Yves here. KLG today focuses on new research on how hunter-gatherers have much more and more diverse intestinal flora, and what that says about their health and our diets.
By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health
What have we done? Toxic “forever chemicals” that make life easier, in the short run, such as found in the cheap non-stick frying pan that works no better than your grandmother’s well-seasoned cast iron skillet, an artifact that will last forever. Ground water mined at rates far beyond natural replenishment for industrial agriculture where rain is scarce. The expanding hypoxic dead zone at the mouth of the Mississippi, the watershed of which extends from Louisiana to North Carolina, New York, Minnesota, the Dakotas, Montana, Alberta, Wyoming, Colorado, and New Mexico (1,151,000 square miles). Microplastics everywhere and in everything, from filter-feeding mussels to you and me.
And then there is the “Western Diet” of food-like substances, which has been a concomitant of the post-WWII industrialization of agriculture in the United States. Industrial Agriculture is a category mistake nourished by a market fundamentalism that has led inexorably to misery, pathology, and environmental degradation. Although a large part of the implicit foundation of this post, our “Modern Food System” is beyond the scope of the topic for today. In my view the best place to begin with our agricultural predicament is The Unsettling of America: Culture & Agriculture by Wendell Berry. Originally published in 1977, this essential book is still in print. I am on probably my fifth reading copy, as I tend to give them away. The Pleasures of Eating is a good summary of his argument: Eating is an agricultural act.
The transformation of our diet began in the 1950s with the “Diet-Heart Hypothesis.” Despite millennia of practical wisdom , this can be summarized (incorrectly) as “eat fat, get fat,” with bad things happening to your heart as a result. Fat and protein calories were replaced by fat substitutes (e.g., margarine and vegetable oil) and refined carbohydrates. Sugar, which is not toxic in moderation, has been replaced with high-fructose corn syrup in many of our “staples.”  What has rightfully become known as the “obesity epidemic” is a most obvious result. This has recently been in the news in the form of Ozempic, which is unlikely to end well as drugs that are effective in the treatment of Type 2 diabetes, which is often caused by obesity, are used as (powerful and expensive) weight loss shortcuts (there are no lasting weight loss shortcuts). One already hears of “Ozempic butt,” which undoubtedly will be treated with implants in those who have not already had one that is shrinking nonetheless. First world problems lead to first world solutions, some of which have been as awful as they have been unnecessary.
Over the past 20 years the biomedical community has learned that the gut microbiome is essential to human health. We simply cannot live without the hundreds of different species of commensal microorganisms that populate our healthy gut at any one time. I first learned of the importance of the microbiome about fifteen years ago when preparing a talk about a new treatment for persistent Clostridiodes difficile infections. C. difficile infection is common in older patients and can be very serious. This bacterium is ubiquitous but is usually kept in check by a healthy gut microbiome. Overuse of antibiotics together with a poor diet depletes this microbiome and allows the C. difficile population to bloom.
The new treatment for C. difficile is the fecal microbiota transplant (FMT), which reestablishes a normal gut microbiome when it works. When I began my talk with the term “fecal transplant,” the pediatrician present, who was at the time primarily a tutor of preclinical medical students, replied in disbelief, “What did you just say?” The treatment remains “experimental” but has a success rate approaching 85%. Early do-it-yourself protocols did not work very well, however.
A corollary to the initial C. difficile intervention and other studies is the gut microbiome varies among populations and that different microbiomes may be healthier than others. Given that the Western Diet is substantially unnatural, the industrial microbiome was immediately suspect, to scientists with imagination. A recent paper in Cellhas compared our industrial microbiome with that of the Hadza of northern Tanzania, one of the few hunter-gatherer peoples remaining on planet Earth: Ultra-deep sequencing of Hadza hunter-gatherers recovers vanishing gut microbes(Open Access; in print July 6, 2023). The results are thorough and thoroughly convincing.
From the Abstract/Summary:
The gut microbiome modulates immune and metabolic health. Human microbiome data are biased toward industrialized populations, limiting our understanding of non-industrialized microbiomes…we performed ultra-deep metagenomic sequencing on 351 fecal samples from the Hadza hunter-gatherers of Tanzania and comparative populations in Nepal and California…recovered 91,662 genomes of bacteria, archaea, bacteriophages, and eukaryotes, 44% of which are absent from existing unified datasets. We identified 124 gut-resident species vanishing in industrialized populations and highlighted distinct aspects of the Hadza gut microbiome…Industrialized gut microbes were found to be enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource, expands our understanding of microbes capable of colonizing the human gut, and clarifies the extensive perturbation induced by the industrialized lifestyle.  (emphasis added)
The major difference between the industrial microbiome and those of more traditional peoples is diversity. The industrial microbiome is much less diverse, probably because of lifeways that include “(1) consumption of highly processed foods, (2) high rates of antibiotic administration, (3) birth via caesarean section and use of baby formula, (4) sanitation of the living environment, and reduced physical contact with animals and soil” (reviewed by the corresponding authors here, paywall). Consistent with this observation is that gut microbiomes of immigrants to the United States become “industrialized.”
The industrial versus non-industrial microbiomes are referred to as “BloSSUM (bloom or selected in societies of urbanization/modernization) and VANISH (volatile and/or associated negatively with industrialized societies of humans). Analysis of coprolites is consistent with the hypothesis that ancient microbiomes resemble current non-industrialized microbiomes more than those from people living in modern industrialized societies. It follows that during the evolution of the human lineage the human microbiome has also changed, here and here (paywall).
Microbiome research has been limited previously to relatively crude DNA sequencing approaches such as the determination of 16S rRNA sequences  from a heterogenous sample. This allows for the identification of (some of) the species present but is a low-resolution technique. In the old days of my scientific middle age, genomes were sequenced slowly and (very) expensively one at a time using DNA from the pure, cultured organism – bacterium, yeast, protist, pathogen, virus, human. In contrast, metagenomic sequencing (construction of whole or nearly whole genomes from environmental samples) allows the researchers to go much deeper into the composition of the microbiome and the relationships among the individual species of the microbiome and the host. How deep metagenomics works is illustrated in Figure 1 (jpg; first time I have seen that emoji in a scientific paper, Figure 1A). In contrast to the use of AI and machine learning to construct our Digital Twin and Virtual You, the advances in DNA sequencing technology and the improved analysis of very large datasets used here will actually answer the very good and essential questions asked.
The Hadza include several thousand individuals who live in the central Rift Valley in northern Tanzania. They live in camps of 5-30 people and move often. Thus, somewhat off topic but perhaps relevant, the Hadza approximate the “normal” of human group according to Robin Dunbar, whose research has shown that the size of a genuine human community has limits, consisting of a social group of 150; close friends, 50; Very close friends, 15; and inner circle: 5. The Hazda get their water from springs and streams, and their diet consists of tubers, berries, hunted animals, and honey (one of the genomes recovered in the study samples is that of the honeybee, Apis mellifera). The result is that 388 metagenomic libraries (33,000,000,000 read pairs) identified:
- 2,437 prokaryotic (bacterial) species
- 13,866 bacteriophage (bacterial virus) species
- 7 eukaryotic species
Summarized in Figure 2 (B,C). Remarkably, nearly half of the bacterial species 1,125/2,437 (46%) are newly described in this research, indicating that our understanding of the gut microbiome has been deficient. The eukaryotic species recovered included several amoebae, including Acanthamoeba castellanii, a very distant cousin of animals that can cause corneal damage, and Blastocystis sp., a stramenopile unrelated to animals and mostly harmless. Overall, how do the Hadza microbiomes differ from others? To answer this question the microbiomes of two populations from Nepal(one forager, one agrarian) and one population from California were analyzed (Figure 3A). The results show that the Hadza have a considerably more diverse gut microbiome than the others:
- Average Hadza: 730 species
- Average Nepali agriculturalist: 436 species
- Average Nepali forager, 317 species
- Average Californian, 277 species
Figure 4 (D, E) shows that VANISH and BloSSUM taxa have different distributions, depending on lifeway. Remember, the expectation is that we “are” BloSSUM and the Hadza are VANISH. From the paper (p. 7): “The observed tradeoff between VANISH and BloSSUM taxa across lifestyles poses the question of whether an accompanying trade-off exists with regard to functional capacity in the human gut microbiome.” Indeed. Consistent with an affirmative answer, the BloSSUM taxa are enriched in proteins involved in the response to an inflammatory state in the host (Figure 4E: antioxidant/Redox sensing, light blue dots and antibiotic resistance, dark blue dots). Chronic inflammation is common in the industrial population, particularly as a response to obesity, and we use antibiotics recklessly, both in human populations and industrial agriculture. Thus, these selection pressures result in variants (mutants) better able to deal with these environmental stresses.
The analysis presented here also shows that one group of the VANISH taxa (phylum Spirochaetota, particularly Treponema succinifaciens, which has been previously associated with the non-industrialized lifeway and identified in paleofeces. The three diverse Spirochaetota taxa are found in other non-industrial populations, but are absent from the California population Figure 5A. These data also show that T. succinifaciens was carried along out-of-Africa human dispersal routes in Figure 5C,D, probably linked to close human contact, including mother-infant intergenerational transmission. Helicobacter pylori, which causes stomach ulcers, is also transmitted in this manner. Why these two gut bacteria have similar modes of transmission is yet to be determined but is likely to be interesting.
A better understanding of gut microbe global dispersal patterns is also likely to identify mechanisms that promote gut health, which is one more reason why basic research is necessary and useful, but I repeat myself. A particularly interesting outcome of this work is the identification of evolutionary trajectories in the Hazda gut microbiomes in response to seasonal diet changes, immune evasion, and bacterial virus (phage) predation (Figure 6). 
So, what does this all mean, aside from being an astonishing tour de force of modern biology? The Hadza are a contemporary but not modern people under pressure from what, for lack of a better term, should be called modernity. Although they do face challenges “related to land dispossession” and cultural disruption, it is not clear that “hunger, lack of access to education, healthcare, and political decision making,” conditions that will be ameliorated “by technologies, food, and medicines from urban centers,” are all that necessary for their continued health and survival. What the Hadza need most is to be left alone to live as they have for a very long time. The world has room for this attractive people (ordered but not read yet; an addition to Evans-Pritchard on the Nuer and the Azande).
The Hadza have much to teach us, and the results of this study will let them do exactly that, as “the data generated from Hadza fecal sample in this study (collected in 2013 – 2014) may thus represent a critical permanent reference point for microbiome scientists to understand the impacts of industrialization on the gut microbiome.” The authors are circumspect, but these data will be particularly useful as a baseline from which to study the industrial microbiome in comparison to what came before. In my view, the VANISH taxa found will “represent lineages of microbes that shaped human development throughout our species’ long history as foragers.” The correlations between the Hadza reference microbiome and human migration patterns will lead to an understanding of which microbes were gained or lost as human populations spread around planet Earth during our long prehistory and until the present day. Identification of which microbes were gained or lost is a precondition to answering why they were gained or lost.
And the authors are surely correct in their conclusion:
An important challenge is to characterize the impact of these microbes on human physiology and determine in which contexts the absence or presence of species and functions are beneficial or detrimental to human health. Overall, our results conclusively show that the differences between industrialized and non-industrialized microbiomes go well beyond simple taxonomic membership and diversity. These findings have substantial implications for how the microbiome may be investigated toward improving the health of both industrialized and non-industrialized populations. (emphasis added)
Although populations such as the Hadza are threatened, the strategy described here will allow other similar populations to provide the broader perspective necessary to better understand the roles of the gut microbiome in human health and evolution.
Which brings us back to the title: Is Industrialism Bad for Our Health? Despite our remarkable and very real advances in hygiene, living standards, life expectancy, and biomedicine, the answer is, well, yes. The bad is not an obligatory companion of the good. As noted in the introduction, industrialism has come with pollution, environmental degradation, and environmental disease. Modern society is quite pathological, as noted by authors as diverse in perspective as Anne Case and Angus Deaton and Kate Pickett and Richard Wilkinson. The “Great American Modern Food System” is a complete disaster, from soon-to-be soilless fields in depopulated country to high fructose-laden food-like substances to food insecurity for a distressingly large number of our neighbors.
The same research group recently published a paper showing that Gut-microbiota-targeted diets modulate human immune status (Open Access, 2021). While a high-fiber diet is healthy, a diet rich in fermented foods has a “noticeable impact on reducing inflammatory markers and modulating immune responses.” The solution to our dysregulated gut microbiome is not “probiotics,” which are primarily patent medicines that might rebalance your gut or mine. Placebo or not? Who knows? Nor is the solution to eat as a hunter-gatherer.
Rather, the correct response is to eat real food in a diet including unsweetened yoghurt, kombucha, and cottage cheese. This can be done, but not as a product of industrial agriculture, the result of which is the end of one aisle of a large supermarket devoted to “local” produce, including the two bottom shelves devoted to very good local craft beer. That’s it. The apples come from New Zealand to a state that in living memory nurtured hundreds of apple growers in its mountains, and the organic tomatoes were shipped more than a thousand miles from Canada. The cut flowers were flown in from Colombia. This, in a state with a growing season approaching 300 days a year, but where most production is highly profitable, due to unaccounted real costs plus “farm” subsidies, commodity crops not meant for direct human consumption. We are not a serious people, but we could be. Our choice.
 “One dies in his full strength, being wholly at ease and secure. His pails are full of milk, and the marrow of his bones is moist. Another man dies in the bitterness of his soul, never having eaten with pleasure.” (NKJV, Job 21: 23-25; thank you to LS for this reminder of my Sunday School lessons long ago).
 Carbotoxicity – Noxious Effects of Carbohydrates is the title of a review in the premier biochemistry, cell and molecular biology journal Cell in late 2018. I thought this might lead to a breakthrough in appreciation of the problem. Alas, the article has been cited fewer than 50 times in nearly five years. That the authors are European is no accident. Still, I expect that their perspective will become the accepted view of human nutrition and health, eventually.
 “Lifestyle” is the term used throughout this paper. “Lifeway” is perhaps the better term, based on my experience in the Anthropology Department at the expense of taking a microbiology class, or several. This research is as much cultural/physical anthropology as it is modern molecular biology and molecular evolution. Thus, lifeway seems to be the more apt term in my view, one that also lacks a certain connotation.
 Ribosomes, which are the machines that turn mRNA into protein in all cells, contain ribosomal RNA (rRNA) that is easily sequenced. Different sequences are diagnostic of different groups, but sometimes the sequences are from unknown taxa. Deeper sequence data (e.g., for protein-encoding genes) is much more useful for identifying taxa in the microbiome.
 Undoubtedly too much information, but the molecular evolutionist in me cannot resist: The genetic code (in the original and correct usage; i.e., not the same as the genome sequence which is commonly called a “genetic code” analogous to computer code, which it also is not) is degenerate, meaning that the third position (sometimes more) of a codon triplet specifying a particular amino acid can vary. In one of the major advances in molecular evolution (1991), it was shown that genes subject to diversifying/directional/positive selection have higher pN/pS ratios (non-synonymous change/synonymous change) that genes not under selective pressure. Thus, in populations of gut microbiota that must adapt due to a dynamic environment, changes in the genes encoding proteins that mediate interactions with the host and bacterial viruses will have a higher ratio pN/pS ratio than “housekeeping” proteins that do just that (metabolism, protein synthesis, DNA replication and repair) to keep the bacterium alive. The utility of the pN/pS ratio depends on evolutionary time. pN/pS changes from deep evolutionary time are not useful in identifying positive selection. The ratio is very useful for populations such as the gut microbiome, which are accessible and evolve in real time.