Target Health Blog

Father of Prebiotics, Elie Metchnikoff (1845-1916)

February 24, 2020

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History of Medicine
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Photograph of Nobel Prize winner, Ilya Ilyich Mechnikov, who discovered phagocytes.
Photo credit: Public domain; Wikipedia Commons

Prebiotics help to grow good gut bacteria. Hippocrates, the ancient Greek physician and "Father of Modern Medicine," once famously said: "All disease begins in the gut." Recent advances in medical technology are finally proving this true.

Prebiotics have been defined as "nondigestible food ingredients (usually carbohydrates) that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon." Potential prebiotics have included bifidobacteria, indigenous microbes epidemiologically associated with long life and other healthful conditions.

Probiotics and prebiotics have become part of the lexicon of food technologists. Probiotics were defined in 1989, as live microbial feed supplements that beneficially affect the host animal by improving its intestinal microbial balance. The concept of probiotics is not new, however. Approximately 100 years ago, Elie Metchnikoff, the father of immunology, investigated intestinal microbes as causative agents in aging, a process he called "autointoxication." He believed that lactic acid-producing bacteria (such as those found in yogurt) would suppress the growth of more proteolytic, autointoxicating bacteria.

The central issue in this field is the following: how can the metabolic activities of the bacterial population in the colon be manipulated to promote health? Rigorous scientific exploration of this question has been limited by two factors: the colonic biota (flora) is vast and also largely undefined. Another important issue is exploring the relationship of the microbial biota and the host, especially the healthy host; such microecologic studies are critical to understanding potential microbial contributions to disease. A third and related issue is defining conditions that might be ameliorated by probiotic or prebiotic therapies. Some researchers have hypothesized that these latter diseases result from a childhood deprived of specific pathogens, the "hygiene hypothesis." Use of probiotics and prebiotics has been advanced as one solution to that problem.

Ilya Ilyich Mechnikov (1845 - 1916), was a Russian zoologist best known for his pioneering research in immunology, and in 1908, received a Nobel Prize in Physiology or Medicine, together with Paul Ehrlich. In particular, he is credited in 1882, with the discovery of phagocytes (macrophages). This discovery turned out to be the major defense mechanism in innate immunity. Mechnikov is also credited by some sources with coining the term gerontology in 1903, for the emerging study of aging and longevity. In immunology, he is given an epithet the "father of natural immunity".

Mechnikov was born in the village Ivanovka, Kharkov Governorate, now Dvorichna Raion, Ukraine. He was the youngest of five children of Ilya Ivanovich Mechnikov, a Russian officer of the Imperial Guard. His mother, Emilia Lvovna (Nevakhovich), the daughter of the Jewish writer Leo Nevakhovich, largely influenced him on his education, especially in science. Mechnikov entered Kharkiv Lycee in 1856 where he developed his interest in biology. In 1864 he went to Germany to study marine fauna on the small North Sea island of Heligoland. He was advised by the botanist Ferdinand Cohn to work with Rudolf Leuckart at the University of Giessen. It was in Leuckart's laboratory that he made his first scientific discovery of alternation of generations (sexual and asexual) in nematodes and then at Munich Academy. In 1865, while at Giessen, Mechnikov discovered intracellular digestion in flatworm, and this study influenced his later works. Moving to Naples the next year he worked on a doctoral thesis on the embryonic development of the cuttle-fish Sepiola and the crustacean Nebalia. In 1867 he returned to Russia to get his doctorate with Alexander Kovalevsky from the University of St. Petersburg. Together they won the Karl Ernst von Baer prize for their theses on the development of germ layers in invertebrate embryos. In 1870 he returned to Odessa to take up the appointment of Titular Professor of Zoology and Comparative Anatomy. In 1882 he resigned from Odessa University due to political turmoil after the assassination of Alexander II. He then went to Sicily to set up his private laboratory in Messina. He returned to Odessa as director of an institute set up to carry out Louis Pasteur's vaccine against rabies. In 1888 he went to Paris to seek Pasteur's advice. When there, Pasteur gave him an appointment at the Pasteur Institute, where he remained for the rest of his life.

Mechnikov became interested in the study of microbes, and especially the immune system. At Messina he discovered phagocytosis after experimenting on the larvae of starfish. In 1882 he first demonstrated the process when he inserted small citrus thorns into starfish larvae, then found unusual cells surrounding the thorns. He realized that in animals which have blood, the white blood cells gather at the site of inflammation, and he hypothesized that this could be the process by which bacteria were attacked and killed by the white blood cells. He discussed his hypothesis with Carl Friedrich Wilhelm Claus, Professor of Zoology at the University of Vienna, who suggested to him the term "phagocyte" for a cell which can surround and kill pathogens. He delivered his findings at Odessa University in 1883. His theory, that certain white blood cells could engulf and destroy harmful bodies such as bacteria, met with skepticism from leading specialists including Louis Pasteur, Behring and others. At the time, most bacteriologists believed that white blood cells ingested pathogens and then spread them further through the body. His major supporter was Rudolf Virchow, who published his research in his Archiv fur pathologische Anatomie und Physiologie und fur klinische Medizin (now called the Virchows Archiv).

In 1887, Mechnikov observed that leukocytes isolated from the blood of various animals were attracted towards certain bacteria. This attraction was soon proposed to be due to soluble elements released by the bacteria. Some 85 years after this seminal observation, laboratory studies showed that these elements were low molecular weight (between 150 and 1500 Dalton (unit)s) N-formylated oligopeptides, including the most prominent member of this group, N-Formylmethionine-leucyl-phenylalanine, that are made by a variety of replicating gram positive bacteria and gram negative bacteria.

Mechnikov also developed a theory that aging is caused by toxic bacteria in the gut and that lactic acid could prolong life. Based on this theory, he drank sour milk every day. He wrote The Prolongation of Life: Optimistic Studies, in which he espoused the potential life-lengthening properties of lactic acid bacteria (Lactobacillus delbrueckii subsp. bulgaricus). He attributed the longevity of Bulgarian peasants to their yogurt consumption.

Mechnikov died in 1916 in Paris from heart failure. According to his will, his body was used for medical research and afterwards cremated in Pere Lachaise Cemetery crematorium. His cinerary urn has been placed in the Pasteur Institute library.

The mid-1990s onwards witnessed exponential growth in probiotics research, and by 2001 the term "microbiome" had entered the literature to refer to the collective genome of our microbial inhabitants. Probiotics now represents both a serious field of medical research and a multibillion dollar global industry, while the US National Institutes of Health has invested in a Human Microbiome Project. Probiotics and the microbiome have been joined by such concepts as prebiotics, metagenomics, and holobionts. Personalized microgenomic medicine itself can now be envisioned. Metchnikoff chose as his remedy the replacement of the native flora with a friendly, exogenously introduced flora, Bacillus bulgaricus. However, by the time Metchnikoff's remedy became widespread in the USA from the 1910s through the 1930s, several key changes had taken place. First, with B bulgaricus apparently found to be unable to survive passage to the colon, bacteriologists such as Yale University's Leo Rettger instead chose to focus on Lactobacillus acidophilus (whether through direct administration, or through altering carbohydrate administration and hence anticipating later notions of "prebiotics"). Second, Metchnikoff's grandiose emphasis on prolonging life was replaced by more modest aspirations to treat gastrointestinal complaints. Third, and most fundamentally, Metchnikoff's emphasis on organismic disharmony was entirely ignored, as researchers chose to focus on ecological notions of intra-organismic balance and harmony, especially between the host and its flora.

The heyday of lactobacillus therapy ended abruptly with the advent of the sulfa drugs and then antibiotics. But the impact of antibiotics on perceptions of our native flora was itself dynamic, the result of multiple intersecting forces. On the one hand, a "war on bugs" approach to infectious diseases initially relegated discussions of friendly flora back to the scientific periphery. On the other hand, the late-1940s discovery of the growth-promoting aspects of antibiotics in farm animals forced attention back upon the very nature and impact of such colonic inhabitants. And from the early 1950s, medical scientists became increasingly aware of the potentially negative impact of antibiotic administration in human beings. The advent of "superinfections" ranging from monilial overgrowth to what would later be termed Clostridium difficile infections, the rising impact of antibiotic resistance, and the specter of a "post-antibiotic" era led researchers again to turn to ecological notions in their invocation of environmental "pollution" with antibiotic-resistant bacteria.

This was fertile soil for the advent of probiotics, although the term emerged in a variety of contexts between the 1950s and the 1970s. It was even used in adjectival form, by Joshua Lederberg in 1960, to describe the chemical soup that preceded the formation of planetary life. By the 1980s, however, the term had stabilized in both the medical and veterinary literature around its use in describing introduced organisms contributing beneficially to host microbial balance. The growth phase of probiotic research and discourse, though, paralleled the dramatic increase in attention given to antibiotic resistance from the early 1990s onwards, in part catalyzed by Lederberg's own role in drawing attention to "emerging infections" and coming plagues. By 2001, Lederberg had also introduced the term microbiome to the literature. And drawing from tools developed for the elucidation of the human genome, while necessarily advancing on and extending such tools in a host of new directions, researchers have sought to carefully characterize the distribution and variability of our microbiota and their micro-genomes, as well as the impact of such exogenous agents as antibiotics, probiotics, nutrition, and prebiotics on such microbial ecosystems. Sources: The Lancet; NIH.gov; Wikipedia; www.ncbi.nlm.nih.gov

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