Mucosal Microbiota and Metabolome along the Intestinal Tract Reveal a Location-Specific Relationship

ABSTRACT The intestinal microbiota is highly metabolically active and plays an important role in many metabolic processes absent from the human host. Altered microbiota metabolism has been linked to diseases such as obesity, cardiovascular disease, and colorectal cancer. However, there is a gap in the current knowledge on how the microbiota interact with its host in terms of metabolic interactions. Here, we performed an integrated analysis between the mucosa-associated microbiota and the mucosa metabolome in healthy, nonhuman primates to investigate these relationships. The microbiota composition was distinct at each tissue location, with variation by host individual also observed. Microbiota-metabolome dynamics were primarily driven by interactions in the distal colon. These interactions were strongly correlated with dietary component, indicating a possibility to modulate microbiota-metabolomic interactions using prebiotic strategies. IMPORTANCE In a healthy colon, the microbiota produces a vast amount of metabolites that are essential to maintaining homeostasis in the colon microenvironment. In fact, these metabolites produced by the microbiota have been linked to diseases such as obesity, cardiovascular disease, and colorectal cancer. In this study, we used healthy nonhuman primate models to investigate the relationship between microbiota and tissue metabolites. We found that both microbiota and metabolites have location-specific signatures along the intestine. Most importantly, we found that metabolites from food sources correlate with multiple bacteria in different intestinal locations. Overall, this work presents a systems-level map of the association between the microbiota and the metabolites in healthy nonhuman primates, provides candidates for experimental validation, and suggests a possibility to regulate the gut microbiota through specific prebiotic combinations.

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Mucosal microbiota and metabolome along the intestinal tracts reveals location specific relationship

10.1101/454496 ◽

2018 ◽

Cited By ~ 2

Author(s):

Ce Yuan ◽

Melanie Graham ◽

Christopher Staley ◽

Subbaya Subramanian

Keyword(s):

Intestinal Microbiota ◽

Metabolic Pathways ◽

Current Knowledge ◽

Distal Colon ◽

Host Tissue ◽

Integrated Analysis ◽

Mucosal Tissue ◽

Interconnected Network ◽

Metabolic Interactions ◽

Small Intestinal

AbstractBackgroundThe intestinal microbiota has been recognized as an important component for maintaining human health. The perturbation to its structure has been implicated in many diseases, such as obesity and cancers. The microbiota is highly metabolically active and plays a role in many metabolic pathways absent from the human host. Altered microbiota metabolism has also been linked to obesity, cardiovascular disease, and colorectal cancer. However, there is a gap in the current knowledge of how the microbiota interacts with its host. Here we performed an integrated analysis between the mucosal-associated microbiota and the mucosal tissue metabolomics in healthy non-human primates (NHPs) to investigate these relationships.ResultsWe found that the overall microbiota composition is influenced by both the tissue location as well as the host individual. The NHPs intestinal microbiota predominantly comprised of members of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. The large intestines contain more Spirochaetes, Tenericutes, and Lentisphaera phyla members. The small intestinal tissues have no significantly different microbiota compositions, while the cecum and distal colon differ greatly in the microbiota compositions. The metabolomics profile reveals a total of 140 metabolites with different concentration between the small and large intestines. The correlations between microbiota and tissue metabolites showed a dense and interconnected network in the small intestines while a sparse network in the large intestines.ConclusionsOur analysis revealed an intricate global relationship between the microbiota and the host tissue metabolome that is mainly driven by the distal colon. Most importantly, we found location specific microbiota-metabolite correlations that have potential implications for studying host-microbiota metabolic interactions.

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Role of Regulatory Oncogenic or Tumor Suppressor miRNAs of PI3K/AKT Signaling Axis in the Pathogenesis of Colorectal Cancer

Current Pharmaceutical Design ◽

10.2174/1381612825666190110151957 ◽

2019 ◽

Vol 24 (39) ◽

pp. 4605-4610 ◽

Cited By ~ 7

Author(s):

Atena Soleimani ◽

Farzad Rahmani ◽

Gordon A. Ferns ◽

Mikhail Ryzhikov ◽

Amir Avan ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Suppressor ◽

Current Knowledge ◽

Akt Signaling ◽

Tumor Tissues ◽

Radio Therapy ◽

Signaling Axis ◽

Cancer Tumor ◽

Novel Biomarkers

Colorectal cancer (CRC) is the leading cause of cancer death worldwide and its incidence is increasing. In most patients with CRC, the PI3K/AKT signaling axis is over-activated. Regulatory oncogenic or tumor suppressor microRNAs (miRNAs) for PI3K/AKT signaling regulate cell proliferation, migration, invasion, angiogenesis, as well as resistance to chemo-/radio-therapy in colorectal cancer tumor tissues. Thus, regulatory miRNAs of PI3K/AKT/mTOR signaling represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies. This review summarizes the current knowledge of miRNAs’ regulatory roles of PI3K/AKT signaling in CRC pathogenesis.

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Free Fatty Acid Receptors as New Potential Targets in Colorectal Cancer

Current Drug Targets ◽

10.2174/1389450120666191112141901 ◽

2020 ◽

Vol 21 (14) ◽

pp. 1397-1404

Author(s):

Adrian Bartoszek ◽

Jakub Fichna ◽

Aleksandra Tarasiuk ◽

Agata Binienda ◽

Adam Fabisiak ◽

...

Keyword(s):

Colorectal Cancer ◽

Fatty Acid ◽

Free Fatty Acid ◽

Current Knowledge ◽

Developed Countries ◽

Future Directions ◽

Screening Programs ◽

Pharmacological Targets ◽

The Family ◽

Free Fatty Acid Receptors

Colorectal cancer (CRC) is one of the most common cancers worldwide. In developed countries, its mortality remains high, yet the prevalence has established owing to effective screening programs; however due to the westernization of lifestyle, the incidences in many other countries have increased. Although the treatment of CRC has improved in the last few years, the side effects of these approaches cannot be neglected. Recently, members of the family of free fatty acid receptors (FFARs) have become attractive pharmacological targets in many diseases, including asthma; studies also point to their role in carcinogenesis. Here, we discuss current knowledge and future directions in FFAR research related to CRC. Contradictory results of FFARs modulation may derive from the pleiotropic effects of FFAR ligands, receptor distribution and different signal transduction. Hence, we indicate directions of further studies to fully use the potential of FFARs in CRC.

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The Role of Major Histocompatibility Complex in Organ Transplantation- Donor Specific Anti-Major Histocompatibility Complex Antibodies Analysis Goes to the Next Stage -

International Journal of Molecular Sciences ◽

10.3390/ijms20184544 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4544 ◽

Cited By ~ 3

Author(s):

Tsukasa Nakamura ◽

Takayuki Shirouzu ◽

Katsuya Nakata ◽

Norio Yoshimura ◽

Hidetaka Ushigome

Keyword(s):

Major Histocompatibility Complex ◽

Organ Transplantation ◽

Current Knowledge ◽

Human Leukocyte ◽

Strongly Correlated ◽

Human Beings ◽

Major Histocompatibility ◽

Antibody Mediated Rejection ◽

Leukocyte Antigens ◽

Histocompatibility Complex

Organ transplantation has progressed with the comprehension of the major histocompatibility complex (MHC). It is true that the outcome of organ transplantation largely relies on how well rejection is managed. It is no exaggeration to say that to be well acquainted with MHC is a shortcut to control rejection. In human beings, MHC is generally recognized as human leukocyte antigens (HLA). Under the current circumstances, the number of alleles is still increasing, but the function is not completely understood. Their roles in organ transplantation are of vital importance, because mismatches of HLA alleles possibly evoke both cellular and antibody-mediated rejection. Even though the control of cellular rejection has improved by recent advances of immunosuppressants, there is no doubt that antibody-mediated rejection (AMR), which is strongly correlated with donor-specific anti-HLA antibodies (DSA), brings a poor outcome. Thus, to diagnose and treat AMR correctly is a clear proposition. In this review, we would like to focus on the detection of intra-graft DSA as a recent trend. Overall, here we will review the current knowledge regarding MHC, especially with intra-graft DSA, and future perspectives: HLA epitope matching; eplet risk stratification; predicted indirectly recognizable HLA epitopes etc. in the context of organ transplantation.

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The Relationship between Inflammation Markers (CRP, IL-6, sCD40L) and Colorectal Cancer Stage, Grade, Size and Location

Diagnostics ◽

10.3390/diagnostics11081382 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1382

Author(s):

Olga Martyna Koper-Lenkiewicz ◽

Violetta Dymicka-Piekarska ◽

Anna Justyna Milewska ◽

Justyna Zińczuk ◽

Joanna Kamińska

Keyword(s):

Colorectal Cancer ◽

Linear Regression ◽

Tumor Size ◽

Distal Colon ◽

Proximal Colon ◽

Model Parameters ◽

Grade Group ◽

Who Grade ◽

The Mean ◽

Mean Concentration

The aim of the study was the evaluation whether in primary colorectal cancer (CRC) patients (n = 55): age, sex, TNM classification results, WHO grade, tumor location (proximal colon, distal colon, rectum), tumor size, platelet count (PLT), mean platelet volume (MPV), mean platelet component (MCP), levels of carcinoembryonic antigen (CEA), cancer antigen (CA 19-9), as well as soluble lectin adhesion molecules (L-, E-, and P-selectins) may influence circulating inflammatory biomarkers: IL-6, CRP, and sCD40L. We found that CRP concentration evaluation in routine clinical practice may have an advantage as a prognostic biomarker in CRC patients, as this protein the most comprehensively reflects clinicopathological features of the tumor. Univariate linear regression analysis revealed that in CRC patients: (1) with an increase in PLT by 10 × 103/μL, the mean concentration of CRP increases by 3.4%; (2) with an increase in CA 19-9 of 1 U/mL, the mean concentration of CRP increases by 0.7%; (3) with the WHO 2 grade, the mean CRP concentration increases 3.631 times relative to the WHO 1 grade group; (4) with the WHO 3 grade, the mean CRP concentration increases by 4.916 times relative to the WHO 1 grade group; (5) with metastases (T1-4N+M+) the mean CRP concentration increases 4.183 times compared to non-metastatic patients (T1-4N0M0); (6) with a tumor located in the proximal colon, the mean concentration of CRP increases 2.175 times compared to a tumor located in the distal colon; (7) in patients with tumor size > 3 cm, the CRP concentration is about 2 times higher than in patients with tumor size ≤ 3 cm. In the multivariate linear regression model, the variables that influence the mean CRP value in CRC patients included: WHO grade and tumor localization. R2 for the created model equals 0.50, which indicates that this model explains 50% of the variance in the dependent variable. In CRC subjects: (1) with the WHO 2 grade, the mean CRP concentration rises 3.924 times relative to the WHO 1 grade; (2) with the WHO 3 grade, the mean CRP concentration increases 4.721 times in relation to the WHO 1 grade; (3) with a tumor located in the rectum, the mean CRP concentration rises 2.139 times compared to a tumor located in the distal colon; (4) with a tumor located in the proximal colon, the mean concentration of CRP increases 1.998 times compared to the tumor located in the distal colon; if other model parameters are fixed.

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Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

International Journal of Molecular Sciences ◽

10.3390/ijms22158117 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8117

Author(s):

Nunzia D’Onofrio ◽

Elisa Martino ◽

Luigi Mele ◽

Antonino Colloca ◽

Martina Maione ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Current Knowledge ◽

Apoptotic Cell ◽

Critical Role ◽

Dependent Manner ◽

Colon Cancer Cells ◽

Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

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A Crosstalk between Diet, Microbiome and microRNA in Epigenetic Regulation of Colorectal Cancer

Nutrients ◽

10.3390/nu13072428 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2428

Author(s):

Małgorzata Guz ◽

Witold Jeleniewicz ◽

Anna Malm ◽

Izabela Korona-Glowniak

Keyword(s):

Colorectal Cancer ◽

Gastrointestinal Tract ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Current Knowledge ◽

Vital Role ◽

Disease States ◽

Health And Disease ◽

Dietary Components ◽

Non Coding Rnas

A still growing interest between human nutrition in relation to health and disease states can be observed. Dietary components shape the composition of microbiota colonizing our gastrointestinal tract which play a vital role in maintaining human health. There is a strong evidence that diet, gut microbiota and their metabolites significantly influence our epigenome, particularly through the modulation of microRNAs. These group of small non-coding RNAs maintain cellular homeostasis, however any changes leading to impaired expression of miRNAs contribute to the development of different pathologies, including neoplastic diseases. Imbalance of intestinal microbiota due to diet is primary associated with the development of colorectal cancer as well as other types of cancers. In the present work we summarize current knowledge with particular emphasis on diet-microbiota-miRNAs axis and its relation to the development of colorectal cancer.

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Race/ethnicity, sex and insurance disparities in colorectal cancer screening among individuals with and without cardiovascular disease

Preventive Medicine Reports ◽

10.1016/j.pmedr.2020.101263 ◽

2021 ◽

Vol 21 ◽

pp. 101263

Author(s):

Swati Sakhuja ◽

Mackenzie E. Fowler ◽

Akinyemi I. Ojesina

Keyword(s):

Colorectal Cancer ◽

Cardiovascular Disease ◽

Cancer Screening ◽

Colorectal Cancer Screening ◽

Race Ethnicity

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Meat and Human Health—Current Knowledge and Research Gaps

Foods ◽

10.3390/foods10071556 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1556

Author(s):

Nina Rica Wium Geiker ◽

Hanne Christine Bertram ◽

Heddie Mejborn ◽

Lars O. Dragsted ◽

Lars Kristensen ◽

...

Keyword(s):

Current Knowledge ◽

Biological Effects ◽

Saturated Fatty Acids ◽

Saturated Fat ◽

Meat Consumption ◽

Metabolic Effects ◽

Food Sources ◽

Current Evidence ◽

Processed Meat ◽

Total Energy Consumption

Meat is highly nutritious and contributes with several essential nutrients which are difficult to obtain in the right amounts from other food sources. Industrially processed meat contains preservatives including salts, possibly exerting negative effects on health. During maturation, some processed meat products develop a specific microbiota, forming probiotic metabolites with physiological and biological effects yet unidentified, while the concentration of nutrients also increases. Meat is a source of saturated fatty acids, and current WHO nutrition recommendations advise limiting saturated fat to less than ten percent of total energy consumption. Recent meta-analyses of both observational and randomized controlled trials do not support any effect of saturated fat on cardiovascular disease or diabetes. The current evidence regarding the effect of meat consumption on health is potentially confounded, and there is a need for sufficiently powered high-quality trials assessing the health effects of meat consumption. Future studies should include biomarkers of meat intake, identify metabolic pathways and include detailed study of fermented and other processed meats and their potential of increasing nutrient availability and metabolic effects of compounds.

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