Homo medicus: The transition to meat eating increased pathogen pressure and the use of pharmacological plants in Homo. Edward H. Hagen, Aaron D. Blackwell, Aaron D. Lightner, Roger J. Sullivan. American Journal of Biological Anthropology, February 23 2023. https://doi.org/10.1002/ajpa.24718
Abstract: The human lineage transitioned to a more carnivorous niche 2.6 mya and evolved a large body size and slower life history, which likely increased zoonotic pathogen pressure. Evidence for this increase includes increased zoonotic infections in modern hunter-gatherers and bushmeat hunters, exceptionally low stomach pH compared to other primates, and divergence in immune-related genes. These all point to change, and probably intensification, in the infectious disease environment of Homo compared to earlier hominins and other apes. At the same time, the brain, an organ in which immune responses are constrained, began to triple in size. We propose that the combination of increased zoonotic pathogen pressure and the challenges of defending a large brain and body from pathogens in a long-lived mammal, selected for intensification of the plant-based self-medication strategies already in place in apes and other primates. In support, there is evidence of medicinal plant use by hominins in the middle Paleolithic, and all cultures today have sophisticated, plant-based medical systems, add spices to food, and regularly consume psychoactive plant substances that are harmful to helminths and other pathogens. We propose that the computational challenges of discovering effective plant-based treatments, the consequent ability to consume more energy-rich animal foods, and the reduced reliance on energetically-costly immune responses helped select for increased cognitive abilities and unique exchange relationships in Homo. In the story of human evolution, which has long emphasized hunting skills, medical skills had an equal role to play.
8 DEFENDING THE BRAIN FROM PATHOGENS WITH PSYCHOACTIVE DRUGS
The final category of pharmacological plant use that requires an evolutionary explanation is the widespread, habitual use of “recreational” drugs like caffeine, nicotine, and THC, which we also conceptualize as (mostly) a constitutive defense. Previously, two of the authors (EHH and RJS) and their colleagues proposed that use of these substances might have evolved as constitutive and inducible defenses against pathogens (Hagen et al., 2009; Hagen et al., 2013; Roulette et al., 2014; Sullivan et al., 2008). Here we extend this hypothesis to the behavioral defense of the CNS specifically, which tripled in size in the Pleistocene and might have been subject to increased virulent infections, as described earlier. This extension is based on the substantial differences in immune defenses of the brain vs. other tissues and organs.
Most tissues have mechanisms to restore functionality when damaged or infected, which typically involves the destruction and removal of injured or infected cells (D'Arcy, 2019; Deretic et al., 2013), and the generation of new cells (Clevers & Watt, 2018; Xia et al., 2018). Herpes simplex virus infection of skin cells, for example, results in massive immune- and virus-mediated cell death, followed by rapid replacement of the cells. Most human neurons, however, cannot be replaced in adulthood because loss of neurons entails the loss of functionality and often irreplaceable information, such as in Alzheimer's disease where neuronal cell death causes permanent loss of memory and other cognitive dysfunctions (Arendt et al., 2015). Although adult neurogenesis has been reported in a wide range of vertebrates, including birds, rodents, and primates, in humans it is very limited and perhaps non-existent (Denoth-Lippuner & Jessberger, 2021; Franjic et al., 2022; Gage, 2019; Lucassen et al., 2020; Moreno-Jiménez et al., 2019; Oppenheim, 2019; Sorrells et al., 2018). The unique value of neurons presents a conundrum to the immune system: how to defend the brain from pathogens if destroying infected neurons would cause permanent loss of critical learned information or other functionality (Miller et al., 2016; Solomos & Rall, 2016)? Moreover, CNS inflammatory responses interfere with CNS functions, sometimes permanently, even without neuronal death (Klein et al., 2017). Constitutive defenses are one solution (Paludan et al., 2021).
8.1 The blood-brain barrier, a constitutive defense
The brain is defended by a physical blood brain barrier (BBB). The BBB prevents most blood-borne pathogens from infecting the brain. It also prevents most plant toxins and other xenobiotics from entering the brain (Banks, 2016; Iadecola, 2017; Villabona-Rueda et al., 2019), including most pharmaceuticals, which often chemically resemble plant toxins (Agúndez et al., 2014). These properties pose a considerable challenge to drug treatment of pathogens that do manage to infect the CNS (Pardridge, 2012; Terstappen et al., 2021). Certain small molecules can cross the BBB via lipid-mediated free diffusion, however, including widely used “recreational drugs” like nicotine and caffeine.
8.2 CNS immune privilege and defense
For much of the last century, knowledge that the BBB prevented most pathogens from reaching the CNS and that tissue grafts implanted in the CNS parenchyma (functional tissue) did not provoke rejection, supported the view that the CNS was an “immune privileged” site. Recent discoveries that the brain parenchyma is connected to the peripheral immune system via meningeal lymphatic vessels have stimulated debate over the nature of immunity in the brain.
One mainstream view is that barriers establish compartments in the CNS that differ functionally in their access to the immune system and some are immune privileged and others are not (Engelhardt et al., 2017). The meninges surrounding the CNS parenchyma, for instance, contain a wide repertoire of immune cells, including monocytes and B cells from special skull and vertebral bone marrow reservoirs, that provide immune surveillance of the CNS (Alves de Lima et al., 2020; Brioschi et al., 2021; Cugurra et al., 2021). Although the CNS parenchyma can mount an inflammatory response to infection via resident microglia (brain-specific macrophages) and other cells, as well as cells migrating from the meninges, it is characterized by a dearth of adaptive and innate immune responses relative to peripheral tissues (Engelhardt et al., 2017).
Immune privilege is a double-edged sword, however. Despite formidable CNS defenses such as the BBB, pathogens do manage to infect the CNS. The protection immune privilege provides to neurons also creates a niche in which pathogens that manage to infect the CNS can evade destruction by the immune system (Cain et al., 2019; Forrester et al., 2018). In fact, to maintain neuronal integrity, immune responses in the CNS might favor controlling pathogens rather than eliminating them (Matta et al., 2021; Miller et al., 2016).
8.3 Habitual recreational drug use as a constitutive pathogen defense
Humans have evolved to be exceptionally reliant on learned information and other CNS functions across a lifespan that exceeds that of most other mammals, and they occupied a dietary niche with high exposure to potentially zoonotic pathogens, including those that infect the CNS. Yet immune defense of the CNS is constrained. Chemoprophylaxis and chemotherapy with compounds that are harmful to CNS pathogens but well-tolerated by the CNS would complement the immune system. Such an evolved chemoprotective strategy for the CNS requires antipathogenic compounds that can cross the BBB.
Most common recreational drugs, including caffeine, nicotine, THC, and arecoline in betel nut, are plant defensive neurotoxins (ethanol, a yeast fermentation product, is the major exception). Sullivan, Hagen, and colleagues argued that the prevailing evolutionary “hijack hypothesis” of recreational drug use, in which evolutionarily novel substances incidentally activate dopamine reward circuits (Kelley & Berridge, 2002; Wise, 1998), was implausible because similar compounds have been part of primate diets for millions of years (Hagen et al., 2009; Hagen et al., 2013; Sullivan et al., 2008; Sullivan & Hagen, 2002).
Psychoactive substance seeking might instead be an evolved self-medication strategy to defend against intestinal helminths and other pathogens (Hagen et al., 2009; Hagen et al., 2013; Sullivan et al., 2008; Sullivan & Hagen, 2002). All globally popular recreational drugs are toxic to helminths, as are some hallucinogenic plants used by Amazonian peoples (Rodríguez et al., 1982); nicotine was widely used to deworm livestock prior to the development of modern anthelmintics, and has the same mechanism of action as some commercial anthelmintics; an aqueous solution of tobacco is still used to deworm livestock in some low-income settings (efficacy quantitatively verified); tobacco is widely mentioned as an anthelmintic in ethnomedical texts; treatment of intestinal helminths in hunter-gatherers transiently reduces tobacco use, and tobacco and cannabis use is negatively associated with worm burden and reinfection; and there is a switch-like transition by virtually all humans to regular use of one or more of these pharmacologically potent substances in adolescence once teratogenic risks to the developing brain have dropped (Hagen et al., 2009; Hagen & Sullivan, 2018; Roulette et al., 2014; Roulette, Kazanji, et al., 2016; Sullivan et al., 2008; Sullivan & Hagen, 2002). In this model, females avoid culturally identified teratogenic substances such as tobacco during pregnancy and their reproductive years, increasing use postmenopause (Hagen et al., 2016, 2013; Hagen & Tushingham, 2019; Placek et al., 2017). See Figures 7 and 8.
Helminths are an important class of CNS parasites, and of course all recreational drugs cross the BBB. Here we extend the antiparasite hypothesis of recreational drug use to pathogens that infect the CNS, focusing on the helminth T. solium as a key example. Humans, dogs, and other animals infected with Taenia and other tapeworm species have often been treated with arecoline hydrobromide (Gemmell, 1958; Li et al., 2012). Arecoline is an agonist of muscarinic acetylcholine receptors, which have numerous roles including in neuromuscular junctions. Arecoline's mechanism of action against cestodes is probably to induce paralysis (Liu et al., 2016). Arecoline readily crosses the BBB and is the primary psychoactive alkaloid in the seed of Areca catechu palm, which is typically chewed with the leaf of the Piper betle and slaked lime, a concoction termed betel quid or paan (Volgin et al., 2019). Betel quid is widely consumed in Asia and the Pacific and is probably the fourth most widely used psychoactive substance after caffeine, alcohol, and tobacco (Arora & Squier, 2019; Gupta & Warnakulasuriya, 2002; Mehrtash et al., 2017). Areca seeds, often combined with pumpkin seeds, were one of several frequently mentioned treatments of Taenia infections in Chinese medical texts dating back about 2000 years (Zou & Ye, 2014). In a controlled study in humans this combination was found to be close to 90% effective at expelling Taenia tapeworms (Li et al., 2012). Whether arecoline also kills Taenia larvae in the brain is unknown, and killing larvae in the brain induces inflammation, potentially creating more problems than it solves. However, most of the medical community has accepted that the benefits of antiparasitic treatment of neurocysticercosis outweigh the risks (García et al., 2003). In an observational study of individuals suffering epileptic seizures, many of whom probably had neurocysticercosis based on the local prevalence of this disease, chewers of Areca catechu (1/3 of the sample) had 59% fewer seizures in the month prior, compared to non-chewers (a mean of 1.4 vs. 3.3 seizures, respectively, Mateen et al., 2017).
It is intriguing that a tapeworm that humans acquired from carnivores in the Pleistocene, and which infects the CNS and other tissues, is potentially treatable with the active compound in one of the world's most popular “recreational” drugs, used on a daily basis by a sizable fraction of the world's population, and that among those with seizures, use of the drug is negatively associated with seizure frequency. It is also intriguing that caffeine, the world's most popular drug, inhibits growth of T. gondii (Munera López et al., 2019), another common neurotropic pathogen. Consumption of ethanol, like consumption of pharmacological plant substances, could also be a self-medication strategy: it is a potent antimicrobial compound, and there is evidence that it mitigates infections of H. pylori in vitro and in vivo (Liu et al., 2016; Xia et al., 2020).
Extending previous work (Hagen et al., 2009; Hagen et al., 2013; Sullivan et al., 2008), we propose that when the benefits exceed the costs, humans, and perhaps other animals, have an evolved propensity to seek out and regularly consume psychoactive plant defensive chemicals, that is, those that cross the BBB and interfere with neural signaling, so as to deter, control, and eliminate pathogen invasions of the immune privileged CNS parenchyma.
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