An Epidemic of Absence

1. The human immune system evolved with parasites and microbes

Homo sapiens ranks among the most parasitised of all animals.

Coevolution shaped immunity. For millions of years, humans coexisted with a diverse array of parasites and microbes. This long-term relationship profoundly influenced the development of our immune system. Parasites like hookworms and whipworms were ubiquitous, as were various bacteria and viruses. Our bodies adapted to their presence, developing regulatory mechanisms to maintain a delicate balance.

Parasites as old friends. Rather than viewing all parasites as harmful, many acted as "old friends" to our immune system. They helped calibrate immune responses, preventing overreaction to harmless stimuli. This symbiotic relationship allowed our ancestors to thrive despite constant microbial exposure. Examples include:

• Helminths (intestinal worms) that modulate inflammation
• Commensal bacteria that aid in digestion and immunity
• Viruses that may offer protection against other pathogens

2. Modern hygiene has disrupted our ancient microbial relationships

We may have made a mistake equivalent to studying and cataloging an exotic-seeming ecosystem, only to discover that we weren't in the jungle at all; we were actually at the Bronx Zoo.

The hygiene revolution. The advent of modern sanitation, antibiotics, and improved living conditions dramatically reduced our exposure to many parasites and microbes. While this undoubtedly saved countless lives from infectious diseases, it also disrupted the delicate ecosystem our immune systems had come to expect.

Unintended consequences. The rapid change in our microbial environment has led to unexpected health challenges:

• Increased rates of allergies and autoimmune diseases
• Rising incidence of inflammatory bowel diseases
• Potential links to neurological disorders like autism
• Altered gut microbiome composition and function

These shifts occurred faster than our genes could adapt, leaving our immune systems in a state of confusion and potential overreaction.

3. Parasites and microbes play a crucial role in immune system regulation

Coevolution leads to codependence.

Immune education. Parasites and microbes act as natural immunomodulators, teaching our immune system to distinguish between harmful invaders and benign substances. This "education" process is critical for developing a balanced immune response.

Regulatory mechanisms. Specific examples of immune regulation include:

• Helminths inducing regulatory T cells (Tregs) that suppress inflammation
• Commensal bacteria producing short-chain fatty acids that maintain gut barrier integrity
• Certain viruses potentially enhancing innate immune responses

Without these regulatory influences, the immune system may become hyperactive, leading to inappropriate responses against harmless substances or the body's own tissues.

4. Autoimmune diseases may result from missing "old friends"

We may actually be born allergic.

The old friends hypothesis. This theory proposes that the absence of evolutionary partners—parasites, bacteria, and viruses we coevolved with—contributes to the rise of autoimmune and allergic diseases. Without these "old friends," our immune system lacks the stimuli it expects to encounter during development.

Evidence from epidemiology and experiments:

• Higher rates of autoimmune diseases in developed countries with less parasite exposure
• Successful treatment of some autoimmune conditions using controlled helminth therapy
• Animal studies showing protective effects of certain parasites against allergic and autoimmune reactions
• Inverse relationship between H. pylori colonization and asthma rates

This hypothesis suggests that reintroducing specific microbes or mimicking their effects could potentially treat or prevent autoimmune disorders.

5. The maternal immune environment shapes fetal development

[M]aternal farm exposure might reflect a natural mode of immunotherapy . . . shaping a child's immune system at an early stage.

Prenatal programming. The immune status of a pregnant mother significantly influences her child's future health. Factors such as maternal infections, stress, and environmental exposures can alter fetal immune development through epigenetic changes.

Key influences on fetal immunity:

• Maternal antibodies and cytokines crossing the placenta
• Microbial exposures during pregnancy (e.g., farm environments)
• Presence of regulatory T cells in the placenta
• Maternal diet and microbiome composition

These early-life influences can have long-lasting effects on the child's immune function, potentially predisposing them to allergies, autoimmune diseases, or neurodevelopmental disorders like autism.

6. Autism spectrum disorders may have roots in prenatal inflammation

Something environmental is causing the rise [of autism].

Maternal immune activation. Growing evidence suggests that inflammation during pregnancy, whether from infection or other causes, may contribute to the development of autism spectrum disorders (ASD). This inflammation can disrupt normal fetal brain development.

Potential mechanisms:

• Maternal antibodies targeting fetal brain proteins
• Elevated pro-inflammatory cytokines affecting neurodevelopment
• Altered microglial activation in the developing brain
• Epigenetic changes induced by maternal immune responses

While genetics play a role in ASD susceptibility, the rapid increase in prevalence points to environmental factors. The link between maternal immune activation and autism offers a potential explanation for this trend and suggests possible avenues for prevention or intervention.

7. Reintroducing certain microbes could potentially treat immune disorders

If some omniscient being had come and said, 'That button on the wall, you press it and Lawrence not only doesn't exist, but he never existed.' I mean, I would have lunged for it.

Helminth therapy. Controlled reintroduction of specific parasites or their products has shown promise in treating some autoimmune and allergic conditions. This approach aims to restore the regulatory immune functions that coevolved with these organisms.

Promising areas of research:

• Use of Trichuris suis ova (pig whipworm eggs) for inflammatory bowel disease
• Hookworm therapy for asthma and allergies
• Potential applications for multiple sclerosis and other autoimmune disorders

While still experimental, these treatments highlight the potential benefits of harnessing our evolutionary relationships with certain microbes. However, careful consideration of risks and ethical implications is necessary.

8. The human virome is an integral part of our immune ecosystem

There is a dimension to human evolution—a microbial evolution—that is likely occurring at a very rapid rate as our societies undergo dramatic shifts.

Viral coevolution. Viruses, often viewed solely as pathogens, have played a crucial role in human evolution. Many have become integrated into our genome, contributing to important biological functions.

Virome functions:

• Potential protection against other pathogens
• Modulation of immune responses
• Contribution to genetic diversity
• Possible influences on brain development and function

Understanding the complex relationship between humans and our virome may lead to new insights into health and disease, as well as novel therapeutic approaches.

9. Diet and antibiotics have profoundly altered our gut microbiome

You are really an ecosystem, a mutually dependent aggregation of life-forms, what scientists call a superorganism.

Microbiome disruption. Modern diets high in processed foods and frequent antibiotic use have dramatically changed the composition of our gut microbiota. These changes may contribute to various health problems, including obesity, diabetes, and inflammatory disorders.

Factors affecting the microbiome:

• Overuse of broad-spectrum antibiotics
• Lack of dietary fiber and complex carbohydrates
• Increased consumption of artificial sweeteners and emulsifiers
• Reduced exposure to diverse environmental microbes

Restoring a healthy, diverse microbiome through dietary changes, probiotics, and reduced antibiotic use may help prevent or treat various modern diseases.

10. Epigenetics links environmental factors to immune system function

Genes are not Stalinist dictators. . . . They live in a democracy, and what they do is conditioned by what else is going on around them.

Environmental influences on gene expression. Epigenetic mechanisms allow environmental factors to influence how our genes are expressed without changing the DNA sequence itself. This provides a link between our experiences and our immune function.

Key epigenetic factors:

• Early-life exposures to microbes and parasites
• Maternal diet and stress during pregnancy
• Environmental toxins and pollutants
• Chronic stress and lifestyle factors

Understanding these epigenetic influences offers new possibilities for disease prevention and treatment by targeting the environmental factors that shape our immune responses.

Last updated: September 28, 2024