid-specific ZIP8 on the maintenance of the gut microbiome structure, and that loss of ZIP8 leads to intestinal dysbiosis and impaired host defense in the lung. Given the high incidence of dietary Zn deficiency and the ZIP8 variant allele in the human population, additional investigation is warranted to improve surveillance and treatment strategies. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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Review

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21 pages, 939 KiB

Open AccessReview

The Role of Next-Generation Probiotics in Obesity and Obesity-Associated Disorders: Current Knowledge and Future Perspectives

by Natalia G. Vallianou, Dimitris Kounatidis, Dimitrios Tsilingiris, Fotis Panagopoulos, Gerasimos Socrates Christodoulatos, Angelos Evangelopoulos, Irene Karampela and Maria Dalamaga

Int. J. Mol. Sci. 2023, 24(7), 6755; https://doi.org/10.3390/ijms24076755 - 4 Apr 2023

Cited by 34 | Viewed by 7909

Abstract

Obesity and obesity-associated disorders pose a major public health issue worldwide. Apart from conventional weight loss drugs, next-generation probiotics (NGPs) seem to be very promising as potential preventive and therapeutic agents against obesity. Candidate NGPs such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Anaerobutyricum hallii, Bacteroides uniformis, Bacteroides coprocola, Parabacteroides distasonis, Parabacteroides goldsteinii, Hafnia alvei, Odoribacter laneus and Christensenella minuta have shown promise in preclinical models of obesity and obesity-associated disorders. Proposed mechanisms include the modulation of gut flora and amelioration of intestinal dysbiosis, improvement of intestinal barrier function, reduction in chronic low-grade inflammation and modulation of gut peptide secretion. Akkermansia muciniphila and Hafnia alvei have already been administered in overweight/obese patients with encouraging results. However, safety issues and strict regulations should be constantly implemented and updated. In this review, we aim to explore (1) current knowledge regarding NGPs; (2) their utility in obesity and obesity-associated disorders; (3) their safety profile; and (4) their therapeutic potential in individuals with overweight/obesity. More large-scale, multicentric and longitudinal studies are mandatory to explore their preventive and therapeutic potential against obesity and its related disorders. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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19 pages, 2313 KiB

Open AccessReview

Gut Microbiome Composition and Its Metabolites Are a Key Regulating Factor for Malignant Transformation, Metastasis and Antitumor Immunity

by Stefan Lozenov, Boris Krastev, Georgi Nikolaev, Monika Peshevska-Sekulovska, Milena Peruhova and Tsvetelina Velikova

Int. J. Mol. Sci. 2023, 24(6), 5978; https://doi.org/10.3390/ijms24065978 - 22 Mar 2023

Cited by 11 | Viewed by 3638

Abstract

The genetic and metabolomic abundance of the microbiome exemplifies that the microbiome comprises a more extensive set of genes than the entire human genome, which justifies the numerous metabolic and immunological interactions between the gut microbiota, macroorganisms and immune processes. These interactions have local and systemic impacts that can influence the pathological process of carcinogenesis. The latter can be promoted, enhanced or inhibited by the interactions between the microbiota and the host. This review aimed to present evidence that interactions between the host and the gut microbiota might be a significant exogenic factor for cancer predisposition. It is beyond doubt that the cross-talk between microbiota and the host cells in terms of epigenetic modifications can regulate gene expression patterns and influence cell fate in both beneficial and adverse directions for the host’s health. Furthermore, bacterial metabolites could shift pro- and anti-tumor processes in one direction or another. However, the exact mechanisms behind these interactions are elusive and require large-scale omics studies to better understand and possibly discover new therapeutic approaches for cancer. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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19 pages, 815 KiB

Open AccessReview

The Role of Microbiota in Liver Transplantation and Liver Transplantation-Related Biliary Complications

by Ulrich Wirth, Tianxiao Jiang, Josefine Schardey, Katharina Kratz, Mingming Li, Malte Schirren, Florian Kühn, Alexandr Bazhin, Jens Werner, Markus Guba, Christian Schulz and Joachim Andrassy

Int. J. Mol. Sci. 2023, 24(5), 4841; https://doi.org/10.3390/ijms24054841 - 2 Mar 2023

Cited by 7 | Viewed by 3160

Abstract

Liver transplantation as a treatment option for end-stage liver diseases is associated with a relevant risk for complications. On the one hand, immunological factors and associated chronic graft rejection are major causes of morbidity and carry an increased risk of mortality due to liver graft failure. On the other hand, infectious complications have a major impact on patient outcomes. In addition, abdominal or pulmonary infections, and biliary complications, including cholangitis, are common complications in patients after liver transplantation and can also be associated with a risk for mortality. Thereby, these patients already suffer from gut dysbiosis at the time of liver transplantation due to their severe underlying disease, causing end-stage liver failure. Despite an impaired gut-liver axis, repeated antibiotic therapies can cause major changes in the gut microbiome. Due to repeated biliary interventions, the biliary tract is often colonized by several bacteria with a high risk for multi-drug resistant germs causing local and systemic infections before and after liver transplantation. Growing evidence about the role of gut microbiota in the perioperative course and their impact on patient outcomes in liver transplantation is available. However, data about biliary microbiota and their impact on infectious and biliary complications are still sparse. In this comprehensive review, we compile the current evidence for the role of microbiome research in liver transplantation with a focus on biliary complications and infections due to multi-drug resistant germs. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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