Nutritional Factors Benefit Postmenopausal Women with NAFLD: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Johanna DiStefano.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition among postmenopausal women that can lead to severe liver dysfunction and increased mortality. There is also growing evidence that specific nutritional factors may help to prevent or treat NAFLD. For example, supplementation with vitamins C, D, and E may exert beneficial effects on liver health or related metabolic features, primarily through their antioxidant and anti-inflammatory properties. Coffee consumption is inversely associated with a number of liver-related conditions, including slower progression of fibrosis, lower transaminase levels, and decreased liver-related mortality, and some of these positive effects may be due to caffeine. Caffeine has also been shown to improve features of metabolic syndrome, including hepatic injury in high carbohydrate, high-fat-diet-fed rat; increase energy expenditure; and reduce total body, trunk, and visceral fat or fat mass. 

  • nonalcoholic fatty liver disease
  • heterogeneity
  • women
  • menopause
  • estrogen

1. Choline

Choline is an essential nutrient that plays a critical role in liver function and is a key component of phosphatidylcholine, a major phospholipid found in cell membranes [76][1]. Dietary choline deficiency, even for a short duration, causes significant liver dysfunction, including hepatic steatosis, in healthy men and women [39,77,78][2][3][4] and laboratory mice [79][5]. The Adequate Intake (AI) for choline is 550 mg/day for men and 425 mg/day for women [80,81,82][6][7][8]. However, dietary choline requirements vary among individuals, with some requiring much greater amounts of choline to avoid the development of metabolic dysfunction [77][3]. There is also evidence indicating that many individuals do not regularly meet the AI recommendations for choline [80,81,82][6][7][8].
Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine [83][9]. Formation of very low-density lipoprotein (VLDL), which conveys triacylglycerols from the liver to the circulation, requires phosphatidylcholine. Low levels of phosphatidylcholine result in insufficient VLDL production, leading to fat accumulation in hepatocytes [83,84,85][9][10][11]. In mice with reduced expression of the PEMT gene (Pemt−/−), hepatic steatosis, inflammation, and fibrosis swiftly developed in response to a high fat/high sucrose diet, and these effects were reversed using dietary choline supplementation [86,87,88,89,90][12][13][14][15][16].
Common PEMT variants disrupt normal phosphatidylcholine synthesis and have been associated with a heightened predisposition to NAFLD [92[17][18],93], which can be further exacerbated by low dietary choline intake [39,94][2][19]. The rs7946 variant, which produces a Val-to-Met substitution at residue 175 of the human PEMT protein, has a higher frequency in NAFLD patients compared to those without NAFLD [92,95,96][17][20][21]. The Met isoform of PEMT also exhibits a specific activity that is 40% lower than the wild-type Val isoform [92][17]. Variant alleles in other common PEMT variants, rs1531100 and rs4646365, were associated with a higher risk of liver damage in postmenopausal women under low choline conditions [94][19].
The effects of choline deficiency on metabolic function may be worsened in postmenopausal women, in part because PEMT gene expression is regulated by estrogen [97,98][22][23]. As estrogen levels decline, the metabolism and utilization of choline shifts. An RCT to investigate the impact of choline depletion found that postmenopausal women were more susceptible than premenopausal women to developing fatty liver or muscle damage in response to the treatment. Specifically, 80% of postmenopausal women (12 out of 15) developed the conditions, whereas only 44% of premenopausal women (7 out of 16) did [77][3], suggesting that estrogen levels may mediate variation in choline requirements. A study examining the impact of choline intake on fibrosis severity in individuals with NAFLD from the NASH Clinical Research Network found that postmenopausal women with deficient choline intake experienced significantly worse fibrosis, even after controlling for other factors associated with NAFLD, such as age, race/ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use [99][24]. However, choline intake was not found to contribute to disease severity in children, men, or premenopausal women [99][24]. Conversely, studies have shown that women with a higher dietary choline intake have a lower risk of developing NAFLD. For instance, in one study, women who reported a higher dietary choline intake had a lower risk of abdominal ultrasound-diagnosed NAFLD [80][6]. This finding was further supported by another study conducted by Mazidi et al. [100][25], which found that postmenopausal participants from the National Health and Nutrition Examination Survey (NHANES) in the highest quartile of choline intake had a 26% lower risk of NAFLD compared to those in the lowest quartile.

2. Soy Isoflavones

Soy isoflavones are compounds found in legumes, with a chemical structure, albeit non-steroidal, similar to estrogen. Soybeans and soy products are the richest sources of isoflavones [101][26], including genistein, daidzein, and glycitein, which are conjugated to different sugars to form glycosides, malonylglucosides, and acetylglucosides [102][27]. However, the conjugated forms are not biologically active or bioavailable until they are hydrolyzed by intestinal glucosidases to release aglycons [103][28]. One such aglycon is S-equol, which is a metabolite of daidzein produced by certain intestinal bacteria. Equol has higher antioxidant activity than vitamins C or E; greater biological potency than its precursor, daidzein; and complete bioavailability [104][29]. Approximately 30% of Western adults and 60% of Asian adults can produce equol after consuming soy foods [105,106][30][31]. Individuals who can generate equol may derive the greatest benefit from soy isoflavone consumption [107][32].
Studies in animals suggest that soy isoflavones can protect against hepatic steatosis and fibrogenesis [108[33][34],109], with higher concentrations of soy isoflavones conferring greater protection [110][35]. Epidemiological studies have found an inverse association between soy food intake and newly diagnosed NAFLD [111][36]. Dietary intervention trials have further supported the beneficial impact of soy supplementation in NAFLD patients (Table 1) [112,113,114,115,116,117][37][38][39][40][41][42]. Although the human clinical trials conducted to date have varied by study design, treatment protocol, method of liver fat imaging, and outcomes, the results have been largely consistent, indicating a positive effect of soy protein on liver function in NAFLD patients.
Table 1.
Effects of soy product consumption on liver related outcomes in adults with NAFLD.
Country N Intervention Duration * (wk) Key Liver Outcomes Ref.
Iran 45 30 g soy nut 8 Reduced ALT and AST levels [116][41]
Iran 70 240 mL soy milk 8 Reduced ALT, no change in fatty liver grade or AST, GGT, ALP levels [112][37]
Germany 22 Soy meal replacement (83% soy protein isolate) 24 Reduced ALT and liver fat, but not different from the lifestyle modification control group [118][43]
* Duration is shown in weeks. Abbreviations: ALP: alkaline phosphatase; ALT: alanine transaminase; AST: aspartate transaminase; GGT: gamma-glutamyltransferase.
Concordant with the consumption of soy isoflavones, the production status of equol may also be an important factor to consider with respect to NAFLD in postmenopausal women. For instance, a study involving 38 NAFLD patients (13 men and 25 women) found that the differences in liver histology by equol production status varied depending on the patient’s sex [108][33]. Specifically, no differences were observed between male equol producers and nonproducers in terms of histological features. However, in postmenopausal women, the degree of fibrosis and hepatocyte ballooning was significantly higher in equol nonproducers compared to equol producers. Moreover, the percentage of postmenopausal nonproducers with a NAFLD activity score (NAS) ≥ 5 was significantly higher than that of producers, and equol production status was found to be the strongest contributor to the development of NASH in postmenopausal NAFLD patients.
Soy isoflavones may provide unique benefits for women who experience a decline in estrogen levels after menopause due to their estrogen-like effects on metabolism. Studies in postmenopausal women have reported ameliorative effects of soy isoflavones on bone health [119[44][45][46],120,121], menopausal symptoms [120[45][47][48][49][50],122,123,124,125], certain types of cancer [120,126[45][51][52][53],127,128], and obesity [120[45][54],129], although not all studies have observed benefits [130[55][56][57][58][59],131,132,133,134], and these discrepancies may be due, in part, to differences in the type, dose, or source of isoflavone used. Furthermore, higher levels of adiposity in both peri- and postmenopausal women have been associated with intestinal microflora that cannot metabolize daidzein [135,136][60][61]. While it is not yet clear whether the ability to produce equol affects the effectiveness of isoflavones on postmenopausal conditions [104][29], equol producers have been found to report fewer and less severe menopausal symptoms than non-producers [137][62]. In contrast, a recent study demonstrated that postmenopausal women consuming a low-fat vegan diet with daily intake of cooked soybeans (86 g) over a period of 12 weeks experienced an 88% reduction in moderate-to-severe hot flashes compared to a control group who did not make any dietary changes, and the degree of improvement in vasomotor symptoms was independent of equol producer status [138][63].
Currently, there are no studies that have specifically investigated the effects of soy isoflavones on hepatic fat content in postmenopausal women. However, Panneerselvam et al. [139][64] conducted an animal study using high-fat-diet-fed ovariectomized rats as an experimental model for human menopause. The results showed that when fed a high-fat diet, ovariectomized rats gained weight and developed hepatic steatosis and hypertriglyceridemia. Treatment with soy isoflavone extract improved these conditions. In addition, soy isoflavones reversed the hepatic overexpression of several lipogenic genes that were upregulated by ovariectomy and high-fat diet; and decreased circulating markers of liver injury, including aspartate transaminase, alanine transaminase, lactate dehydrogenase, total protein, and total bilirubin. Although this study was conducted in rats, the results suggest that soy isoflavones may have similarly beneficial effects on liver health and lipid metabolism in postmenopausal women.
The extent of isoflavone intake among postmenopausal women remains poorly characterized. According to the Framingham Heart Study, postmenopausal participants had a median isoflavone intake of 0.15 mg/day (with a range of 0.99–0.24 mg/day), and those in the highest quartile of isoflavone intake had significantly lower plasma triglyceride levels and a lower mean cardiovascular risk factor metabolic score compared to those in the lowest quartile [140][65]. This is in contrast to Asian countries, where typical soy isoflavone intake ranges from 25–50 mg/day, which is significantly higher than in the United States [141][66].
While there is some evidence to suggest that soy isoflavones may be beneficial for postmenopausal women, more research is needed to fully understand their effects and potential risks. Furthermore, inconsistent findings in human clinical trials highlight the need for more controlled mechanistic studies in vivo, due to the significant interpersonal variations in the human gut microbiome, which can lead to conflicting outcomes [142][67]. Soy isoflavone intake may therefore be particularly important for postmenopausal women who are equol producers and do not have gut dysbiosis.

3. Probiotics

Gut dysbiosis is a condition characterized by an imbalance in the relative abundance of certain bacterial species or groups, which is often accompanied by lower overall diversity of the gut microbiota [143,144][68][69]. This condition has been linked to the development and progression of NAFLD [144,145,146][69][70][71]. The imbalance in the gut microbiota can cause increased intestinal permeability, which enables bacterial products such as lipopolysaccharides (LPSs) to enter the circulation, triggering an immune response and leading to systemic inflammation and liver damage. In animal models, LPSs have been shown to promote the development of NAFLD, and high levels of LPSs have been found in the blood of NAFLD patients [147,148][72][73]. Moreover, gut dysbiosis can also affect bile acid metabolism, leading to changes in the composition of bile acids produced and excreted into the small intestine. Alterations in bile acid composition can affect lipid absorption and lead to the accumulation of lipids in the liver, thereby contributing to the development of NAFLD [149][74]. Additionally, dysbiosis can promote the growth of pro-inflammatory bacteria while reducing the abundance of anti-inflammatory bacteria, resulting in chronic low-grade systemic inflammation that may further contribute to NAFLD development [150][75].
Menopause has been linked to decreased alpha-diversity and changes in the abundance of different bacterial groups [143,151,152,153,154][68][76][77][78][79]. Peters et al. [143][68] conducted a large shotgun metagenomic sequencing study and discovered that postmenopausal women (N = 1027) had a gut microbiome diversity and overall composition that was similar to that found in men (N = 978) and lower than that in premenopausal women (N = 295). Menopause-related changes in the gut microbiome were also associated with an unfavorable cardiometabolic profile. Despite some heterogeneity, several studies of gut microbial composition in postmenopausal women have revealed a lower abundance of Firmicutes and Ruminococcus and a higher abundance of Butyricimonas, Dorea, Prevotella, Sutterella, and Bacteroides relative to premenopausal women [155][80]. However, the implications of these findings are not yet clear as the functions and health effects of these bacteria are not fully understood. Therefore, the health consequences of menopause-related gut microbiome alterations remain to be determined [155][80].
Several RCTs have investigated the impact of probiotic supplementation on liver-related outcomes in individuals with NAFLD. Despite variations in the types of treatments used, the duration of the interventions, and the outcomes measured across these studies, the findings suggest that probiotic supplementation has beneficial effects on liver health (Table 2). A meta-analysis of 21 RCTs, comprising 1252 participants, identified significant decreases in ALT levels and liver stiffness, and improvement in hepatic steatosis in response to probiotic/synbiotic use [156][81]. An independent meta-analysis of 18 studies demonstrated that the use of probiotics as adjuvant therapy for NAFLD patients improved liver function and reduced levels of liver transaminases, such as ALT, AST, and GGT, particularly when the duration of treatment was greater than 12 weeks [157][82]. This analysis also indicated positive effects on various cardiometabolic measures, including levels of triglycerides, total cholesterol, fasting blood glucose, insulin, insulin resistance, and BMI associated with probiotic supplementation. Based on this evidence, therapies aimed at targeting the gut microbiome could be a promising approach for the management of NAFLD.
Table 2.
Effects of probiotic supplementation on liver-related outcomes in adults with NAFLD.
Country N Intervention Duration * Key Liver Outcomes Ref.
Spain 28 Lactobacillus bulgaricus and Streptococcus

thermophilus		 12 Reduced ALT, AST, and GGT levels [158][83]
Iran 72 Probiotic-enriched yogurt 8 Reduced ALT and AST levels [159][84]
Egypt 30 Lactobacillus acidophilus 4 Reduced ALT and AST levels, no change in AUS findings [118][43]
Ukraine 75 Lactobacilli, Bifidobacteria, and Streptococcus thermophilus 12 Decreased ALT levels and liver stiffness [160][85]
Ukraine 58 Multistrain probiotic 8 Decreased fatty liver index, reduced AST and GGT levels [161][86]
Korea 68 Multistrain probiotic 12 Decreased intrahepatic fat [162][87]
Iran 89 Multistrain probiotic 12 Decreased ALT, AST, GGT, and ALP levels [163][88]
Iran 53 Bacillus coagulans plus inulin 12 Decreased levels ALT and GGT levels, improved steatosis [164][89]
Malaysia 33 Multistrain probiotic 24 No significant changes in steatosis, inflammation, fibrosis, or ALT levels [165][90]
United Kingdom 35 VSL#3 10 No significant changes in transaminases, fibrosis risk score and ASQ [166][91]
* Duration is shown in weeks. Abbreviations: ALP: alkaline phosphatase; ALT: alanine transaminase; ASQ: acoustic structure quantification; AUS: abdominal ultrasound; AST: aspartate transaminase; GGT: gamma-glutamyltransferase.
To date, there have been no studies specifically examining the effects of probiotic supplementation on liver health in postmenopausal women. Nevertheless, a RCT in 81 postmenopausal women with obesity found that a 12-week course of multispecies probiotic supplements led to reduced levels of visceral and subcutaneous fat, lower waist circumference, and improved cardiometabolic markers, including uric acid, glucose, insulin, and HOMA-IR [167][92], all of which would be expected to yield hepatic benefit. However, 24 weeks of probiotic supplementation in individuals with biopsy-proven NASH (15 female/8 male; mean age 51.7 ± 11.4 years) did not result in any significant changes in liver function (ALT, AST, or GGT) or metabolic health (i.e., fasting glucose, HbA1c, insulin, triglycerides, cholesterol) [168][93]. Although menopause was not specifically considered in this study, the age range of the female participants is consistent with the average age of menopause in the United States [169][94]. The discrepancy between studies may be due to the experimental design and differences in both the study sample size and clinical endpoints. In general, the positive results of previous RCTs conducted in male and female participants of various ages [170][95] suggest that probiotic supplementation may also be a useful adjuvant therapy for postmenopausal NAFLD patients with gut dysbiosis.
Overall, menopause appears to be associated with lower gut microbiome diversity and a shift toward greater similarity to the male gut microbiome. However, further studies for identifying consistent and reproducible changes that occur in the taxa as a result of menopause are warranted, as are studies to better understand the contribution of the gut microbiota to menopause-related NAFLD risk and the impact of menopausal hormone therapy on the gut microbiome-NAFLD axis.

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