Gut health and chronic disease (Part I): Understanding the connection

What is gut health? Key signs, clinical markers, and their impact on resilience and disease risk.

This article marks the first in a collaborative series on gut health and chronic disease by Dr. Mike Hunter, MD, a career gastroenterologist, and Kristen Deuel, an MSc candidate in Integrative Health. Together, we explore the science, clinical relevance, and practical implications of gut health, examining why it matters, how to measure it, and its impact on whole-person resilience.

Of all the health buzzwords circulating today, none attracts more interest (or more misinformation) than “gut health." The term appears everywhere: in journal articles, patient consultations, supplement ads, and wellness blogs. Yet unlike cholesterol, blood pressure, or HbA1c, there is no single biomarker that can declare a gut ‘healthy’ or ‘unhealthy.’ That is because the gut isn’t just one organ. It is a living system: a gastrointestinal tract lined by barrier tissues, powered by enzymes, and inhabited by trillions of microbes. It is an immune ecosystem that trains tolerance and defense, and a neural network that constantly communicates with our brain. When we discuss gut health, what we really mean is how well these interwoven systems adapt and remain resilient in the face of stress. A healthy gut efficiently regulates digestion, immunity, metabolism, and even our mood. When these systems start to fail, the effects ripple outward, shaping risks for metabolic, autoimmune, and neurocognitive disease.

Why is defining gut health so challenging?

Unlike diabetes, which can be defined by blood glucose levels, or hypertension by systolic/diastolic cutoffs, gut health lacks a universally accepted diagnostic test. Instead, researchers and clinicians must rely on proxies:

• Symptoms such as bloating, diarrhea, or pain are useful but subjective, and are not always correlated with dysfunction.

• Inflammatory markers like calprotectin or C-reactive protein are valuable but incomplete on their own.

• Microbiome sequencing (mapping) is a promising science, but still lacks standardized clinical interpretation.

Each measure offers part of the overall picture, but no single measure tells the whole story. This is why gut health is best understood as a system property, the emergent outcome of multiple and interconnected physiological domains working in synchrony. To organize this complexity, researchers have outlined four key pillars that, together, can help us better understand gut health. Each can be assessed as a measurable biomarker, and when disrupted, each may drive distinct clinical consequences.

The four pillars of gut health

1. Digestion and absorption

The gut’s foundational task is efficient digestion and nutrient absorption. Enzymes, bile salts, and epithelial transporters convert food into usable molecules. Meanwhile, commensal microbes ferment fibers into short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. These SCFAs regulate sugar and fat metabolism, fuel the cells of our colon, and exert anti-inflammatory effects. Microbes also synthesize key vitamins (K, and B group) and modulate mineral uptake.

Lab markers used to measure efficient digestion and nutrient absorption:

• Stool elastase for pancreatic function, fecal fat, breath tests for malabsorption.

• Serum nutrient panels: iron, B12, folate, vitamin D.

• SCFAs levels in stool or plasma.

If left unchecked, malabsorption can lead to digestive symptoms, as well as micronutrient deficiencies, anemia, fatigue, an increased risk of osteoporosis, and impaired metabolic regulation. Over time, this can weaken immune function and reduce resilience to stress.

2. Intestinal barrier integrity

The intestinal barrier is a selective gatekeeper. It is porous enough to absorb nutrients, impermeable enough to block pathogens and toxins. It is composed of epithelial cells sealed by tight junctions, mucus, antimicrobial peptides, and secretory IgA. Beyond serving as a physical wall, this barrier actively communicates with the immune and nervous systems, shaping systemic inflammation and overall health.

Lab markers used to measure effective intestinal barrier integrity:

• Lactose-mannitol permeability tests.

• Zonulin levels (still debated but commonly referenced).

• Calprotectin or LPS-binding protein as indirect signals of inflammation or translocation.

Barrier dysfunction, also known more generically as ‘leaky gut,’ allows bacterial products into circulation, triggering systemic inflammation. This state has been linked to food sensitivities, autoimmune disease, metabolic disorders, and neuroinflammation. Stress, alcohol, NSAIDs, and poor diet are common disruptors.

3. Microbiota balance

The gut microbiome is an ecosystem of bacteria, fungi, viruses, and archaea. A healthy microbiota is diverse, stable, and functionally redundant, traits that create resilience against infection, antibiotics, and dietary shifts. Its influence now extends far beyond digestion, with research linking microbial composition to immunity, mood, metabolism, and even chronic disease.

Lab markers used to measure gut microbiome balance:

• Sequencing-based diversity indices (alpha and beta diversity).

• Relative abundance of beneficial or pathogenic taxa.

• Stool organic acids and metabolomics for functional outputs.

Dysbiosis, the loss of beneficial species or overgrowth of pathobionts, has been associated with obesity, type 2 diabetes, inflammatory bowel disease, and depression. Low diversity also reduces ecosystem resilience, leaving the host more vulnerable to infections and chronic disease.

4. Immune and hormonal function

About 70% of our body’s immune system lives in the gut. This is where immune cells learn to make choices: tolerate food and friendly microbes while staying ready to attack real threats. If that training goes off track, the system can become over-reactive or sluggish, leading to widespread problems. The gut also has its own nervous system, often referred to as the “second brain.” With hundreds of millions of neurons, it runs digestion behind the scenes but also sends constant updates to the brain through the vagus nerve. This back-and-forth shapes how we process stress, how our gut moves food along, and even how we feel emotionally. Gut microbes play an active role in this conversation, producing the majority of the chemical messengers the brain uses, including serotonin, dopamine, and GABA. It regulates motility locally, but also influences mood, focus, and resilience through the gut-brain axis.

Lab markers used to measure efficient immune and hormonal function:

• Secretory IgA in stool for first-line immune defense.

• Inflammatory markers like CRP, IL-6, or TNF-α.

• Neurotransmitter metabolites (serotonin, dopamine, gamma-aminobutyric acid (GABA)) in urine or plasma.

When this gut-immune-brain network is disrupted, the results aren’t confined to digestion. Chronic low-grade inflammation, mood disorders such as anxiety or depression, reduced mental clarity, and even links to neurodegenerative disease can emerge.

Why gut health matters to whole-person health

Taken together, these four pillars position the gut as a central regulatory hub. When one pillar falters, the disturbance rarely stays local; it reverberates through the entire system. For example, the following all contribute to obesity and diabetes:

• Disrupted SCFA production

• Dysbiosis

• Barrier dysfunction

Further, a compromised intestinal barrier, paired with impaired microbial training of the immune system, has been implicated in:

• Autoimmune diseases like rheumatoid arthritis

• Allergic diseases

Breakdowns in the gut-brain communication and altered neurotransmitter production are increasingly recognized as drivers of:

• Anxiety

• Depression

• Other mental health disorders

In short, gut health is not simply about gastrointestinal comfort. For practitioners, it represents a foundation of systemic resilience, one that underpins disease prevention, cognitive performance, and long-term vitality. For practitioners and health seekers alike, this means gut health should be evaluated not through a single test or symptom, but through a constellation of markers, lifestyle factors, and functional assessments. Clinical tools, such as stool form, SCFA levels, microbial diversity, and inflammatory markers, provide useful signals; however, they must be interpreted in conjunction with one another, and clinicians must triangulate across multiple domains, including patient symptoms, lifestyle context, and functional testing.

P.S. The future of gut health is rapidly evolving, with personalized nutrition on the horizon, where diets and synbiotics can be tailored to each individual’s microbiome and health goals. Innovative therapies are emerging that may extend far beyond digestion, addressing systemic conditions through gut-based interventions. Yet even as science advances, everyday choices remain the most powerful levers: dietary diversity, fiber, and polyphenol intake, microbial exposure, stress management, and the mindful use of probiotics or fermented foods. These practices not only alleviate digestive discomfort but also promote whole-person health and enhance performance. Yet the gut does not act alone. Its influence depends on constant cross-talk with other microbial communities in the mouth, lungs, skin, and beyond.

Read on in Part II, where Dr. Hunter and I zoom out to explore how the other microbiomes are connected and why understanding them is crucial to both resilience and the progression of chronic disease.

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