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Dietary walnuts prevented indomethacin-induced gastric damage via AP-1 transcribed 15-PGDH, Nrf2-mediated HO-1, and n-3 PUFA-derived Resolvin E1.

Park, J.M., K.B. Hahm, 2024. Dietary walnuts prevented indomethacin-induced gastric damage via AP-1 transcribed 15-PGDH, Nrf2-mediated HO-1, and n-3 PUFA-derived Resolvin E1. Int J Mol Sci. 25(13):7239. https://doi.org/10.3390/ijms25137239.

Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, cause gastric mucosal damage, including ulcers, directly or indirectly, by which the development of GI-safer (-sparing) NSAIDs relates to unmet medical needs. This study aimed to document the preventive effects of walnut polyphenol extracts (WPEs) against NSAID-induced gastric damage along with the molecular mechanisms. RGM-1 gastric mucosal cells were administered with indomethacin, and the expressions of the inflammatory mediators between indomethacin alone or a combination with WPEs were compared. The expressions of the inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and antioxidant capacity, were analyzed by Western blot analysis, RT-PCR, and ELISA, respectively. HO-1, Nrf-2, and keap1 were investigated. The in vivo animal models were followed with in vitro investigations. The NSAIDs increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but the WPEs significantly attenuated the NSAID-induced COX-2 expression. Interestingly, the WPEs induced the expression of 15-PGDH. By using the deletion constructs of the 15-PGDH promoter, we found that c-Jun is the most essential determinant of the WPE-induced up-regulation of 15-PGDH expression. We confirmed that the knockdown of c-Jun abolished the ability of the WPEs to up-regulate the 15-PGDH expression. In addition, the WPEs significantly increased the HO-1 expression. The WPEs increased the nuclear translocation of Nrf2 by Keap-1 degradation, and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We found that the WPE-induced HO-1 up-regulation was attenuated in the cells harboring the mutant Keap1, in which the cysteine 151 residue was replaced by serine. These in vitro findings were exactly validated in indomethacin-induced gastric rat models. Daily walnut intake can be a promising nutritional supplement providing potent anti-inflammatory, antioxidative, and mucosa-protective effects against NSAID-induced GI damage.

Key Area: Gut Health

Nut consumption, gut microbiota, and body fat distribution: results of a large, community-based population study.

Shi Y, Kan J, Wang W, Cao Y, Wu Y, Chen X, Zheng W, Yang F, Du J, He W, Zhu S., 2024. Nut consumption, gut microbiota, and body fat distribution: results of a large, community-based population study. Obesity (Silver Spring). 32(9):1778-1788.

Objective: We aimed to investigate the relationships among nut consumption, gut microbiota, and body fat distribution. Methods: We studied 2255 Chinese adults in the Lanxi Cohort living in urban areas in Lanxi City, China. Fat distribution was assessed by dual-energy x-ray absorptiometry, and nut consumption was assessed using food frequency questionnaires. 16S ribosomal RNA (rRNA) sequencing was performed on stool samples from 1724 participants. Linear regression and Spearman correlation were used in all analyses. A validation study was performed using 1274 participants in the Lanxi Cohort living in rural areas. Results: Nut consumption was beneficially associated with regional fat accumulation. Gut microbial analysis suggested that a high intake of nuts was associated with greater microbial α diversity. Six genera were found to be associated with nut consumption, and the abundance of genera Anaerobutyricum, Anaerotaenia, and Fusobacterium was significantly associated with fat distribution. Favorable relationships between α diversity and fat distribution were also observed. Similar relationships between gut microbiota and fat distribution were obtained in the validation analysis. Conclusions: We have shown that nut consumption is beneficially associated with body fat distribution and gut microbiota diversity and taxonomy. Furthermore, the microbial features related to high nut intake are associated with a favorable pattern of fat distribution.

The effects of almond consumption on cardiovascular health and gut microbiome: A comprehensive review.

Singar, S., S. Kadyan, C. Patoine, G. Park, B. Arjmandi, R. Nagpal, 2024. The effects of almond consumption on cardiovascular health and gut microbiome: A comprehensive review.  Nutrients. 4, 16, 1964. https://doi.org/10.3390/nu16121964

The consumption of almonds has been associated with several health benefits, particularly concerning cardiovascular and intestinal health. In this comprehensive review, we compile and deliberate studies investigating the effects of almond consumption on cardiovascular disease (CVD) risk factors and gut health. Almonds are rich in monounsaturated fats, fiber, vitamins, minerals, and polyphenols, which contribute to their health-promoting properties. Regular intake of almonds has been shown to improve lipid profiles by reducing LDL cholesterol and enhancing HDL functionality. Additionally, almonds aid in glycemic control, blood pressure reduction, and chronic inflammation amelioration, which are critical for cardiovascular health. The antioxidant properties of almonds, primarily due to their high vitamin E content, help in reducing oxidative stress markers. Furthermore, almonds positively influence body composition by reducing body fat percentage and central adiposity and enhancing satiety, thus aiding in weight management. Herein, we also contemplate the emerging concept of the gut–heart axis, where almond consumption appears to modulate the gut microbiome, promoting the growth of beneficial bacteria and increasing short-chain fatty acid production, particularly butyrate. These effects collectively contribute to the anti-inflammatory and cardioprotective benefits of almonds. By encompassing these diverse aspects, we eventually provide a systematic and updated perspective on the multifaceted benefits of almond consumption for cardiovascular health and gut microbiome, corroborating their broader consideration in dietary guidelines and public health recommendations for CVD risk reduction.

Effect of nuts on gastrointestinal health. 

Mandalari, G., T. Gervasi, D.W. Rosenberg, K.G. Lapsley, D.J. Baer, 2023. Effect of nuts on gastrointestinal health. Nutrients. 15(7):1733. https://doi.org/10.3390/nu15071733

Nuts are high nutrient-dense foods containing healthy lipids, dietary fiber, and bioactive phytochemicals, including vitamins and minerals. Although the beneficial effect of nut consumption on different chronic diseases has been well documented, especially in relation to their cardiometabolic benefits, less scientific evidence is available on their possible beneficial effects on gastrointestinal health. In this narrative review, we summarize the most important findings and new research perspectives in relation to the importance of nut consumption on gastrointestinal health. The integrity of the cell wall structure, cell size and particle size after mastication are known to play a crucial role in energy, nutrient and bioactive release from nuts during digestion, therefore affecting bioaccessibility. Other mechanisms, such as cell wall composition, thickness and porosity, as well as stability of the membranes surrounding the oil bodies within the cell, are also important for energy extraction. As the undigested nutrients and phytochemicals are delivered to the colon, effects on gut microbiota composition are predicted. Although the overall effect of nut consumption on microbial alpha- and beta-diversity has been inconsistent, some scientific evidence suggests an increase in fecal butyrate after almond consumption, and a beneficial role of walnuts on the prevention of ulcerative colitis and protection against the development of gastric mucosal lesions.

Walnut consumption and gut microbial metabolism: Results of an exploratory analysis from a randomized, crossover, controlled-feeding study.

Petersen, K.S., M. Chandra, J.R. Chen See, J. Leister, F. Jafari, A. Tindall, P.M. Kris-Etherton, R. Lamendella, 2023. Walnut consumption and gut microbial metabolism: Results of an exploratory analysis from a randomized, crossover, controlled-feeding study. Clin Nutr. 42(11):2258-2269. https://doi.org/10.1016/j.clnu.2023.09.023

Background & aims: The effect of walnut-related modulation of gut microbiota composition on microbiota functionality is unknown. The aim was to characterize the effect of a walnut-enriched diet (WD), compared to a fatty acid-matched diet devoid of walnuts (WFMD) and a diet where oleic acid replaces alpha-linolenic acid (ORAD), on bacterial gene expression. Methods: A 3-period, randomized, crossover, controlled-feeding study was conducted. Participants were provided a 2-week run-in standard western diet (SWD; 50% kcal carbohydrate, 16% protein, 34% fat, 12% SFA). Following the SWD in random sequence order, participants were provided the WD, WFMD, and ORAD (48% carbohydrate; 17% protein; fat 35%; 7% SFA). The WD contained 18% of energy from walnuts (57 g/d/2100 kcal). The WFMD and ORAD were devoid of walnuts; liquid non-tropical plant oils were included in these diets. Metatranscriptomic analyses were performed as an exploratory outcome. Results: The analytical sample included 35 participants (40% female) with a mean ± SD age of 43 ± 10 y and BMI of 30.3 ± 4.9 kg/m2. The ⍺-diversity of taxa actively expressing genes, assessed by observed species (p = 0.27) and Pielou’s Evenness (p = 0.09), did not differ among the diets. The ⍺-diversity of actively expressed genes was greater following the WD compared to the WFMD and ORAD as assessed by the observed genes and Pielou’s Evenness metrics (p < 0.05). β-Diversity of the actively expressed genes differed following the WD compared to the WFMD (p = 0.001) and ORAD (p = 0.001); β-diversity did not differ between the WFMD and ORAD. Active composition analyses showed increased Gordonibacter (p < 0.001) activity following the WD vs. the ORAD. Greater expression of many genes was observed following the WD compared to the WFMD and ORAD. Following the WD, greater expression of metabolism-related genes encoding glycine amidinotransferase (GATM; K00613) and arginine deiminase (K01478) was observed compared to the WFMD. Greater expression of glycine amidinotransferase (GATM; K00613) by Gordonibacter was also observed following the WD vs. the WFMD and ORAD. Conclusion: Our results suggest walnut intake may increase endogenous production of homoarginine through gut microbiota-mediated upregulation of GATM, which is a novel mechanism by which walnuts may lower cardiovascular disease risk. However, given the exploratory nature replication is needed.

Effect of nuts on gastrointestinal health.

Mandalari, G., T. Gervasi, D.W. Rosenberg, K.G. Lapsley, D.J. Baer, 2023. Effect of nuts on gastrointestinal health. Nutrients. 15(7):1733. https://doi.org/10.3390%2Fnu15071733

Abstract: Nuts are high nutrient-dense foods containing healthy lipids, dietary fiber, and bioactive phytochemicals, including vitamins and minerals. Although the beneficial effect of nut consumption on different chronic diseases has been well documented, especially in relation to their cardiometabolic benefits, less scientific evidence is available on their possible beneficial effects on gastrointestinal health. In this narrative review, we summarize the most important findings and new research perspectives in relation to the importance of nut consumption on gastrointestinal health. The integrity of the cell wall structure, cell size and particle size after mastication are known to play a crucial role in energy, nutrient and bioactive release from nuts during digestion, therefore affecting bioaccessibility. Other mechanisms, such as cell wall composition, thickness and porosity, as well as stability of the membranes surrounding the oil bodies within the cell, are also important for energy extraction. As the undigested nutrients and phytochemicals are delivered to the colon, effects on gut microbiota composition are predicted. Although the overall effect of nut consumption on microbial alpha- and beta-diversity has been inconsistent, some scientific evidence suggests an increase in fecal butyrate after almond consumption, and a beneficial role of walnuts on the prevention of ulcerative colitis and protection against the development of gastric mucosal lesions.

The impact of almonds and almond processing on gastrointestinal physiology, luminal microbiology, and gastrointestinal symptoms: a randomized controlled trial and mastication study.

Creedon, A. C., E. Dimidi, E.S. Hung, M. Rossi, C. Probert, T. Grassby, J. Miguens-Blanco, J.R. Marchesi, S.M. Scott, S.E. Berry, K. Whelan, 2022. The impact of almonds and almond processing on gastrointestinal physiology, luminal microbiology, and gastrointestinal symptoms: a randomized controlled trial and mastication study. Am. J. Clin. Nutr. 116(6):1790–1804. https://doi.org/10.1093/ajcn/nqac265

Background: Almonds contain lipid, fiber, and polyphenols and possess physicochemical properties that affect nutrient bioaccessibility, which are hypothesized to affect gut physiology and microbiota. Objectives: To investigate the impact of whole almonds and ground almonds (almond flour) on fecal bifidobacteria (primary outcome), gut microbiota composition, and gut transit time. Methods: Healthy adults (n = 87) participated in a parallel, 3-arm randomized controlled trial. Participants received whole almonds (56 g/d), ground almonds (56 g/d), or an isocaloric control in place of habitual snacks for 4 wk. Gut microbiota composition and diversity (16S rRNA gene sequencing), SCFAs (GC), volatile organic compounds (GC-MS), gut transit time (wireless motility capsule), stool output and gut symptoms (7-d diary) were measured at baseline and endpoint. The impact of almond form on particle size distribution (PSD) and predicted lipid release was measured (n = 31). ResultsModified intention-to-treat analysis was performed on 79 participants. There were no significant differences in mean ± SD abundance of fecal bifidobacteria after consumption of whole almonds (8.7% ± 7.7%), ground almonds (7.8% ± 6.9%), or control (13.0% ± 10.2%; q = 0.613). Consumption of almonds (whole and ground pooled) resulted in higher mean ± SD butyrate (24.1 ± 15.0 μmol/g) than control (18.2 ± 9.1 μmol/g; P = 0.046). There was no effect of almonds on gut microbiota at the phylum level or diversity, gut transit time, stool consistency, or gut symptoms. Almond form (whole compared with ground) had no effect on study outcomes. Ground almonds resulted in significantly smaller PSD and higher mean ± SD predicted lipid release (10.4% ± 1.8%) than whole almonds (9.3% ± 2.0%; P = 0.017). Conclusions: Almond consumption has limited impact on microbiota composition but increases butyrate in adults, suggesting positive alterations to microbiota functionality. Almonds can be incorporated into the diet to increase fiber consumption without gut symptoms.This trial was registered at clinicaltrials.gov as NCT03581812.

The effects of the Green-Mediterranean diet on cardiometabolic health are linked to gut microbiome modifications: a randomized controlled trial. 

Rinott, E., A.Y. Meir, G. Tsaban, H. Zelicha, A. Kaplan, D. Knights, K. Tuohy, M.U. Scholz, O. Koren, M.J. Stampfer, D.D. Wang, I. Shai, I. Youngster, 2022. The effects of the Green-Mediterranean diet on cardiometabolic health are linked to gut microbiome modifications: a randomized controlled trial. Genome Med. 14(1):29. https://doi.org/10.1186/s13073-022-01015-z

Background: Previous studies have linked the Mediterranean diet (MED) with improved cardiometabolic health, showing preliminary evidence for a mediating role of the gut microbiome. We recently suggested the Green-Mediterranean (Green-MED) diet as an improved version of the healthy MED diet, with increased consumption of plant-based foods and reduced meat intake. Here, we investigated the effects of MED interventions on the gut microbiota and cardiometabolic markers, and the interplay between the two, during the initial weight loss phase of the DIRECT-PLUS trial. Methods: In the DIRECT-PLUS study, 294 participants with abdominal obesity/dyslipidemia were prospectively randomized to one of three intervention groups: healthy dietary guidelines (standard science-based nutritional counseling), MED, and Green-MED. Both isocaloric MED and Green-MED groups were supplemented with 28g/day walnuts. The Green-MED group was further provided with daily polyphenol-rich green tea and Mankai aquatic plant (new plant introduced to a western population). Gut microbiota was profiled by 16S rRNA for all stool samples and shotgun sequencing for a select subset of samples. Results: Both MED diets induced substantial changes in the community structure of the gut microbiome, with the Green-MED diet leading to more prominent compositional changes, largely driven by the low abundant, “non-core,” microorganisms. The Green-MED diet was associated with specific microbial changes, including enrichments in the genus Prevotella and enzymatic functions involved in branched-chain amino acid degradation, and reductions in the genus Bifidobacterium and enzymatic functions responsible for branched-chain amino acid biosynthesis. The MED and Green-MED diets were also associated with stepwise beneficial changes in body weight and cardiometabolic biomarkers, concomitantly with the increased plant intake and reduced meat intake. Furthermore, while the level of adherence to the Green-MED diet and its specific green dietary components was associated with the magnitude of changes in microbiome composition, changes in gut microbial features appeared to mediate the association between adherence to the Green-MED and body weight and cardiometabolic risk reduction. Conclusions: Our findings support a mediating role of the gut microbiome in the beneficial effects of the Green-MED diet enriched with Mankai and green tea on cardiometabolic risk factors.

Transcriptome profiling analysis of the response to walnut polyphenol extract in Helicobacter pylori-infected cells.

Park, J.M., Y.M. Han, H.J. Lee, S.J. Hwang, S.J. Kim, K.B. Hahm, 2021. Transcriptome profiling analysis of the response to walnut polyphenol extract in Helicobacter pylori-infected cells. J Clin Biochem Nutr. doi.org/10.3164/jcbn.20-128.

Dietary intervention to prevent Helicobacter pylori (H. pylori)-associated gastric diseases seems to be ideal with no risk of bacterial resistance, safe long-term intervention, and correcting pathogenic mechanisms including rejuvenation of precancerous atrophic gastritis and anti-mutagenesis. A transcriptome as set of all RNAs transcribed by certain tissues or cells demonstrates gene functions and reveals the molecular mechanism of specific biological processes against diseases. Here, we have performed RNAseq and bioinformatic analysis to explain proof of concept that walnut intake can rescue from H. pylori infection and explore unidentified mode of actions of walnut polyphenol extract (WPE). As results, BIRC3, SLC25A4, f3 transcription, VEGFA, AZU1, HMOX1, RAB3A, RELBTNIP1, ETFB, INPP5J, PPME1, RHOB, TPI1, FOSL1, JUND.RELB, KLF2, MUC1, NDRG1, ALDOA, ENO1, PFKP, GPI, GDF15, and NRTN genes were newly discovered to be enriched with WPE, whereas CCR4, BLNK, CCR7, CXCR4, CDO1, KLSG1, SELE, RASGRP2, PIK3R3, TSPAN32, HOXC-AS3, HCG8, BTNL8, and CXCL3 genes as inhibitory targets by WPE in H. pylori infection. We identified additional genes what WPE afforded actions of avoiding H. pylori-driven onco-inflammation and rejuvenating precancerous atrophic gastritis. Conclusively, after applying RNAseq analysis in order to document walnut intake for precision medicine against H. pylori infection, significant transcriptomic profiling applicable for validation were drawn.

Neural correlates of future weight loss reveal a possible role for brain-gastric interactions.

Levakov, G., A. Kaplan, A. Yaskolka Meir, E. Rinott, G. Tsaban, H. Zelicha, N. Meiran, I. Shelef, I. Shai, G. Avidan, 2021. Neural correlates of future weight loss reveal a possible role for brain-gastric interactions. Neuroimage. 224:117403. doi: 10.1016/j.neuroimage.2020.117403.

Lifestyle dietary interventions are an essential practice in treating obesity, hence neural factors that may assist in predicting individual treatment success are of great significance. Here, in a prospective, open-label, three arms study, we examined the correlation between brain resting-state functional connectivity measured at baseline and weight loss following 6 months of lifestyle intervention in 92 overweight participants. We report a robust subnetwork composed mainly of sensory and motor cortical regions, whose edges correlated with future weight loss. This effect was found regardless of intervention group. Importantly, this main finding was further corroborated using a stringent connectivity-based prediction model assessed with cross-validation thus attesting to its robustness. The engagement of senso-motor regions in this subnetwork is consistent with the over-sensitivity to food cues theory of weight regulation. Finally, we tested an additional hypothesis regarding the role of brain-gastric interaction in this subnetwork, considering recent findings of a cortical network synchronized with gastric activity. Accordingly, we found a significant spatial overlap with the subnetwork reported in the present study. Moreover, power in the gastric basal electric frequency within our reported subnetwork negatively correlated with future weight loss. This finding was specific to the weight loss related subnetwork and to the gastric basal frequency. These findings should be further corroborated by combining direct recordings of gastric activity in future studies. Taken together, these intriguing results may have important implications for our understanding of the etiology of obesity and the mechanism of response to dietary intervention.