Fruit and Vegetable Consumption Associated with Reduced Mortality / Respiratory Diseases and Aquaporins, ENaC & PON1

The eat 'five a day' (referring to servings of fruits and vegetables) recommendation of the World Health Organization and many national health agencies has new support based on findings by Wang et al. (2021) from the Nurses' Health Study and the Health Professionals Follow-up Study.  

- link to open access article: https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.048996

The study found a reduction in all-cause mortality as well as reductions in mortality due to respiratory diseases, cardiovascular disease and cancer. The thresholds for reductions in mortality were achieved at two servings of fruit and three servings of vegetables per day. No additional benefit was seen for over five servings. Sadly, there was no significant reduction found for neurodegenerative diseases (but see the Michley et al. (2017, open access) study on Parkinson disease re: fresh vs. canned/frozen).

Wang et al. (2021)

Above is Figure 1 from Wang et al. (2021); it is quite small and the reader may want to download the article to view it.

Particularly striking is the reduction in mortality from respiratory diseases associated with  fruit consumption.  Of course, correlation is not causation (we all know that, don't we?), but there was an interventional trial of increased fruit and vegetable consumption for COPD that found a reduction in disease progression - which is usually relentless. https://pubmed.ncbi.nlm.nih.gov/20150206/ (open access). COPD is responsible for the majority of deaths due to respiratory diseases.

The Keranis et al. (2010) study is reviewed here by Dr Michael Greger:

It seems likely that the relationship is indeed causal, and it would be nice to know why, exactly. Dr Greger discusses two possibilities - the first is proposed by the study authors and served as the rationale for the trial - that increasing plant-derived antioxidant consumption is protective. The second is that consuming more plant based foods was accompanied by a reduction in animal product consumption, and the reduction in harmful substances from animal foods is what caused the benefit. Certainly the latter is possible (mTOR activation, Neu5Gc, etc.) and should be investigated - similar future observational and interventional studies should aim to control for total grams / calories of fat and protein derived from animal products. 

Wang et al. (2021) discusses the potential role of increased potassium intake from fruit and vegetable consumption. Another observational study found potassium and magnesium (another nutrient abundant in plant foods) intakes correlated with better lung function in children:

https://pubmed.ncbi.nlm.nih.gov/11790675/

I could not find an interventional study of either potassium or magnesium supplementation in COPD, unfortunately.  There is a listing for a clinical trial of Mg supplementation in COPD with the completion date in 2018, but the results don't appear to have been published yet:

https://clinicaltrials.gov/ct2/show/NCT02680769

None of the preceding explanations really address why fruit in particular appears to have such a marked impact. Aquaporins (AQPs) and the epithelial sodium channel (ENaC) play important roles in lung function and polyphenols that are often present in fruit are known to modulate the function of AQPs and ENaC in animals. 

https://www.resmedjournal.com/article/S0954-6111(20)30333-4/fulltext (paywalled review on aquaporins and lung pathophysiology)

https://www.karger.com/Article/FullText/485417 (ENaC and lung regeneration)

https://pubmed.ncbi.nlm.nih.gov/26346093/ (open access review on aquaporins and polyphenols in health and disease)

https://pubmed.ncbi.nlm.nih.gov/27592201/ (example of effect of polyphenols on ENaC )

 

MicroRNAs are another class of orally bioavailable plant active constituents that warrant more investigation.  https://nutritionandmetabolism.biomedcentral.com/track/pdf/10.1186/s12986-018-0305-8.pdf (see update below)

It bears mentioning that that plant active constituents don't just function as either direct antioxidants or exert their effects by upregulating antioxidant defenses through hormesis (whereby low doses cause small amounts of harm that stimulate protective mechanisms). Of course there are phytochemicals that act by one or both mechanisms - however, many act by effecting changes in various evolutionarily conserved pathways without actually inducing harm as in hormesis.   https://academic.oup.com/advances/article/5/5/515/4565758

Expression of genes related to aquaporin function increases in plants in the process of fruit ripening and under drought stress. Is it possible air dried fruit could contain higher levels of active constituents capable of modulating aquaporin function than fresh? For example, apple slices are living tissue and likely respond to the stress of desiccation as they would under drought conditions. It would be interesting to test the difference between air dried and fresh fruit (e.g., apples, prunes/plums, raisins/grapes) consumption on lung function.

Another consideration is the effect of fruit and vegetable consumption on the gut microbiome, which is found to be altered in people with COPD, who experience higher incidence of ulcerative colitis and Crohn's disease. 

https://pubmed.ncbi.nlm.nih.gov/33208745/

 Typically fiber is thought to be major component of plant foods that influences the gut microbiome, however, polyphenols can also affect the gut microbiome. Foods rich in a particular type of polyphenols, anthocyanins - which color foods blue, purple and magenta - have been found to increase paraoxonase 1 (PON1) activity, as in this clinical trial of bilberry (Vaccinium myrtillus) and black currant (Ribes nigrum) extract:

https://pubmed.ncbi.nlm.nih.gov/24285687/

PON1 is most well-known for its influence on cardiovascular health, however, it is also a microbial biofilm disruptor by virtue of its lactonase function. PON1 is expressed in the lungs and its activity may have effects on the lung microbiome as well as innate immune response.

https://pubmed.ncbi.nlm.nih.gov/28433610/

Anthocyanins are converted to active metabolites by gut microbiota, so differences in the gut microbiome will affect physiological responses to anthocyanins and other polyphenols. 

https://pubmed.ncbi.nlm.nih.gov/27881391/

A recent in vitro study of cultured hepatocytes found no effect of two major dietary anthocyanins and their microbial metabolites on PON1 expression and activity. The study found that at high concentrations, cyanidin actually lowered the lactonase activity of PON1, but had no effect at physiological concentrations. Perhaps anthocyanins and their metabolites do not act directly on hepatocytes or the culture conditions impede their effects:

https://pubmed.ncbi.nlm.nih.gov/31771252/

The high oxygen tension of the culture conditions (~20%) relative to what is experienced in the liver in situ (~5%) could have affected the results. Shibuya et al. (2020) found that acai berry extract induced 'hypoxic condition' in the kidneys of mice:

https://www.mdpi.com/2072-6643/12/2/533/pdf

If anthocyanins act through induction of hypoxia response pathways, then hyperoxic culture conditions could abrogate their effects. It is quite lamentable that scientific research is not funded well enough that incubators that can provide physiological oxygen tensions are accessible to all.

On the other hand, Shibuya et al, (2020) also found no effect from pure cyanidine-3-glucoside [C3Glc]:

"However, C3Glc alone did not alter the erythropoietin or Epo levels (Figure 2), suggesting that not only polyphenols but also iron and fatty acids of acai contribute to erythropoiesis."

So perhaps anthocyanins are not the active constituents but serve as a marker for the active substance(s)(microRNAs? something with structural similarity to dimeric PKM2?). Or perhaps as Shibuya et al. suggest, other substances present in the extracts are needed in combination with anthocyanins for an effect.

Whether consumption of anthocyanins affects lactonase activity of paraoxonases in animals does not appear to have been studied yet. However, anthocyanins have been reported to have direct anti-quorum sensing activity and can act as biofilm disruptors independently of any effects on paraoxonases:

https://pubmed.ncbi.nlm.nih.gov/27162376/

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Updates:

Abnormal stem cell differentiation has been implicated in the etiology of COPD:

https://www.sciencedaily.com/releases/2020/04/200415133646.htm

Aquaporins function as regulators of mesenchymal stem cell differentiation:
https://pubmed.ncbi.nlm.nih.gov/33322145/

"Recently, it was reported that intracellular potassium (K+) is involved in human MSC proliferation and cell cycle regulation. Marakhova et al. [94] showed that a decline in K+ levels is associated with an accumulation of cells in the G1 phase and a delay in proliferation. Moreover, K+ levels have also been found to be correlated with MSC age, which highlights the importance of this ion in stem cell proliferation and its potential application as a biomarker. ... The presence of AQPs in the apical membranes of different MSCs, their co-localisation with other systems such as the Na+/K+ATP pump, and the effect of AQP inhibitors including HgCl2 and TEA suggest that AQPs may regulate the migration and differentiation of MSCs [119]."

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Update 2021-4-30

 Food-derived microRNAs have been dubbed xeno-miRNAs (xenomiRs) ; a recent review article:

Potential Mechanisms Linking Food-Derived MicroRNAs, Gut Microbiota and Intestinal Barrier Functions in the Context of Nutrition and Human Health (2021)

https://www.frontiersin.org/articles/10.3389/fnut.2021.586564/full

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Update 2021-6-14

Low dose aspirin has been suggested for prevention of 'lung attacks' in COPD:

https://thorax.bmj.com/content/69/7/603

"The human and societal burden of COPD is alarming. Despite large reductions in smoking rates across industrialised nations, COPD mortality has increased by 60% over the past 20 years, making it the second leading cause of morbidity and mortality in the USA and elsewhere.1 Most of the COPD-related deaths occur during or shortly following acute exacerbations (or ‘lung attacks’). Unfortunately, severe lung attacks are common, with one in six patients requiring hospitalisation for urgent care each year.2 Despite best therapy, 1 in 12 of these patients will succumb to their disease in hospital.3 ...

Harrison and colleagues assessed the prognostic value of blood platelet count, which is widely available, cheap and well standardised, during acute lung attacks of COPD. In this large, well conducted cohort study of 1343 patients, who were hospitalised for an exacerbation, they found that thrombocytosis defined as a blood platelet count of >400 × 10⁹ cells/mm³ at admission was associated with a 137% increase in the risk of in-hospital mortality and a 53% increase in 1-year mortality. Most importantly, they observed that treatment with an anti-platelet drug such as aspirin or clopidogrel was associated with a threefold reduction in the 1-year mortality rate.6 Interestingly, none of this appeared to be directly related to a reduction in cardiovascular risk, suggesting mechanisms beyond the salutary effects on the cardiovascular system."

It is possible the antiplatelet activity is responsible for the benefits of fruit consumption.

Review of the antiplatelet activity of dietary supplements, several of which are fruit-derived:

https://academic.oup.com/advances/article/9/1/51/4848950

Paywalled article - Anthocyanin Supplementation Alleviates Antithrombotic Risk by Inhibiting Platelet Activity in Humans - https://pubmed.ncbi.nlm.nih.gov/33789251/

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Update 2023-12-29

Another possible explanation might be fructose -> FGF-21 -> reduction in fibrosis. However, one study found high serum FGF-21 associated with high risk of exacerbation of COPD. It might be analogous to IL-6 and type 2 diabetes. Exercise spikes IL-6 and exercise is protective against T2D, but serum IL-6 is chronically elevated in T2D.

refs on FGF-21 (IL-6 stuff is easy to find):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314524/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10230495/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569360/