A Healthy Gut is…

For those involved in functional medicine, the significance of the human gut in the onset, persistence, and exacerbation of various health disorders is well established. A comprehensive care package often includes strategies for healing a dysfunctional gut, focusing on restoring the community of microorganisms and their connections both locally and systemically. While there are numerous safe and effective interventions available, the definition of a “healthy gut” can vary significantly among practitioners and researchers.

A paper out in the journal GUT in September 2024, undertakes a comprehensive look at the many variable characteristics[1].

A healthy gut is characterised by a complex interplay of microbial diversity, functional capabilities, metabolite production, and host interactions. While there is no universally accepted definition of a “healthy gut,” several key characteristics have emerged from recent research:

Microbial Diversity and Composition

A healthy gut microbiome typically exhibits high bacterial diversity. This diversity contributes to robust digestion, nutrient absorption, metabolite production, and immune system regulation. However, it’s important to note that high diversity alone doesn’t necessarily equate to better health, as there are at least 7 exceptions to this rule[2].

1. High gut microbial diversity is linked to extended colonic transit time, potentially leading to the systemic circulation of harmful protein degradation products.
2. The benefits of microbial diversity can vary widely among individuals due to differences in genetics, environment, and lifestyle.
3. Research indicates that high microbial diversity alone does not always guarantee better health outcomes.
4. Functional diversity, which encompasses the range of functions performed by the microbiota, may be more crucial than taxonomic diversity in assessing gut health. While only about 45% of bacterial species are shared between individuals, approximately 82% of their microbiota share common metabolic pathways.
5. The presence of certain pathogenic bacteria does not always indicate disease; some individuals can carry these bacteria without experiencing negative health effects.
6. Strain specificity is essential; different strains of the same bacterial species can have vastly different impacts on host health. For instance, some strains of Escherichia coli are beneficial, while others can cause illness.
7. In addition to diversity, the composition, functional capabilities, and metabolite production of the gut microbiota are critical in determining overall gut health.

The composition of the gut microbiota is also crucial. A healthy gut typically has a balanced ratio of different bacterial phyla, with Bacillota (formerly Firmicutes) and Bacteroidota (formerly Bacteroidetes) representing roughly 90% of the gut microbiota. The presence of beneficial bacteria like Bifidobacterium, Lactobacillus, and Akkermansia muciniphila is often associated with good gut health. However, the specific composition can vary significantly between healthy individuals. Recent research suggests that functional diversity may be more important than taxonomic diversity in determining gut health[3].

Functional Capabilities

The functional diversity of the gut microbiome is perhaps more important than compositional diversity. A healthy gut microbiome should possess a wide range of metabolic capabilities, including:

1. Ability to break down complex carbohydrates
2. Production of short-chain fatty acids (SCFAs)
3. Synthesis of essential vitamins
4. Metabolism of bile acids
5. Modulation of the immune system

These functional capabilities contribute to overall host health and metabolism. Recent studies have shown that while only about 45% of bacterial species are shared between two individuals, their microbiota share about 82% of common metabolic pathways, highlighting the importance of functional redundancy in maintaining gut health[4].

Metabolite Production

The production of beneficial metabolites is a key indicator of a healthy gut. These include:

1. Short-chain fatty acids (SCFAs): Notably acetate, propionate, and butyrate, which are vital for maintaining gut barrier integrity, modulating immune responses, serving as an energy source for colonic cells, and regulating metabolism[5].
2. Secondary bile acids: Derived from primary bile acids by gut bacteria, these acids play a role in cholesterol metabolism and influence host metabolism and immune function[6].
3. Tryptophan metabolites: Compounds like indole and kynurenine provide insights into both microbial and host metabolism, reflecting gut-brain interactions[7].
4. Polyphenol metabolites: Gut microbes convert dietary polyphenols into various beneficial compounds, such as[8]:
   1. Phenylpropionic acid (PPA): Anti-inflammatory and supportive of gut barrier function.
   2. Hydroxyphenylacetic acids (HPAA and 4-HPAA): Known for their anti-inflammatory and antioxidant effects.
5. Polyunsaturated fatty acid (PUFA) derivatives: Including conjugated linoleic acid (CLA) and other derivatives, which may benefit various health conditions[9].
6. Specific bacterial lipids: Such as commendamide, which has immunomodulatory properties, and GABA-lipopeptides, associated with reduced visceral pain[10].
7. Bacterial membrane lipids: Particularly phospholipids and sphingolipids, which exhibit immunomodulatory effects[11].

Gut Barrier Function

A healthy gut is characterised by a strong and intact gut barrier. This includes:

1. A well-maintained mucus layer
2. Tight junctions between epithelial cells
3. Proper production of antimicrobial peptides

An intact gut barrier prevents the translocation of harmful substances into the bloodstream and helps maintain immune homeostasis. Recent research has highlighted the importance of specific bacteria, such as Akkermansia muciniphila, in maintaining the mucus layer and gut barrier integrity[12].

Immune Function

A healthy gut microbiome supports proper immune function[13]. This includes:

1. Cytokine Balance: It maintains a balance between pro-inflammatory cytokines (like TNF-α and IL-6) and anti-inflammatory cytokines (such as IL-10). Beneficial bacteria, including Faecalibacterium prausnitzii, promote IL-10 production, which is essential for effective immune responses while preventing excessive inflammation.
2. Immune Cell Development: The microbiome influences the differentiation and activity of various immune cells, including regulatory T cells (Tregs) and Th17 cells, which are important for mucosal immunity. Microbial metabolites, especially short-chain fatty acids, enhance immune cell function.
3. Tolerance and Response: A balanced microbiome fosters oral tolerance to commensal microbes and food antigens while enabling robust responses to pathogens. This is achieved through the production of anti-inflammatory metabolites and the activation of regulatory immune mechanisms.
4. Early Immune Education: Exposure to diverse microbes in early life is vital for developing a robust immune system, shaping T cell subsets and cytokine profiles that can influence long-term health and susceptibility to allergies.
5. Systemic Effects: The gut microbiome impacts immune responses beyond the intestines, influencing systemic inflammation and immune activity in distant sites like the lungs and brain.
6. Barrier Function: It supports the integrity of gut barriers by promoting the production of antimicrobial peptides, enhancing mucus production, and competing with pathogens for resources, thereby preventing infections.

The gut microbiota plays a crucial role in training and modulating the immune system, particularly in early life. A healthy gut-immune interaction is essential for preventing autoimmune diseases and maintaining overall health.

Resilience

A healthy gut microbiome should demonstrate resilience, meaning it can maintain stability in the face of perturbations such as dietary changes or antibiotic use, and quickly return to its baseline state. This resilience is crucial for long-term gut health and may be influenced by factors such as microbial diversity, functional redundancy, and host-microbe interactions[14].

Absence of Inflammation

Low levels of inflammatory markers such as calprotectin and lactoferrin in the stool are indicative of a healthy gut. Chronic low-grade inflammation is often associated with various gut disorders and should be absent in a healthy state[15].

Proper pH Levels

In the colon, a pH around 5.5-7 is often associated with a healthy microbiota. This pH range supports the growth of beneficial bacteria and inhibits pathogenic species. However, pH levels can fluctuate based on diet, health status, and other factors, making it a variable marker of gut health.

Efficient Digestion and Absorption

A healthy gut should efficiently digest food and absorb nutrients. This is reflected in regular bowel movements, absence of digestive discomfort, and proper nutrient status in the body.

Bidirectional Communication with Other Systems

A healthy gut maintains proper communication with other body systems, particularly the liver (through the gut-liver axis) and the brain (through the gut-brain axis). This communication helps regulate various physiological processes and maintain overall health[16].

Gas Production

The production of various gases, such as hydrogen, methane, and hydrogen sulfide, can be an indicator of gut health and microbial composition. While some gas production is normal, excessive or imbalanced gas production may indicate gut dysbiosis or functional gastrointestinal disorders[17].

Strain Specificity

Recent research has highlighted the importance of bacterial strain specificity in gut health. Different strains of the same bacterial species can have vastly different functions and effects on host health. For example, some strains of Escherichia coli are beneficial, while others can be pathogenic[18].

Summary

The definition of a healthy gut can vary between individuals due to factors such as genetics, diet, environment, and lifestyle. Moreover, our understanding of what constitutes a healthy gut is continually evolving as research in this field progresses.

Challenges in defining a universally healthy gut microbiome include:

1. Individual variability in microbiome composition and function
2. The dynamic nature of the gut microbiome, which changes over time and in response to various factors
3. The complex interplay between the microbiome and host physiology
4. The need for more precise and affordable methods to assess microbiome function
5. The lack of long-term longitudinal studies to elucidate the temporal dynamics of the gut microbiome

In conclusion, there is significant progress in understanding the characteristics of a healthy gut, there is still much to learn. The complex and dynamic nature of the gut microbiome, coupled with individual variability and environmental influences, makes it challenging to establish a one-size-fits-all definition of gut health. Nonetheless, the markers and characteristics discussed above provide a framework for assessing and promoting gut health in clinical and research settings.

 

References

[1] Van Hul M, Cani PD, Petitfils C, et al What defines a healthy gut microbiome? Gut 2024;73:1893-1908

[2] Lozupone, C., Stombaugh, J., Gordon, J. et al. Diversity, stability and resilience of the human gut microbiota. Nature 489, 220–230 (2012).

[3] Leviatan, S., Shoer, S., Rothschild, D. et al. An expanded reference map of the human gut microbiome reveals hundreds of previously unknown species. Nat Commun 13, 3863 (2022).

[4] Tian, L., Wang, XW., Wu, AK. et al. Deciphering functional redundancy in the human microbiome. Nat Commun 11, 6217 (2020).

[5] Mann, E.R., Lam, Y.K. & Uhlig, H.H. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol 24, 577–595 (2024).

[6] Collins, S.L., Stine, J.G., Bisanz, J.E. et al. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 21, 236–247 (2023).

[7] Kearns R. Gut-Brain Axis and Neuroinflammation: The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders. Cell Mol Neurobiol. 2024 Oct 8;44(1):64.

[8] Quesada-Vázquez S, Eseberri I, Les F, Pérez-Matute P, Herranz-López M, Atgié C, Lopez-Yus M, Aranaz P, Oteo JA, Escoté X, Lorente-Cebrian S, Roche E, Courtois A, López V, Portillo MP, Milagro FI, Carpéné C. Polyphenols and metabolism: from present knowledge to future challenges. J Physiol Biochem. 2024 Oct 8.

[9] Patel D, Evanchuk J, Wang R, Dunbar CL, Munhoz J, Field CJ. Regulation of immune function in healthy adults: one-stop guide on the role of dietary fatty acids, gut microbiota-derived short chain fatty acids, and select micronutrients in combination with physical activity. Appl Physiol Nutr Metab. 2023 Aug 1;48(8):554-568.

[10] Cohen LJ, Kang HS, Chu J, Huang YH, Gordon EA, Reddy BV, Ternei MA, Craig JW, Brady SF. Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist. Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):E4825-34.

[11] Ryan E, Joyce SA, Clarke DJ. Membrane lipids from gut microbiome-associated bacteria as structural and signalling molecules. Microbiology (Reading). 2023 Mar;169(3):001315

[12] Meng EX, Verne GN, Zhou Q. Macrophages and Gut Barrier Function: Guardians of Gastrointestinal Health in Post-Inflammatory and Post-Infection Responses. Int J Mol Sci. 2024 Aug 30;25(17):9422

[13] Wiertsema SP, van Bergenhenegouwen J, Garssen J, Knippels LMJ. The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies. Nutrients. 2021 Mar 9;13(3):886.

[14] Sharon I, Quijada NM, Pasolli E, Fabbrini M, Vitali F, Agamennone V, Dötsch A, Selberherr E, Grau JH, Meixner M, Liere K, Ercolini D, de Filippo C, Caderni G, Brigidi P, Turroni S. The Core Human Microbiome: Does It Exist and How Can We Find It? A Critical Review of the Concept. Nutrients. 2022 Jul 13;14(14):2872.

[15] Calder PC, Bosco N, Bourdet-Sicard R, Capuron L, Delzenne N, Doré J, Franceschi C, Lehtinen MJ, Recker T, Salvioli S, Visioli F. Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev. 2017 Nov;40:95-119.

[16] Gut Microbiome Communication: The Gut-Organ Axis. American Society for Microbiology.

[17] Villanueva-Millan MJ, Leite G, Wang J, Morales W, Parodi G, Pimentel ML, Barlow GM, Mathur R, Rezaie A, Sanchez M, Ayyad S, Cohrs D, Chang C, Rashid M, Hosseini A, Fiorentino A, Weitsman S, Chuang B, Chang B, Pichetshote N, Pimentel M. Methanogens and Hydrogen Sulfide Producing Bacteria Guide Distinct Gut Microbe Profiles and Irritable Bowel Syndrome Subtypes. Am J Gastroenterol. 2022 Dec 1;117(12):2055-2066.

[18] Hu M, Zhang T, Miao M, Li K, Luan Q, Sun G. Expectations for employing Escherichia coli Nissle 1917 in food science and nutrition. Crit Rev Food Sci Nutr. 2024 Jan 8:1-9. doi: 10.1080/10408398.2023.2301416