The Intestinal Microbiome, an Underappreciated Metabolic Organ

We live, eat, and breathe in a sea of microorganisms. Bacteria, fungi, viruses, parasites, midges, mites, prions, and Archaea are teeming within and around us. We humans evolved within this richly complex and constantly changing bouillabaisse of microbes in a mostly synergistic, mutually beneficial relationship. The sum of this diverse group of ‘bugs’ we carry with us everywhere is called our microbiome. The microbiome has been described as a separate organ akin to the liver in metabolic importance. The introduction of rapid nucleic acid sequencing of the microbiome in the early 2000’s and intensive research in the metabolic activity that the intestinal lumen has on human health and longevity has yielded a whole new lens with which to view human physiology and health. Examples of the physiologic importance of the microbiome:

Immune system and systemic inflammation regulation:

• The gut microbiota maintain immune homeostasis by interacting with gutassociated lymphoid tissue (GALT), promoting the development of regulatory T cells, and stimulating the production of anti-inflammatory cytokines. This relationship ensures that the immune system distinguishes between harmful pathogens and harmless antigens, preventing unnecessary immune activation.

• The gut flora also produce metabolites like short-chain fatty acids (SCFAs), such as butyrate, which have systemic anti-inflammatory effects. SCFAs reinforce the intestinal barrier, reducing the translocation of harmful microbes and endotoxins into the bloodstream, a key driver of systemic inflammation.

• Dysbiosis, an imbalance in gut microbial composition, is associated with chronic inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, and metabolic syndrome.

Gut-brain axis:

• The gut-brain axis is a complex, bidirectional communication system connecting the gastrointestinal tract and the brain, crucial for maintaining both physical and mental health. It operates through neural pathways, such as the vagus nerve, or via immune signaling and microbial metabolites such as short-chain fatty acids (SCFAs). The gut microbiota influence neurotransmitter production, including serotonin and gamma-aminobutyric acid (GABA), which are vital for mood regulation and cognitive function.

• Disruptions in this communication system, often caused by dysbiosis or chronic stress, are linked to neurologic conditions including anxiety, depression, autism, and neurodegenerative diseases like Parkinson’s or Alzheimer’s diseases.

Coronary artery disease and hypertension:

• The gut microbiome significantly influences coronary artery disease (CAD) and hypertension by modulating systemic inflammation, metabolic pathways, and vascular health. o Dysbiosis can lead to the production of harmful metabolites from the gut like trimethylamine-N-oxide (TMAO), which promotes atherosclerosis by enhancing cholesterol deposition and vascular inflammation. Elevated TMAO levels are strongly linked to an increased risk of CAD.

• The microbiome also affects blood pressure regulation. Beneficial gut microbes produce short-chain fatty acids (SCFAs) like butyrate, which improve endothelial function, reduce oxidative stress, and lower inflammation, contributing to blood pressure control. Conversely, dysbiosis disrupts these processes, increasing susceptibility to hypertension.

• Impaired gut barrier function due to dysbiosis allows endotoxins to enter the bloodstream, triggering chronic low-grade inflammation—a contributor to both CAD and hypertension.

Kidney stones:

• The microbiome influences kidney stone formation by modulating oxalate metabolism, a key factor in stone development. Certain gut bacteria, like Oxalobacter formigenes, degrade dietary oxalate, reducing its absorption and excretion in urine.

• Dysbiosis, or the loss of these beneficial microbes, increases urinary oxalate levels, raising the risk of calcium oxalate stones.

• Additionally, microbial imbalances can alter the production of metabolites, such as short-chain fatty acids, which impact kidney health and inflammation.

• By maintaining a balanced microbiome through probiotics, prebiotics, or dietary changes, oxalate metabolism can be optimized, reducing the likelihood of kidney stone formation and recurrence.

Gut-pulmonary axis:

• The gut-pulmonary axis is a bidirectional communication network linking the gut microbiome and the lungs, playing a critical role in respiratory health and immune regulation.

• This axis functions through immune signaling, microbial metabolites, and systemic inflammation. The gut microbiome produces short-chain fatty acids (SCFAs) like butyrate, which modulate immune responses, enhance lung barrier function, and reduce inflammation. A balanced microbiome supports the development of regulatory T cells, essential for controlling lung inflammation and preventing excessive immune activation.

• Dysbiosis disrupts this axis, leading to increased systemic inflammation and altered lung immunity and has been associated with respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). Conversely, lung inflammation and infections can influence gut microbiota composition through immune feedback. Supporting gut health with a fiber-rich diet or probiotics can enhance the gut-lung axis, promoting respiratory resilience and reducing disease risk

Diabetes and insulin sensitivity:

• The gut microbiome plays a vital role in the development and regulation of diabetes and insulin sensitivity through its effects on inflammation, glucose metabolism, and energy balance. Beneficial gut bacteria produce short-chain fatty acids (SCFAs), such as butyrate, which improve insulin sensitivity by reducing systemic inflammation and enhancing glucose uptake in tissues. They also strengthen the gut barrier, preventing the leakage of endotoxins like lipopolysaccharides (LPS) into the bloodstream, a key trigger for chronic lowgrade inflammation and insulin resistance. o GLP-1, the agent in Ozempic and others, is produced naturally in the intestines and regulated by bowel bacteria such as Akkermansia muciniphila, which is often depleted in Western intestines.

• Dysbiosis contributes to impaired glucose metabolism by increasing inflammation and altering the production of SCFAs and has been linked to altered bile acid metabolism, further affecting insulin signaling pathways.

• Restoring microbial balance through dietary interventions, probiotics, or prebiotics can help improve insulin sensitivity, lower inflammation, and reduce the risk of type 2 diabetes, highlighting the microbiome’s importance in metabolic health.

Fatigue:

• The gut microbiome significantly influences fatigue and energy levels in humans by modulating nutrient absorption, mitochondrial function, and systemic inflammation. Gut bacteria assist in breaking down complex carbohydrates and fibers into short-chain fatty acids (SCFAs), such as butyrate, which serve as an energy source for intestinal cells and influence energy metabolism throughout the body. A healthy microbiome supports efficient digestion, ensuring optimal nutrient availability for energy production. Additionally, the gut microbiota affects mitochondrial function and oxidative stress, key factors in cellular energy production. Beneficial microbes help regulate the production of co-factors like B-vitamins and amino acids, essential for energy generation and neurotransmitter synthesis. Conversely, dysbiosis, or an imbalance in gut flora, has been linked to chronic fatigue by promoting systemic inflammation and altering the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress and energy.

• Low-grade inflammation caused by increased gut permeability (leaky gut) allows endotoxins like lipopolysaccharides (LPS) to enter the bloodstream, impairing energy metabolism and contributing to fatigue. Restoring gut balance through a fiber-rich diet, probiotics, or prebiotics can enhance gut health, improve mitochondrial function, and reduce inflammation, ultimately promoting higher energy levels and alleviating fatigue. This underscores the pivotal role of gut flora in sustaining vitality and overall well-being.

Cancer detection, prevention, and treatment:

• The gut microbiome significantly influences cancer detection, prevention, and treatment through its effects on immune regulation, inflammation, and metabolism. In cancer prevention, a balanced microbiome promotes immune surveillance by stimulating regulatory T cells and natural killer (NK) cells, which detect and eliminate abnormal cells. Beneficial gut bacteria produce metabolites like butyrate, which exhibit anti-inflammatory and anti-carcinogenic properties by inhibiting tumor-promoting pathways and promoting healthy cell growth.

• In cancer detection, microbial byproducts can serve as biomarkers. Changes in microbial composition or metabolite levels, such as elevated levels of certain polyamines or altered short-chain fatty acids, are being investigated as early indicators of cancers like colorectal cancer (CRC). Stool-based microbiome analyses are emerging as non-invasive diagnostic tools with promising accuracy.

• In cancer treatment, the gut microbiome influences the efficacy and toxicity of therapies. Certain microbes enhance the effectiveness of immunotherapies by boosting anti-tumor immune responses, while others may metabolize chemotherapy drugs, reducing their efficacy or causing side effects. Dysbiosis can impair treatment outcomes and increase treatment-related complications.

• Strategies like probiotics, prebiotics, and microbiota transplants are being explored to optimize the microbiome for cancer prevention and to enhance treatment responses, demonstrating its critical role in advancing oncology care and outcomes.

References:

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2. J Goldenberg et al, ‘The Association Between the Microbiome and Cognition, an Umbrella Review Protocol’ British Medical Journal Open, 2024. What is the association between the microbiome and cognition? An umbrella review protocol - PubMed

3. Mincic et al, ‘Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.’ Clin Nutrition Volume 43, Issue 7 p1832-1849 July 2024 Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review - Clinical Nutrition

4. Shen et al, ‘Gut Microbiota and Atherosclerosis-Focusing on Plaque Stability’ Frontiers in Cardiovascular Medicine, Aug 2021. Microbiota and Atherosclerosis

5. Cho et al, ‘Novel strategies for modulating the gut microbiome for cancer therapy,’ Advanced Drug Delivery Reviews 2024. https://doi.org/10.1016/j.addr.2024.115332

6. Hanstock et al, ‘The Role of the Gut Microbiome in Kidney Stone Disease’ Urologic Clinics of N America 2024 Urol Clin NA 2024