Historical Perspective on the Rise and Fall and Rise of Antibiotics and Human Weight Gain

In a 2014 New York Times article, The Fat Drug (1), journalist Pagan Kennedy related that inappropriate antibiotic use, already associated with the antibiotic resistance crisis, had been tentatively linked to yet another epidemic: the dramatically increasing (and incompletely explained) obesity rates across the United States in recent decades. With the notion further popularized in the media and by scientist Martin Blaser in his best-selling book, Missing Microbes (2, 3), audiences have been asked to consider whether the same antibiotics used to stimulate the growth of livestock have also stimulated our own waistlines by altering our intestinal flora. Articles in PubMed related to both microbiome and obesity increased from 1 in 2004, to 42 in 2009, to 336 (and climbing) in 2014. In 2015, Time summarized, Antibiotics may wipe out existing microbiomes and replace them with other, less beneficial bugs, and that may adversely affect weight (4). At the same time, with escalating attention to the human microbiome keeping pace with that devoted to antibiotic resistance and obesity themselves, we have been offered the possibility, by more rationally prescribing and taking antibiotics, of confronting 2 epidemics at once. As Kennedy further discussed, the historical irony is that more than 6 decades ago, scientists purposefully studied whether antibiotics could stimulate human weight gain. Yet the story behind the rise and fall and rise of attention paid to antibiotics and human weight gain is more than ironic and more complicated than Kennedy depicted. Such history offers lessons about the complexity of human growth and disease development; the temptations of magic bullets (therapeutic or explanatory); the role and complications of clinical investigation; and the interconnectedness of culture, commerce, and science in the evolution of microbes and medical models alike. Wonder Drugs: Antibiotics as a Growth Industry and as Growth Stimulants The advent of such broad-spectrum antibiotics as Lederle's aureomycin (chlortetracycline) in 1948 transformed both clinical medicine and the fortunes of the pharmaceutical industry (5). But the growth-stimulatory effect of such antibioticsand the possibility for still additional markets for the drugswere recognized almost immediately. Scientists at Lederle, including Thomas Jukes, were immersed in identifying the apparent animal protein factor necessary for livestock weight gain and found that aureomycin stimulated the growth of young chicks beyond the effects of vitamin B12 alone (6, 7). Lederle's subsequent efforts to disseminate aureomycin to animal husbandry researchers have been well-described, along with the effect of such drugs for growth promotion on the livestock industry worldwide (8). Although the documentary evidence is less robust, it seems Lederle, Merck (penicillin), and Pfizer (oxytetracycline) also recognized human growth as a potential market. As T.D. Luckey, one of the earliest investigators of the growth-stimulatory effects of antibiotics, would later recall, The power of the calliope in the antibiotic band wagon increased spectacularly during the [early 1950s] while poultry, pigs, and patents danced to its tune. Geese, pheasants, chicks, turkeys, pigs, mink, calves, rats, mice and men responded to the stimulus of antibiotics (9). In an era of wonder-drug optimism, companies began to send materials and grants to researchers in various clinical settings worldwide. The first published studies concerned premature infants in hospital settings, with small, somewhat impressionistic, and imperfectly controlled studies yielding the suggestion of utility, although there was nothing dramatic enough to transform the field (1012). Other researchers studied the growth-promoting effect of the drugs on institutionalized, mentally defective children; publicly enrolled school children exhibiting simple growth failure (reportedly found in one third of all school-aged children); and naval recruits. They also found small, inconsistent trends toward weight gain that seemingly called for more prolonged, intensive investigations (1315). The most extensive investigations, focused on the largest public health burden (and perhaps market), concerned impoverished, malnourished children in the developing world at a time when the World Health Organization (WHO) and others were increasingly focusing on the global problem of malnutrition (16). Potentially growth-stimulating antibiotics seemed to be magic bullets for malnutrition itself. As one research group, encouraged by its findings among Haitian children, suggested, The growth promoting effects of [Pfizer's oxytetracycline] can be supplied economicallyan important factorto children with simple growth failure in food deficient tropical countries while broader agricultural and food preservation programs are being developed. As a matter of fact, the addition of growth-promoting substances to deficient tropical diets may be even then the most economically practical way to overcome simple growth failure in native tropical children (17). Lorna Macdougall attempted to run an 8-week, placebo-controlled trial of aureomycin involving 72 children in Kenya; although the trial was difficult to conduct, with treatment periods ranging from 2 to 7 weeks, it seemed that the children treated with aureomycin gained nearly 30 grams per day more than their counterparts (18). Macdougall regretted the lack of follow-up studies, however, and although she hoped to do a follow-up report, none came from either her group or the aforementioned group in Haiti. Moreover, researchers reporting on a similar study in Jamaica found that aureomycin seemed only to have a slight effect on weight gain. They lamented that for the practical purpose of alleviating malnutrition these results are disappointing and it is unlikely that such factors would be of any practical value in dealing with the problem of growth failure where marginal malnutrition exists (19). The most important of this first wave of global studies, however, was conducted in Central America and led by the young nutritionist Nevin Scrimshaw. He became the founding director of the Institute of Nutrition of Central America and Panama (INCAP) in 1949, just as aureomycin was appearing on the market. The institute had stemmed from the combined interests of the Rockefeller Institute, the Kellogg Foundation, and the Pan American Health Organization and was formed in the early Cold War era to assess and help solve nutritional and related health issues throughout Central America (20). Studies about supplementation with aureomycin and vitamin B12 were among the earliest interventional trials conducted by INCAP and began in May of 1950. Early results from Guatemala were promising and led The New York Times in March of 1951 to cite Scrimshaw as declaring that if aureomycin succeeds as a growth-producing element children may some day be eating aureomycin candy to improve their diets (8, 21). The New York Times concluded that out of INCAP's work may come the answer that will lift undernourished children in Latin America to normal physical development. Despite such pronouncements, Scrimshaw and colleagues knew that their early studies, although suggestive, were difficult to conduct and may have been confounded by the fact that a separate village was used as a control group and contextual environmental factors could have explained the results. As they wrote in 1953, a control group of equal size and equivalent initial status, receiving some kind of comparable placebo treatment would seem to be absolutely essential to rendering valid conclusions (22). They thus divided children within villages into comparable groups and randomly assigned them to treatment or placebo. By the First International Conference on the Use of Antibiotics in Agriculture in late 1955, study sponsors reported that no ill effects or outbreaks of resistant organisms occurred among children receiving continuous aureomycin or penicillin for 2 years. But as a nutritional public health measure, the benefits were disappointing, with apparent early weight gains offset over time (23). By 1958, Scrimshaw and colleagues concluded that despite the obvious value of antibiotics in clinical medicine there is no present justification for considering their continued administration to children in underdeveloped areas to be an effective or desirable public health measure (24). Methodologically, the entire enterprise had shown that for complicated public health interventions in necessarily messy real-world settings, the study of the behavior of multiple experimental and placebo control groups in several time periods is essential for sound conclusions (24). As Scrimshaw and his colleagues summarized more broadly for the WHO in 1968, infection and malnutrition in humans were to be deemed synergistic contributors to poor health. This necessitated attention to specific infections and nutritional deficiencies if well-intentioned researchers were to interrupt the processes whereby malnutrition led to infection, and infection often led to worsening malnutrition (25). There was to be no simple, nonspecific antibiotic answer to widespread malnutrition. By 1974, and in the context of increasing concern about the relationship between low-dose agricultural antibiotic administration and antibiotic resistance, the Subcommittee on Interactions of Nutrition and Infections of the Committee for International Nutrition Programs of the National Research Council still considered it unwise and inappropriate to recommend large field trials of small-dose antibiotic feeding in human populations (26). However, they did recommend more focused, rigorously conducted studies moving forward. Researchers thereafter have thus taken a cautious, measured approach to the effect of antibiotics as part of a broader approach to severe malnutrition (as defined over time). Recent studies in sub-Saharan Africa have been