The COVID-19 pandemic with evolution of more transmittable variants has brought evolutionary thinking into everyday life. However, physician knowledge of the importance of evolutionary principles to many other diseases is limited by insufficient teaching and few articles in general medical and specialty journals. We discuss evolutionary perspectives on 2 common conditions and summarize 3 hypotheses, each of which offers causative explanations for multiple diseases in gastroenterology and hepatology practice.
WHAT IS EVOLUTIONARY MEDICINE?
Evolutionary medicine uses “principles of evolutionary biology to better understand, prevent and treat disease” (1). It applies to both individual health care and public health. Evolutionary medicine does not replace or contradict traditional medical science. Instead, this evidence-based framework integrates our knowledge of biology, anthropology, psychology, history, epidemiology, and clinical medicine. It “consists of the intersections where evolutionary insights bring something new and useful to the medical profession, and where medical research offers new insights, questions, and research opportunities for evolutionary biology” (2).
The Association of American Medical Colleges and the Howard Hughes Medical Institute recommended in 2009 that graduating physicians have core competency in specific aspects of evolution (3). Nevertheless, after this publication, biology undergraduates manifested misconceptions and intuitive thinking about antibiotic resistance (4), and 51 North American medical school curriculum deans reported a wide variation in importance and coverage of evolutionary medicine topics in their institutions (5). Forty-eight percent of 45 of them reported that adding evolution content would arouse controversy, including 10% who said the controversy would complicate additional teaching (5). Shortly thereafter, experts recommended that physicians master specific evolutionary concepts (6). To the best of our knowledge, residents, gastroenterology fellows, and fully trained practicing gastroenterologists have not been surveyed regarding their knowledge of evolutionary principles.
Principles of evolutionary medicine
The core principles of evolutionary medicine are summarized in Table 1 (7). We expand on a few concepts that are relevant to human disease, but a detailed discussion of all the principles is beyond the scope of this article.
One of the most valuable contributions of evolutionary medicine is that it considers causation of health and disease at 2 levels simultaneously. Proximate causes are the immediate molecular, anatomical, and physiological mechanisms that are the focus of most medical practice; e.g., the mechanisms through which genetically susceptible individuals develop celiac disease when they ingest gluten. An evolutionary perspective expands questions about causation to ultimate causes: What is the phylogenetic history of the disease, and what are the inherited characteristics that predispose to the disease? When did these traits appear during the evolution of our species? What were their previous forms in our ancestors? What is their adaptive significance? that is, did trait variations influence reproductive success in our prehistoric ancestors and modern humans? Consideration of the ultimate causes improves clinicians' insight into health and disease overall, provides practical clues on prevention and treatment for individual patients, and generates powerful hypotheses to be tested by basic and clinical research, eventually enhancing patient care.
Events that have influenced the frequency of many human diseases include small-population effects, especially population bottleneck and founder effects. A population bottleneck occurs when a population rapidly decreases markedly in size, with random survival chance for each individual; e.g., due to a catastrophic environmental event. This diminishes genetic variation, potentially with radical changes in allele frequencies, some of which may disappear completely. The founder effect is a special case of population bottleneck that occurs when a small subgroup separates from the main population and emigrates to a new place (1,8). For example, Finnish populations have expanded in isolation after bottlenecks, causing 36 Mendelian diseases to be much more common in Finns than in other Europeans (9).
Finally, it is worth noting an important principle that may seem paradoxical to nonbiologists. Natural selection maximizes reproductive success (the passage of genes within a lineage to future generations), often at the expense of health and longevity. This occurs because trade-offs are ubiquitous in biology; any trait that improves 1 condition almost always worsens another. Therefore, a trait that improves reproductive success will be selected for, even if it predisposes the individual to poorer health or shorter life (1,7).
EXAMPLES OF EVOLUTIONARY THINKING IN GASTROENTEROLOGY AND HEPATOLOGY
Helicobacter pylori infection
More than half of all humans are infected by Helicobacter pylori (10). They invariably have gastritis, but most never exhibit clinical sequelae. Approximately 10%–20% develop peptic ulcer disease, an uncertain proportion experience functional dyspepsia, while noncardiac gastric adenocarcinoma or mucosa-associated lymphoid tissue lymphoma occur in less than 5% (11,12). Some extra-gastric disorders are associated with infection with variable levels of evidence, including iron and vitamin B12 deficiency anemias, immune thrombocytopenia, and some skin and neurological diseases. However, inverse associations of infection include gastroesophageal reflux disease, Barrett's esophagus, esophageal and esophagogastric junction adenocarcinoma, childhood allergic conditions, and inflammatory bowel disease (IBD) (13–16). The possibility of unmeasured confounders notwithstanding, these diverse associations suggest evolutionary trade-offs.
Much time has enabled evolutionary processes in both the bacterium and its host. H. pylori has been detected in ancient human remains in Europe, Asia, and the Americas, including retrieval of the complete bacterial genome from the 5,300-year-old Iceman discovered in the Italian alps (17,18). Phylogenetic analyses of known H. pylori species reveal transfer from an unknown species to African humans approximately 100,000 years ago, long preceding the migration of anatomically modern humans out of Africa, which carried the bacterium to other continents (19). H. pylori probably host jumped from humans to large felines (lions, tigers, and cheetahs) approximately 50,000 years ago and evolved to Helicobacter acinonychis, the closest related Helicobacter species (19). The current distribution of H. pylori strains reflects prehistoric and historic human migrations, including forced relocation of West African slaves to North and South America and the Caribbean, resulting in admixture of bacterial and human populations. Its distribution and virulence factors seem to underlie geographic variations in gastric cancer incidence (Figures 1 and 2) (12,20,21).
H. pylori manifests high genetic diversity and variable virulence. Factors contributing to its carcinogenic potential include cytotoxin-associated gene A oncoprotein, the toxic form of vacuolating cytotoxin and host genetic polymorphisms that alter cytokine expression (22,23). Other factors include age of initial infection, diet, medications, alcohol consumption, smoking, and the gut microbiota (11). However, there is great variation in progression to cancer among infected individuals from different geographic regions that current knowledge of these features does not fully explain, but is largely explained by coevolution. For example, the “African enigma” refers to the relatively low age-adjusted incidence of gastric cancer in Africa, even after accounting for incomplete reporting, despite high H. pylori prevalence (24). Important research of Cavadas et al. found that H. pylori of African origin caused less in vitro cytotoxicity in gastric cells of subjects of African ancestry than in those of European ancestry, indicating coevolution of H. pylori and its host in Africa and maladaptation of Europeans to African H. pylori (25). Remarkably, there is a 25-fold difference in incidence rates of cancer between mountainous and coastal regions of Colombia despite similarly high prevalence of H. pylori infection (Figure 3) (26). In a study of gastric biopsies and genomic variation in matched human and H. pylori samples from Colombians, Kodaman et al. found that H. pylori of African ancestry was relatively benign in people of African ancestry who predominated in low-risk, coastal areas but caused more severe premalignant gastric lesions in individuals with major Amerindian ancestry who predominated in the mountains (Figure 2) (21,27). The human–pathogen ancestry interaction was 5 times larger than the effect of cytotoxin-associated gene A, and the host–pathogen ancestry interaction completely accounted for the difference in the severity of gastric lesions in the 2 regions (Figure 4). Thus, coevolution for better coexistence of H. pylori and its host likely modulated disease risk. Besides mismatched host–pathogen ancestry, founder effects and rapid population growth could have contributed to disruption of this balance (21,27).
Evolutionary factors underlie the increasing antibiotic resistance of H. pylori, and eradication therapy is less effective than treatment of many other pathogens (28,29). In the presence of an antibiotic, bacteria can become resistant from chromosomal mutation or horizontal gene transfer from other species via plasmids or other modes of DNA transfer (30). At sites such as the mouth or stomach, microorganisms have access to extensive public libraries of antibiotic resistance genes that are available for horizontal gene transfer. Resistant bacteria undergo rapid and strong selection. Besides being a random process, mutation can be promoted by active mechanisms. Instead of developing new antibiotics, a developing approach to antibiotic resistance targets promutagenic proteins at specific steps in the intracellular evolutionary process (31,32). Merrikh and Kohli detail potential promutagenic proteins (evolvability factors) and ideal characteristics of antievolutionary agents, which could target these mutation mechanisms and be administered concomitantly with traditional antimicrobial agents (31).
Therefore, the geographic ancestry and migration of both H. pylori and infected people, their coevolution, and the evolution of antibiotic resistance strongly affect bacterial toxicity, carcinogenesis, and response to eradication therapy. These factors contribute to worldwide regional variation in rates of eradication by antibiotics (28) and complicate the decision to screen asymptomatic subjects for H. pylori to prevent gastric cancer. Reported cost-effectiveness in low- to intermediate-risk Western countries should be considered in light of uncertainties concerning screening benefits in patients with dyspepsia and hazards of antibiotic resistance induced by wide-spread eradication therapy (33). In addition, unassessed evolutionary factors that likely confound screening decisions prevent accurate prediction of which Westerners would benefit most but support a consensus that they would be subjects who have immigrated from regions of high H. pylori and gastric cancer prevalence.
Human infants and babies, as all other mammals, rely on their mother's milk for nutrition. Their intestinal enzyme lactase cleaves lactose into glucose and galactose, which are easily absorbed. Before the Neolithic period approximately 11,000 years ago, also called the Agricultural Revolution, humans and all other mammals would normally have stopped expressing lactase after weaning, most likely because there was no selective advantage in synthesizing an enzyme that has no substrate during adulthood (lactase nonpersistence). In general, when individuals who lack lactase persistence consume milk, they experience symptoms due to lactose maldigestion, although interestingly, the threshold of tolerable consumption of lactose seems to depend on the composition of the individual's gut microbiota (34). A lactose-free environment has been present for most adults during most of human history (35,36). However, where domestication of milk-producing goats, sheep, and cattle occurred, the ability to digest lactose conferred a strong nutritional advantage to individuals with mutations that resulted in lactase persistence throughout adulthood. At least 5 such mutations appeared independently in the Middle East and Africa after dairying began. After human migration, one of these mutations reached very high frequencies in Central and Western Europe, a sequence supported by the failure to detect this allele in Neolithic archeological bone specimens from multiple sites that dated before dairying development (37). The other mutations show pockets of high frequencies of lactase persistence in Africa, the Middle East, and the Indian subcontinent (Figure 5). Lactose persistence is rare in East Asia (38,39).
The practical implication of this evolutionary perspective is that what patients and physicians have traditionally labeled as disease (lactose intolerance or lactase deficiency) is, in fact, common—only approximately 35% of the world's population exhibit lactase persistence—and should be framed neutrally as lactase nonpersistence instead. Most individuals with symptomatic lactase nonpersistence feel relieved if their physician explains the evolutionary facts that remove the “abnormal” label. They should consider themselves as normal in the context of a lactose-free environment.
Functional gastrointestinal disorders (FGID), including functional dyspepsia and irritable bowel syndrome, are the most common gastrointestinal disorders (40). Despite extensive research, their etiology and pathophysiology remain largely unknown, but the Rome Foundation explains them with the widely accepted biopsychosocial model (Figure 6). It describes how the complex interactions among genetic, environmental, psychological, social, and biological factors contribute to the development and maintenance of FGID (1,41).
Evolution of the mammalian autonomic nervous system underlies the polyvagal theory, proposed by Porges in 1995 (42). We believe that current evidence better supports the term, “hypothesis” (43,44), which applies directly to some of the components of the biopsychosocial model. It proposes that severe stress causes acute neural defense responses that are adaptive and beneficial in the short term, but are often maintained chronically and become maladaptive, leading to FGID or other chronic pain, such as fibromyalgia. It also suggests that respiratory sinus arrhythmia (RSA, the variation in heart rate during each breathing cycle) and related indices, such as vagal efficiency (VE, calculated through the association of RSA and heart rate) are valid markers of autonomic nervous system function. Therefore, the dampened RSA in patients with irritable bowel syndrome and other FGID is a marker of a chronic maladaptive state of the neural, mainly vagal, control mechanisms.
The polyvagal hypothesis generates testable research questions that have direct application to the treatment of FGID. A recent example is the study by Kovacic et al., which identified VE as a predictor of pain improvement in adolescents with functional abdominal pain disorders who participated in a randomized sham-controlled trial of auricular percutaneous electrical nerve field stimulation (45). Notwithstanding the methodological limitations of this study, if the results are replicated and confirmed, VE will be the first simple noninvasive biomarker that predicts response of FIGD to treatment (46).
Thrifty gene hypothesis
Sixty years ago, geneticist Neel (47) proposed that a thrifty genotype conferred survival advantages to Paleo-Indians crossing the Bering Strait land bridge (Beringia) from present-day Siberia to North America, 17,500 to 14,600 years ago (48). He proposed that cycles of feast or famine resulted in selection of individuals who were metabolically thrifty regarding fat storage, glucose tolerance, and insulin regulation. He also hypothesized that this prehistoric advantageous ability became detrimental to their modern descendants whose regular plentiful diet and more sedentary lifestyle were mismatched with their ancestors' environment.
Of importance to gastroenterology and hepatology, Indigenous Americans exhibit high rates of obesity, type 2 diabetes, and metabolic syndrome. These abnormalities are strongly associated with nonalcoholic fatty liver disease (NAFLD), which can lead to cirrhosis and hepatocellular carcinoma. Approximately 40%–75% of body mass variation is attributed to genetic differences (49). Amerindians also often experience cholesterol gallstone disease (50); for example, it occurs in 80% of female and 70% of male Pima Indians, cumulatively, often in early adulthood (51). An assessment of Pima Indian diseases in the early twentieth century did not disclose gallstone disease, and the rarity of gallstones in pre-Colombian burials suggests their widespread absence much longer ago (48). There is an approximately 25% genetic component to gallstone disease (52), particularly the ABCG8 D19H genotype (53), but associated genetic variants at many loci have been found (54), and epigenetic and environmental factors contribute to the pathogenesis (55,56). Gallstone disease is the greatest risk factor for gallbladder cancer (47,57), and this malignancy is increased in populations with high prevalence rates of gallstones, including Indigenous Americans (47,58).
Research on Amerindians and others who reflect genetic admixture with them has revealed evidence both for and against a role of thrifty genes. The infrequency of gallstone disease in Siberians who are possibly genetically related to the prehistoric migrants (59) supports the onset of factors giving rise to gallstones during the migration. However, ethnographic data compiled in the mid-20th century revealed that foragers were no more likely to experience cycles of feast and famine than agriculturalists (60), but the similarity of the foragers' and late Pleistocene era migrants' circumstances can be questioned. A genome-wide association study identified 2 genes associated with gallstones and gallbladder cancer in Chilean Latinos with Mapuche Indian ancestry (61). However, as Reddon et al. suggested, the classic approach to the thrifty gene hypothesis that assumes that each gene has a single effect may be simplistic; the evolutionary origins of obesity can be better explained if we account for gene pleiotropy (the influence of each gene on multiple unrelated characteristics) (62) and other factors, such as bottleneck and founder effects. Genné-Bacon (63) emphasized the complexity of this issue in a discussion of other proposed evolutionary mechanisms for obesity.
Regardless of the mechanisms, some evolutionary role is likely. An important point for practitioners is that patients from North, Central, or South America who have at least partial Indigenous ancestry may be predisposed to have certain disorders, including NAFLD and gallstone disease and their complications. However, if physicians attribute obesity and NAFLD mainly to unalterable evolutionary effects, patients may be less motivated to make needed changes in diet and physical activity. Of importance, too much emphasis on this hypothesis can also distract attention from societal factors, such as poor access to healthy food (64).
The hygiene hypothesis resulted from the speculation by Strachan (65) in 1989 that increasing prevalence rates of asthma were due to improved hygiene that prevented childhood infection. It posited that the modern sanitized lifestyle disrupted humans' beneficial microbiota, with which we have coevolved for millennia, too rapidly for evolutionary adaptation, resulting in allergic diseases (66). The hypothesis has been expanded to explain observations of gastrointestinal disorders, including decreasing infectious diseases and concurrent increasing autoimmune disorders in developed countries, lack of autoimmune disease in tropical countries with widespread helminth infection (67–69), and the role of gut microorganisms in immune activity, including food allergy development (70,71).
Increasingly, alterations of the gut microbiome are being linked with disease. Acid-suppressing drug use alters the gut microbiota. Eosinophilic esophagitis (EoE) has increased in incidence with increased proton pump inhibitor use, and a case–control study found that proton pump inhibitor use in the first year of life was the strongest predictor of pediatric EoE (7). Infant antibiotic use is also strongly correlated with EoE (72). IBD incidence is reduced by rural residence during the first 5 years of life, associated with migrating from developing countries to more economically developed countries, and increased by antibiotic use in infancy. IBD relapse after stopping infliximab is associated with gut dysbiosis (73). Several studies point to incitement of the autoimmune process underlying celiac disease by pediatric viral intestinal and respiratory infections (74).
These observations emphasize the importance of preserving the early-life microbiota, especially through prudent antibiotic use in very young patients. Despite a low incidence of IBD in Subsaharan Africa where intestinal helminth infestation is common and the possibility that parasites could modify the immune pathogenesis of IBD (69), small, randomized, double-blind, placebo-controlled trials in IBD patients with eggs of Trichuris suis, a porcine whipworm that is nonpathogenic in humans, have revealed no statistically significant benefits (75). However, further research could identify microbiome and other features in patients with IBD, which predict successful therapy stemming from this hypothesis.
Evolutionary medicine perspectives broaden our understanding of why people have diseases and their pathogenesis. It can contribute to policies on screening, provide an explanatory framework for patients, influence treatment, and lead to productive research.
CONFLICTS OF INTEREST
Guarantor of the article: Grigorios I. Leontiadis, MD, PhD, CAGF.
Specific author contributions: The review was conceived by G.I.L. Both authors drafted the manuscript and approved the final draft submitted.
Financial support: None to report.
Potential competing interests: None to report.
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