Exploration of Foods and Foodomics

Table 7. Compilation of studies on pomegranate metabolomics.

S. No.	Short study title	Key methods	Main findings	Relevance	Author/Year
1	Metabolic profiling and untargeted 1H-NMR-based metabolomics study of different Iranian pomegranate ecotypes	1H-NMR and 2D-NMR spectroscopy for untargeted metabolomics; comparison across Iranian ecotypes.	Identified variations in anthocyanins, ellagic acid derivatives and other metabolites. Bajestan, Ferdows, and Yazd ecotypes showed higher anthocyanin & ellagic acid levels.	Demonstrates geographical & varietal differences in pomegranate metabolome, aiding breeding of bioactive-rich cultivars.	Hasanpour et al. (2020) [71]
2	Study of nutritional quality of pomegranate juice using 1H NMR-based metabolomic approach: A comparison between conventionally & organically grown fruits	1H-NMR metabolomics coupled with multivariate analysis; comparison of conventional vs. organic juices.	Organic juices showed enhanced levels of bioactive molecules. Clear divergences in metabolomic profiles, with organic cultivation improving nutraceutical properties.	Highlights cultivation impacts on pomegranate juice metabolome, supporting organic farming.	Villa-Ruano et al. (2020) [72]
3	Development of a new extraction method for pomegranate and metabolite profiling by a LC-MS & 1H NMR combined approach	LC-ESI/MS and 1H-NMR; solid-liquid dynamic extraction (SLDE-Naviglio) with ethanol.	Extract from peel using SLDE-Naviglio was richest in hydrolysable tannins, flavonoids, ellagic acid & phenol glucosides. Ethanol-juice mixture yielded the highest phenolic, tannin, & flavonoid.	Optimizes green extraction for metabolomics, revealing bioactive enrichment in pomegranate by-products.	Polcaro et al. (2024) [73]
4	Evaluation of morphological, qualitative, and metabolomic traits during fruit ripening in pomegranate	NMR-based metabolomics; physico-chemical analysis during ripening stages.	Ripening altered anthocyanins, polyphenols, and sugars; NMR identified metabolic shifts linked to color, size, and flavor.	Maps temporal metabolomic dynamics, informing harvest timing for optimal bioactive content.	Cirillo et al. (2022) [74]
5	Metabolomic NMR analysis and organoleptic perceptions of pomegranate wines: Influence of cultivar and yeast on the product characteristics	NMR metabolomics; sensory analysis of wines from different cultivars and yeasts.	Cultivar-specific profiles in polyphenols and volatiles; yeast influenced urolithin precursors and flavor compounds.	Extends metabolomics to fermented pomegranate products, linking metabolites to sensory quality.	Girelli et al. (2023) [75]
6	Phytochemical composition of methanolic extract of pomegranate flower petals by GC-MS	GC-MS for methanolic extract of flower petals.	Identified squalene and gallic acid as major compounds; eight peaks revealed diverse secondary metabolites.	Early GC-MS profiling of floral metabolome for medicinal uses.	Hendre et al. (2012) [76]
7	Ultra-HPLC–MSn (Poly)phenolic profiling and chemometric analysis of juices from ancient Punica granatum L. cultivars: A nontargeted approach	UHPLC-MSn with chemometrics for ancient cultivar juices.	Diverse phenolic profiles; chemometrics clustered cultivars by metabolite patterns, including ellagitannins.	Nontargeted approach for biodiversity in pomegranate metabolome.	Calani et al. (2013) [77]
8	GC-MS analysis of phytochemical constituents in ethanolic extract of Punica granatum peel and Vitis vinifera seeds	GC-MS for ethanolic peel extract.	Detected ethyl acetate, pentanoic acid, succinamic acid; high antioxidant potential.	Focuses on peel metabolome, linking to antimicrobial properties.	Kumar and Vijayalakshmi (2011) [78]
9	Influence of drought stress on increasing bioactive compounds of pomegranate juice. Exploratory study using LC–MS-based untargeted metabolomics approach	UHPLC-QTOF-MS untargeted metabolomics under irrigation levels.	Drought increased secondary metabolites (e.g., ellagitannins); first UHPLC-QTOF study on irrigation effects.	Stress-induced metabolomic changes for resilient, bioactive-rich cultivars.	Gómez-Bellot et al. (2023) [79]
10	Antimicrobial activity and bio-active compounds analysis in ethanolic plant extract of Punica granatum using GC-MS	GC-MS for peel ethanolic extract; antifungal assays.	Identified major phytochemicals; strong inhibition against Candida and filamentous fungi.	Links metabolomics to antimicrobial bioactivity in peel.	Attia (2019) [80]
11	Profiling phenolic composition in pomegranate peel from nine selected cultivars.	UHPLC-QTOF-MS and UPLC-QQQ-MS for peel phenolics.	Comprehensive phenolic map across cultivars; high ellagitannin diversity.	Cultivar-specific peel metabolomics for bioactive selection.	Man et al. (2022) [81]
12	Liquid chromatography coupled with tandem MS for phenolic characterization of pomegranate fruit & flower extracts used as botanical dietary supplements	LC-TOF-MS/MS for fruit and flower extracts.	Identified 21 phenolics in fruit (including new ellagitannin pomellatannin) and 15 in flowers	Metabolomics for supplement standardization.	Liu et al. (2018) [82]
13	The main components identified by GC-MS in the petroleum ether extract of pomegranate peel	GC-MS for petroleum ether peel extract.	Key components linked to insecticidal activity; reduced enzyme activity in treated larvae.	GC-MS for bioactive screening in peel against pests.	Farag et al. (2021) [83]
14	A comprehensive study of pomegranate flower polyphenols and metabolites in rat biological samples by HPLC-QTOF-MS	HPLC-QTOF-MS for flower metabolites in rat plasma/urine.	Detected polyphenols and metabolites post-administration.	In vivo metabolomics of flowers.	Yisimayili et al. (2019) [84]
15	A review on phytochemicals, metabolic profiles & pharmacokinetic studies of the different parts of pomegranate.	Review of LC-HRMSn for multi-part metabolomics.	Comprehensive profiles across plant parts; pharmacokinetics of ellagitannins/urolithins.	Holistic review of pomegranate metabolome.	Yisimayili and Chao (2022) [85]
16	The gut microbiota metabolism of pomegranate ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers	UPLC-ESI-QTOF-MS for urine metabolomics; intervention with pomegranate extract/nuts.	Two metabotypes (UM-A, UM-B); UM-B linked to higher cholesterol/LDL; UM-A protective.	Links urolithin production to cardiometabolic health via metabolomics.	Selma et al. (2018) [86]
17	Targeted metabolic profiling of pomegranate polyphenols & urolithins in plasma, urine & colon tissues from colorectal cancer (CRC) patients	HPLC-ESI-QTOF-MS/MS for ET/urolithin profiling post-pomegranate intake.	Detected EA conjugates and 12 urolithins in colon tissues; potential CRC biomarkers.	Tissue-specific urolithin metabolomics in cancer patients.	Nuñez-Sánchez et al. (2014) [87]
18	Urolithins: A comprehensive update on their metabolism, bioactivity, and associated gut microbiota	Review of metabolomics (LC-MS/NMR) on urolithin production.	Urolithins as pleiotropic bioactives; microbiota-dependent metabotypes.	Updates urolithin metabolomics from ET sources like pomegranate.	García-Villalba et al. (2022) [88]
19	Urolithins, intestinal microbial metabolites of pomegranate ETs, exhibit potent antioxidant activity in a cell-based assay	Cell-based antioxidant assays; LC-MS for urolithin identification.	Urolithin A/B showed strong antioxidant potency (IC₅₀ ~13.6 μM).	Mechanistic metabolomics linking urolithins to pomegranate’s antioxidant effects.	Bialonska et al. (2009) [89]
20	Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: The evidence so far	Review of in vitro metabolomics on urolithin bioactivity.	Urolithins mediate anti-inflammatory/anticancer effects; better absorbed than EA.	Evidence for urolithins as key pomegranate metabolites.	Espín et al. (2013) [90]
21	Pomegranate’s ellagitannins: metabolism and mechanisms of health promoting properties	Review of urolithin pathways (Nrf2, HO-1 activation).	Urolithins localize in prostate/colon; anti-cancer via phase II conjugates.	Metabolic pathways of ellagitannins to urolithins.	Benedetti et al. (2023) [91]
22	Pomegranate ellagitannins	Pharmacokinetics via LC-MS; urolithin conjugation studies.	Urolithins persist in urine up to 48 h; prostate localization.	Bioavailability metabolomics of ETs.	Kmail (2006) [92]
23	EA recovery by solid state fermentation of pomegranate wastes by Aspergillus niger & Saccharomyces cerevisiae: A comparison	HPLC for EA post-fermentation; ultrasound/microwave extraction.	S. cerevisiae yielded 12% EA from wastes; fungal tannase hydrolyzes ETs.	Biotechnological metabolomics for EA/urolithin precursors.	Moccia et al. (2019) [93]
24	Pomegranate ET-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation	In vitro assays with BV-2 microglia/SH-SY5Y neurons; LC-MS for urolithins.	Urolithins reduced neuroinflammation; potential AD protection.	Urolithin metabolomics in neuroprotection.	DaSilva et al. (2019) [94]
25	Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, & host health status	Review of metabotypes via LC-MS interventions	Three urolithin metabotypes; dysbiosis links to health risks.	Metabotype classification in pomegranate consumption.	Tomás-Barberán et al. (2017) [95]
26	Direct supplementation with urolithin A overcomes limitations of dietary exposure & gut microbiome variability in healthy adults to achieve consistent levels across the population	Intervention with urolithin A; plasma/urine LC-MS.	Supplementation ensures consistent levels despite microbiome variability; 40% produce UA from diet.	Bypassing gut metabolomics variability.	Singh et al. (2022) [96]
27	Absorption and metabolism of Urolithin A and ellagic acid in mice and their cytotoxicity in human colorectal cancer cells	Comparative metabolomics (LC-MS); in vivo mouse model.	Urolithin A derivatives cytotoxic to CRC cells; gut microbiota key for transformation.	Mouse metabolomics of urolithins.	Lin et al. (2023) [97]
28	Pomegranate ETs stimulate the growth of Akkermansia muciniphila in vivo	16S rRNA sequencing; urolithin LC-MS post-extract.	70% participants produced urolithin A, which correlated with A. muciniphila abundance.	Microbiota-metabolite interactions.	Henning et al. (2017) [98]
29	Urolithins: The gut-based metabolites of ellagitannins in cancer prevention.	Review of LC-MS on urolithins in cancer models.	Urolithins arrest cell cycle/induce apoptosis in bladder/prostate cancers.	Anticancer urolithin metabolomics.	Al-Harbi et al. (2021) [99]
30	Pomegranate extract induces ellagitannin metabolite formation & changes stool microbiota in healthy volunteers	4-week 1,000 mg pomegranate extract; urinary/fecal urolithin A profiling.	Three metabotype groups; microbiota modulation in responders.	Intervention metabolomics and microbiota shifts.	Li et al. (2015) [100]
31	Neuroprotective effects of pomegranate juice against Parkinson’s disease & presence of ellagitannins-derived metabolite-urolithin A in the brain	Rotenone PD rat model; LC-MS for brain urolithin A.	Pomegranate juice reduced motor deficits/α-synuclein; urolithin A in midbrain.	Brain metabolomics in PD.	Kujawska et al. (2019) [101]
32	Pomegranate juice & extracts provide similar levels of plasma & urinary ET metabolites in humans	Crossover with pomegranate juice, liquid extract, & powder extract; LC-MS for metabolites.	Equivalent urolithin-A glucuronide (~1,000 ng/mL); powdered extract showed delayed peak.	Comparative metabolomics of juice vs. extracts.	Seeram et al. (2008) [102]
33	Ellagitannins	Review of ET digestion/metabolism to urolithins via LC-MS/NMR.	ETs hydrolyzed to EA, then urolithins; three phenotypes in trials.	Overview of ET metabolomics pathways.	Nasef et al. (2023) [103]

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1H-NMR: proton nuclear magnetic resonance; 2D: 2 dimensional; LC-MS: liquid chromatography-mass spectrometry; ESI: electrospray ionization; SLDE: solid-liquid dynamic extraction; GC-MS: gas chromatography-mass spectrometry; UHPLC-MSn: ultra-high performance liquid chromatography-multistage mass spectrometry; UHPLC-QTOF-MS: ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry; QQQ: triple quadrupole; ET: ellagitannins; EA: ellagic acid; IC: inhibitory concentration; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase 1; BV-2: immortalized murine cell line; SH-SY5Y: human derived neuroblastoma cell line; AD: Alzheimer’s disease; rRNA: ribosomal ribonucleic acid; PD: Parkinson’s disease.

Declarations

Acknowledgments

The authors are thankful to Professor Abdul Wadood, former director, National Institute of Unani Medicine, Bengaluru, for giving us the opportunity to explore this medicinal fruit plant, and Mr. Ehtesham Ahmed, librarian, National Institute of Unani Medicine, Bengaluru, for providing all the required classical Unani textbooks for the literature review. During the preparation of this work, the author(s) used ChatGPT to generate Figure 1 and NotebookLM for creating Figure 2. After using the tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Author contributions

MN, FR: Conceptualization, Data curation, Visualization, Formal analysis. MN: Writing—original draft. FR: Writing—review & editing. Both authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

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