Several differential panels of metabolites have been associated with the presence of metabolic syndrome and its related conditions, namely non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This study aimed to perform a systematic review to summarize the most recent finding in terms of circulating biomarkers following NAFLD/NASH syndromes. Hence, the research was focused on NAFLD/NASH studies analysed by metabolomics approaches. Following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, a systematic search was conducted on the PubMed database. The inclusion criteria were (i) publication date between 2010 and 2021, (ii) presence of the combination of terms: metabolomics and NAFLD/NASH, and (iii) published in a scholarly peer-reviewed journal. Studies were excluded from the review if they were (i) single-case studies, (ii) unpublished thesis and dissertation studies, and (iii) not published in a peer-reviewed journal. Following these procedures, 10 eligible studies among 93 were taken into consideration. The metabolisms of amino acids, fatty acid, and vitamins were significantly different in patients affected by NAFLD and NASH compared to healthy controls. These findings suggest that low weight metabolites are an important indicator for NAFLD/NASH syndrome and there is a strong overlap between NAFLD/NASH and the metabolic syndrome. These findings may lead to new perspectives in early diagnosis, identification of novel biomarkers, and providing novel targets for pharmacological interventions.

Ferulic acid (FA) is a polyphenol pertaining to the class of hydroxycinnamic acids present in numerous foods of a plant origin. Its dietary consumption leads to the formation of several phase I and II metabolites in vivo, which represent the largest amount of ferulates in the circulation and in the intestine in comparison with FA itself. In this work, we evaluated their efficacy against the proinflammatory effects induced by lipopolysaccharide (LPS) in intestinal Caco-2 cell monolayers, as well as the mechanisms underlying their protective action. LPS-induced overexpression of proinflammatory enzymes such as inducible nitric oxide synthase (iNOS) and the consequent hyperproduction of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) were limited by physiological relevant concentrations (1 µM) of FA, its derivatives isoferulic acid (IFA) and dihydroferulic acid (DHFA), and their glucuronidated and sulfated metabolites, which acted upstream by limiting the activation of MAPK p38 and ERK and of Akt kinase, thus decreasing the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) translocation into the nucleus. Furthermore, the compounds were found to promote the expression of Nrf2, which may have contributed to the downregulation of NF-ĸB activity. The overall data show that phase I/II metabolites retain the efficacy of their dietary free form in contrasting inflammatory response.

High-dose of vitamin C (L-ascorbic acid, ascorbate) exhibits anti-tumoral effects, primarily mediated by pro-oxidant mechanisms. This cytotoxic effect is thought to affect the reciprocal crosstalk between redox balance and cell metabolism in different cancer types. Vitamin C also inhibits the growth of papillary thyroid carcinoma (PTC) cells, although the metabolic and redox effects remain to be fully understood. To shed light on these aspects, PTC-derived cell lines harboring the most common genetic alterations characterizing this tumor were used. Cell viability, apoptosis, and the metabolome were explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, and UHPLC/MS. Changes were observed in redox homeostasis, with increased reactive oxygen species (ROS) level and perturbation in antioxidants and electron carriers, leading to cell death by both apoptosis and necrosis. The oxidative stress contributed to the metabolic alterations in both glycolysis and TCA cycle. Our results confirm the pro-oxidant effect of vitamin C as relevant in triggering the cytotoxicity in PTC cells and suggest that inhibition of glycolysis and alteration of TCA cycle via NAD⁺ depletion can play an important role in this mechanism of PTC cancer cell death.

Cancer cells adjust their metabolism to meet energy demands. In particular, glutamine addiction represents a distinctive feature of several types of tumors, including colorectal cancer. In this study, four colorectal cancer cell lines (Caco-2, HCT116, HT29 and SW480) were cultured with or without glutamine. The growth and proliferation rate, colony-forming capacity, apoptosis, cell cycle, redox homeostasis and metabolomic analysis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, high-performance liquid chromatography and gas chromatography/mass spectrometry techniques. The results show that glutamine represents an important metabolite for cell growth and that its deprivation reduces the proliferation of colorectal cancer cells. Glutamine depletion induces cell death and cell cycle arrest in the GO/G1 phase by modulating energy metabolism, the amino acid content and antioxidant defenses. Moreover, the combined glutamine starvation with the glycolysis inhibitor 2-deoxy-D-glucose exerted a stronger cytotoxic effect. This study offers a strong rationale for targeting glutamine metabolism alone or in combination with glucose metabolism to achieve a therapeutic benefit in the treatment of colon cancer.

Inflammatory bowel diseases (IBD) are the most common gastrointestinal inflammatory pathologies. Previous work evidenced a lower content of nicotinic acid (NA) in feces of IBD patients compared to healthy subjects. In the present study, we aimed to understand the effects of NA on intestinal inflammation, as several studies reported its possible beneficial effect, and investigate its influence on inflammation-driven metabolism. NA was tested on a Caco-2 in-vitro model in which inflammation was induced with interleukin-1β (IL-1β) and lipopolysaccharide (LPS), two mayor proinflammatory compounds produced in IBD, that stimulate the production of cytokines, such as interleukin 8. A metabolomics approach, with gas chromatography–mass spectrometry (GC-MS) and nuclear proton magnetic resonance (¹H-NMR), was applied to study the metabolic changes. The results showed that NA significantly reduced the level of IL-8 produced in both LPS and IL-1β stimulated cells, confirming the anti-inflammatory effect of NA also on intestinal inflammation. Moreover, it was demonstrated that NA treatment had a restoring effect on several metabolites whose levels were modified by treatments with IL-1β or LPS. This study points out a possible use of NA as anti-inflammatory compound and might be considered as a promising starting point in understanding the beneficial effect of NA in IBD.

Metabolomics represents a promising non-invasive approach that can be applied to identify biochemical changes in colorectal cancer patients (CRC) and is potentially useful for diagnosis and follow-up. Despite the literature regarding metabolomics CRC-specific profiles, discrimination between metabolic changes specifically related to CRC and intra-individual variability is still a problem to be solved. This was a preliminary case-control study, in which ¹H-NMR spectroscopy combined with multivariate statistical analysis was used to profile urine metabolites in subjects undergoing colonoscopy for colon cancer diagnosis. To reduce intra-individual variability, metabolic profiles were evaluated in participants’ urine samples, collected just before the colonoscopy and after a short-term dietary regimen required for the endoscopy procedure. Data obtained highlighted different urinary metabolic profiles between CRC and unaffected subjects (C). The metabolites altered in the CRC urine (acetoacetate, creatine, creatinine, histamine, phenylacetylglycine, and tryptophan) significantly correlated with colon cancer and discriminated with accuracy CRC patients from C patients (receiver operator characteristic (ROC) curve with an area under the curve (AUC) of 0.875; 95% CI: 0.667–1). These results confirm that urinary metabolomic analysis can be a valid tool to improve CRC diagnosis, prognosis, and response to therapy, representing a noninvasive approach that could precede more invasive tests.