Ethanol: Evolution’s Fine-tuning of a Natural and Ancestral Molecule

Ethanol and its Catabolic Enzymes are over three Billion years

Without downing any ethanol containing beverage,  according to one credible source, the average human digestive system produces approximately 3 g of ethanol per day through fermentation of food and thanks to the microbiota’s “partying” activities, which both makes alcohol and breaks it down.  (Source)

“Colonic microbes take part in ethanol metabolism  by both fermenting sugars to ethanol and  also by oxidizing exogenous ethanol to acetaldehyde” (Jokelainen, 1997; Salaspuro, 1996, 1997). (Source)

Furthermore, when there is bacterial overgrowth, it would appear that endogenous ethanol is not only produced, but exogenous alcohol that is drunk gets better oxidized thanks to which its toxic metabolites don’t reach system blood circulation. Indeed once acetaladehyde is converted to acetate, ethanol toxicity is cleared.

“Our results indicate that bacterial overgrowth in the proximal segments of the gastrointestinal tract results in the production of endogenous ethanol, and also in a strikingly enhanced capacity to oxidize exogenous ethanol. As a consequence of this increased oxidation, a large fraction of ingested ethanol does not reach the systemic circulation but is converted to acetaldehyde and acetate, which reach high concentrations in the intestinal lumen and in the portal blood”. (Source) 

However, there’s “overgrowth and overgrowth”, meaning that the overgrowth of deleterious bacteria transform alcohol into too many toxic metabolites whereas an abuandance of good bacteria produce useful ethanol while better clearing alcohol’s toxic metabolites. (Ibid.) Furthermore, it’s well known that people who have damaged livers (cirrhosis) because of severe alcoholism also suffer from dysbiosis, gut imbalance and pathology, which is one reason why alcohol’s metabolites become more and more toxic and damaging, fueling accelerated aging and a plethora of degenerative diseases.

In this perspective, these liver damaged people spur the deleterious gut bugs to actually contribute in the “death ritual” by producing even more endogenous alcohol. (Source). Postmortem production of alcohol due to fermentation of sugar by bacteria is also well documented. Toxicological analysis of a specimen from a deceased 14-year-old adolescent revealed high amounts of alcohol both in blood and in tissue.

“The authors concluded that postmortem alcohol in this adolescent was due to the action of the bacterial strain Lactococcus garvieae in the blood, which is capable of producing alcohol from glucose [118]. In another study, ethyl glucuronide was observed in the postmortem blood of 93 cases with antemortem blood alcohol…(…) The authors concluded that the presence of ethyl glucuronide in postmortem blood is a marker of antemortem ingestion of alcohol [119]. (Source).

Catabolic degradation of ethanol is thus key.  It is essential to life, not only of humans, but of all known organisms. Certain amino acid sequences in the enzymes used to oxidize ethanol are conserved (unchanged) going back to the last common ancestor over 3.5 bya.  (Source)

Such a function is necessary because all organisms produce alcohol in small amounts by several pathways, primarily through carbohydrate fermentation,  fatty acid synthesis, (Source) glycero-lipid metabolism, (Source) and bile acid biosynthesis pathways. (Source) 

In this perspective, and from the point of view of evolutionary biology, one of the finalities of alcohol is to produce quick-acting calorie-based energy via pyruvate, glycolysis (1) and the citric cycle. (2)

The key issues in wine drinking of ethanol’s breakdown is therefore central, especially for a wine as medicine blog. If the body had no mechanisms for catabolizing the alcohols, its  metabolites would build up in the body and become toxic. (3)

A basic organizing theme in biological systems is that increasing complexity in specialized tissues and organs, allows for greater specificity of function. This occurs for the processing of ethanol in the human body. The enzymes required for the oxidation reactions are confined to certain tissues and the microbiota. In particular, much higher concentration of such enzymes are found in the liver (Source)  which is the primary site for alcohol catabolism, in association with the gut’s microbiota. Variations in genes also influence alcohol metabolism. (Source)

Making Evolutionary Sense of Ethanol

In terms of Evolution, the “Drunken Monkey Hypothesis” proposes that human attraction to ethanol may derive from primates biological need to ingest ripe and fermenting fruit as a dominant food source and a quick source of calories. Ethanol naturally occurs in ripe and overripe fruit when yeasts ferment sugars into alcohol and CO2. Animal ethanol consumption has thus been ongoing at least since edible plants have been around, more than 45 million of years ago.

This hypothesis was originally proposed by Dr. Robert Dudley of the University of California at Berkeley.  It  was the object of a symposium at the 2004 annual meeting of the Society for Integrative and Comparative Biology. Dudley’s book The Drunken Monkey: Why We Drink and Abuse Alcohol was published in 2014 by the University of California Press. It was in 2000 when Robert Dudley developed this thesis relative to this historical link between fruit-eating animals and alcohol intake. (Source)

Dudley suggests that attraction to and consumption of ethanol by various primates may go back to tens of millions of years. The odors of ripening fruit would help primates find scarce calories in tropical rain forests, given that ethanol is a relatively light molecule and is moved rapidly by winds through vegetation. It is Dudley’s main argument that this once-beneficial attraction to and consumption of ethanol at low concentrations may underlie modern human tendencies for alcohol use.

Analysis

Fruit has formed an important part of the primate diet for over 45 million years.  (Source) Even though our more recent ancestors moved from a plant to a meat-based diet about 2.6 million years ago, they continued to eat fruit. (Source)

To this day, our closest cousins the chimpanzees and bonobos spend a lot of time feasting on ripe and over-ripe fruits. Other primates like gorillas, orangutans and gibbons, relish fruits as well. (Cf Exhibit A) Thus, it is reasonable to propose the idea that alcohol likely shaped the evolution of fruit-eating primates for several million years. 

Furthermore, the ethanol wafting (odor floating) from fermenting fruits may have been a cue to locate caloric and nutrient-dense rewards that could ward off starvation. Quality and moderate ethanol also has health promoting properties like blood thinning and brain cleaning via the glymphatics. Fruit alcohol also stimulates the appetite, so on all fronts, fermented ethanol rich fruits were a win-win for those animals and primates who had access to them.

Critical Appraisal

Dudley’s Drunken Monkey theory initially faced criticism on the following grounds. First off, certain  scientists argued that primates generally tend to prefer ripe fruits over rotting and the alcohol content of ripe fruits is so poor, it is not enough to get them “drunk”. Two, if they do get drunk, balancing on trees under the influence of alcohol would be risky, particularly for babies. A third argument was that high-alcohol, low-sugar fruits should deter, rather than attract, primates. Added to that is the fact that primates had rarely been seen getting wasted on fermented fruits in the wild.  (Source)

All of these criticisms however are not well supported by the evidence. Furthermore, these claims do not undermine Dudley’s main thesis according to which human’s ability to digest alcohol is well-developed today because exposure to alcohol happened early on in our ancestory. Digesting ethanol quickly would have been life-saving for our ancestors in terms of benefiting from fast-acting calorie fuel.

 Favorable Genetic mutations of ADH4 Ten Million Years ago

Evidence of this can be seen in our genetic make-up. A study published in 2014 looked at evolution of an alcohol dehydrogenase enzyme named ADH4, which is one of many that break down alcohol in human bodies. Because it is present in the mouth, the gastro-intestinal tract and stomach, ADH4 is the first  enzyme that gets activated when ethanol rich foods or drinks are place in the mouth. (Source)

In this perspective, Matthew Carrigan et al of Santa Fe College found that a genetic mutation in  human’s evolutionary past made ADH4 40 times better at breaking down ethanol. This occured about ten million years ago. (Source)

Digesting ethanol-laden fruits quickly and without the mental impairment that too much alcohol and not enough liver enzymes generate would have been life-saving for our ancestors. Thanks to this mutated ADH4 gene,  alcohol-rich fruits would have provided quick ready made calories needed for extra energy.  (Source) 

ADH4 liver enzymes are also efficient in metabolising different alcohols like geraniol, cinnamyl, coniferyl and anisyl alcohols. These alcohols have similar structures, are large hydrophobic alcohols, and as the name implies are found in geranium, cinnamon, conifer and anise plants. (Ibid.) Thus, when humans first produced alcoholic beverages from grain, honey and fruit (Source), their alcohol break-down liver enzymes were thus fine-tuned.

Other research supports Dudley’s central thesis. For instance, in 2015, a long-term study spanning 17 years reported that wild chimpanzees relish fermenting tree sap. (4) Furthermore, the Aye-ayes, who are also primates, are also attracted to ethanol ripe fruits. (5)

“Alcohol is widespread in nature, existing in fermented nectars, saps and fruits. It is therefore a natural part of many primate diets, and it follows that primates have evolved to digest alcohol quickly to minimize toxic effects. But given that alcohol is also a source of calories, it is plausible that alcohol is attractive to some primates, including, hypothetically, our human ancestors. In fact, previous research found that humans and African great apes have a genetic mutation that radically accelerates alcohol digestion. However, this mutation is also shared with the aye-aye, one of the oddest animals on Earth. The question, then, is whether aye-ayes are attracted to alcohol. In the first controlled study of its kind, Dartmouth researchers found that two aye-ayes and another prosimian primate (a slow loris) could discriminate different concentrations of alcohol, and further, that each species preferred the highest concentrations of alcohol available to them. The findings of this Dartmouth study will be published in the open-access journal, Royal Society Open Science.” (Source)

Likewise with Pentailed treeshrews (Ptilocercus lowii), all of which showed no signs of intoxication, notwithstanding a relatively high dose of ethanol in fermenting flower buds.

“…  Here, we provide a detailed account of chronic alcohol intake by mammals as part of a coevolved relationship with a plant. We discovered that seven mammalian species in a West Malaysian rainforest consume alcoholic nectar daily from flower buds of the bertam palm (Eugeissona tristis), which they pollinate. The 3.8% maximum alcohol concentration (mean: 0.6%; median: 0.5%) that we recorded is among the highest ever reported in a natural food. Nectar high in alcohol is facilitated by specialized flower buds that harbor a fermenting yeast community, including several species new to science. Pentailed treeshrews (Ptilocercus lowii) frequently consume alcohol doses from the inflorescences that would intoxicate humans. Yet, the flower-visiting mammals showed no signs of intoxication. Analysis of an alcohol metabolite (ethyl glucuronide) in their hair yielded concentrations higher than those in humans with similarly high alcohol intake. The pentailed treeshrew is considered a living model for extinct mammals representing the stock from which all extinct and living treeshrews and primates radiated. Therefore, we hypothesize that moderate to high alcohol intake was present early on in the evolution of these closely related lineages. It is yet unclear to what extent treeshrews benefit from ingested alcohol per se and how they mitigate the risk of continuous high blood alcohol concentrations”. (Source)

Putting the “natural ethanol” animal attraction theory to the test

At the Duke Lemur Center in Durham, N. C., Gochman conducted multiple-choice feeding experiments with two aye-ayes, Morticia and Merlin, and a slow loris, Dharma, to test for an aversion or preference to varying concentrations of alcohol in simulated nectar. The alcohol concentrations were low (0.0 to 5.0%) to reflect levels found in nature. Each liquid treatment, together with two controls, was placed in a circular array of small-recessed containers in a round resin outdoor table. The position of the liquids was randomized and behavioral data were collected blind to the contents, to avoid observational bias. Each of the two aye-ayes participated in a trial once a day for 15 days for a total of 30 trials. The slow loris participated in a trial each day over five days for a total of five trials, as time was limited. The authors found that the aye-ayes could discriminate between tap water and the varying concentrations of alcohol, and that they adjusted their intake accordingly.

When the containers holding higher alcohol contents had run out, the aye-ayes continued to compulsively dip and lick their fingers. This suggests that they really like those concentration. But the animals did not show any obvious signs of inebriation, which goes back to their ability to breakdown alcohol because of  this efficient ADH4 enzyme that i have invoked above.

“Further statistical analysis showed that the aye-ayes preferred the highest concentrations of alcohol. Unexpectedly, the aye-ayes continued to probe the containers with the highest concentrations long after they were emptied, suggesting that they wanted more”. (Source)

Ripe fruits ferment and decay because of yeast that grows inside and on the fruits. Yeast breaks down sugar into alcohol, primarily ethanol. As yeast cells multiply, the fruit sugar content decreases and both ethanol and CO2 increase. Inside of mammilian and human cells, ethanol activates the mitochondrial machinery relative to glycolysis, thanks to which ATP can be rapidly produced. (Exhibit B).

In studies published in 2002 and 2004, Dudley reported the alcohol content in wild fruits of the Astrocaryum palm, which Panama’s mantled howler monkeys eat. (Source)

The unripe fruits contain zero ethanol, ripe hanging fruits contain 0.6%, ripe fallen fruits contain 0.9% and over-ripe fallen fruits contain 4.5% ethanol (by weight) on an average (Ibid).

Discussion

Without Ethanol, Wine is not a Longevity Elixir

Alcohol (ethanol) is fundamental to the character of wine. But grape juice must be allowed to ferment holistically and traditionally. A wine is regarded to be holistic and well balanced if its alcoholic strength, acidity, sweetness, fruitiness and tannin structure complement each other so that no single component dominates on the palate.

Long must maceration helps lots, if only because this process produces much more resveratrol and pynogenol, two of wine’s key health and longevity molecules.

Organic, biodynamic and sustainable viticulture with extended harvest time to increase grape maturity and enhance the degree of fruit flavours and colour intensity can also be a good strategy. A higher degree of grape maturity results in increased yeast activity and grape sugar concentration, thanks to which wine’s ethanol increase.

In these 14 or 15 percent ethanol containing wines, added sulfites are therefore not needed as much as for low alcohol red wine or white wine because alcohol in of itself is a preservative.

Full-bodied, these wines are warm and quick-acting in terms of psychotropic effects.  Hence, they may be watered down for those who are not used to them or if they are not accompanied with meals. For those who prefer low-alcohol wine, certain yeasts like Saccharomyces cerevisiae and other strains can  reduce ethanol formation during the fermentation of grape musts with high sugar content in favor glycerol.

Tentative Conclusion

Natural selection in the animal Kingdom appears to have  favored this special ability to ingest ethanol rich ripe fermenting ethanol-containing fruits so that animals can have access to quick calories. As we have seen, ethanol has been around for over three billion years. And for the last 10 million years, alcohol’s break-down system has been fine-tued to near perfection. All animal produce ethanol to a varying degree. “Alcohol” is therefore not the “Enemy”. It is bad quality ethanol drinks, lack of synergy, excessive alcoholic drinks and drinking untimely that can be problematic. When wine is used under the guidance of most of the twelve “rules” the Medicinal Wine Institute proposes, it then becomes a longevity and health elixir.

Pr. Joubert

Exhibit A

Ethanol-containing fruits have been quick calorie-energy food for animals for millions of years

Exhibit B

Ethanol in animal cells is ubiquitous

References

(1).  When normal, oxygen-using (aerobic) cellular respiration is not possible, that is, when oxygen isn’t around to act as an acceptor at the end of the electron transport chain,  anerobic fermentation starts.  This fermentation pathways consist of glycolysis with some extra reactions tacked on at the end. In yeast, the extra reactions make alcohol, while in exhansted muscles that also lack oxygen, they make lactic acid. In ethanol fermentation,  one glucose molecule breaks down into two pyruvates. The energy from this exothermic reaction is used to bind the inorganic phosphates to ADP and convert NAD+ to NADH.  The two pyruvates are then broken down into two acetaldehydes and give off two CO2 as a by-product.  The two acetaldehydes are then converted to two ethanol by using the H- ions from NADH, converting NADH back into NAD+. Ethanol fermentation, a biological process which converts sugars such as glucose, fructose, and sucrose into cellular energy, produces ethanol and carbon dioxide as by-products. Because yeasts perform this conversion in the absence of oxygen, alcoholic fermentation is considered an anaerobic process. It also takes place in some species of fish (including goldfish and carp) where (along with lactic acid fermentation) it provides energy when oxygen is scarce. (Source)
(2). The citric acid cycle(CAC),  also known as theTCA cycle(tricarboxylic acid cycle) or theKrebs cycle is a series of chemical reactionsused by all aerobic organismsto release stored energy through the oxidationof acetyl-CoAderived from carbohydrates, fats, and proteins, into adenosine triphosphate(ATP) and carbon dioxide. In addition, the cycle provides precursorsof certain amino acids, as well as the reducing agentNADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it wasone of the earliest established components of cellular metabolism.  The name of this metabolic pathway is derived from the citric acid (a type of tricarboxylic acid, often called citrate, as the ionized form predominates at biological pH) that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD+to NADH, and produces carbon dioxide as a waste byproduct. The NADH generated by the citric acid cycle is fed into the oxidative phosphorylation(electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP. In eukaryoticcells, the citric acid cycle occurs in the matrix of the mitochondrion. In prokaryoticcells, such as bacteria, which lack mitochondria, the citric acid cycle reaction sequence is performed in the cytosol
(3). Alcohol is broken down via multiple processes, from alcohol dehydrogenase enzyme to acetaldehyde dehydrogenase, catalase, cytochrome 450 enzymes, sulfotransferase and microbiota activity.
(4). 2014 review of the drunken monkey hypothesis. (Source)  In the village of Bossou in Guinea, West Africa, locals crop the crown of mature raffia palms and hang plastic jugs to collect the sap dripping from it. The sugary sap soon ferments into alcohol, which is a popular drink among the locals. It is known as palm wine. On an average, the wine contains 3.1% ethanol (by volume) but it can go up to 6.9% depending on how long it is left to ferment. While the wine is brewing, it can draw the attention of chimpanzees living or foraging nearby. The uninvited guests help themselves to the free drinks, with either an individual hogging the jug or two drinking buddies alternating their take, while others wait. To get the wine, chimps use a tool: they crush some leaves in their mouth, dunk the leaves into the wine and put them back into their mouth to squeeze wine out, like a sponge. This way, the wine is drunk by young and old, male and female chimps alike – and they come back for more. Some even get tipsy. (Source) Kimberley J. Hockings of Oxford Brookes University in the UK, writes in an email from Guinea-Bissau that, though she has not formally recorded the behavioural effects of alcohol, she did notice some signs of intoxication: chimps lying down or becoming agitated after drinking too much. (Source)
(5). 2014 PNAS article reconstructing ancestral hominid enzymes involved in metabolism of dietary ethanol. (Source). 2008 PNAS paper showing natural attraction of the slow loris and pen-tailed treeshrew to fermenting nectar. (Source)  Laboratory of Professor Robert Dudley at the University of California, Berkeley (Source)
See also
The Drunken Monkey: Why We Drink and Abuse Alcohol, University of California Press, 154 pp., 2014.
“Evolutionary origins of human alcoholism in primate frugivory”. Quarterly Review of Biology 75:3-15, 2000
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