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What are SCFA? 

SCFA stands for Short Chain Fatty Acids.

These are fatty acids that contain fewer than six carbon atoms in their chemical structure.

  • The short-chain fatty acids (SCFAs) butyrate, propionate, and acetate are microbial metabolites, and their availability in the gut and other organs is determined by environmental factors such as diet and the use of antibiotics, which shape the diversity and metabolism of the microbiota.
  • SCFAs regulate epithelial barrier function as well as mucosal and systemic immunity via evolutionary conserved processes that involve G protein-coupled receptor signaling or histone deacetylase activity.
  • Indicatively, the anti-inflammatory role of butyrate is mediated through direct effects on the differentiation of intestinal epithelial cells, phagocytes, B cells, and plasma cells, as well as regulatory and effector T cells.
  • Intestinally derived SCFAs also directly and indirectly affect immunity at extra-intestinal sites, such as the liver, the lungs, the reproductive tract, and the brain, and have been implicated in a range of disorders, including infections, intestinal inflammation, autoimmunity, food allergies, asthma, and responses to cancer therapies.
  • An ecological understanding of microbial communities and their interrelated metabolic states, as well as the engineering of butyrogenic bacteria, may support SCFA-focused interventions for the prevention and treatment of immune-mediated diseases

https://www.nature.com/articles/s41577-024-01014-8

The most prominent SCFAs found in the human gut are

  • Acetate (C2)
  • Propionate (C3)
  • Butyrate (C4)

Butyrate specifically refers to butyric acid, a type of SCFA with four carbon atoms.

Butyrate plays several crucial roles in the body, especially in the gastrointestinal tract.

  • Evidence is accumulating that short chain fatty acids (SCFA) play an important role in the maintenance of gut and metabolic health.
  • The SCFA acetate, propionate, and butyrate are produced from the microbial fermentation of indigestible carbohydrates and appear to be key mediators of the beneficial effects elicited by the gut microbiome.
  • Microbial SCFA production is essential for gut integrity by regulating the luminal pH, mucus production, providing fuel for epithelial cells, and effects on mucosal immune function.
  • SCFA also directly modulate host metabolic health through a range of tissue-specific mechanisms related to appetite regulation, energy expenditure, glucose homeostasis, and immunomodulation.
  • Increased microbial SCFA production can be considered a health benefit, but data are mainly based on animal studies, whereas well-controlled human studies are limited.
  • An expert group by ILSI Europe’s Prebiotics Task Force discussed the current scientific knowledge on SCFA to consider the relationship between SCFA and gut and metabolic health with a particular focus on human evidence.
  • Overall, the available mechanistic data and limited human data on the metabolic consequences of elevated gut-derived SCFA production strongly suggest that increasing SCFA production could be a valuable strategy in preventing gastro-intestinal dysfunction, obesity, and type 2 diabetes mellitus.
  • Nevertheless, there is an urgent need for well-controlled longer-term human SCFA intervention studies, including measurement of SCFA fluxes and kinetics, the heterogeneity in response based on metabolic phenotype, the type of dietary fiber and fermentation site in fiber intervention studies, and the control for factors that could shape the microbiome like diet, physical activity, and use of medication.

https://pubmed.ncbi.nlm.nih.gov/32865024/

It serves as a primary energy source for the cells lining the colon (colonocytes) and plays a role in maintaining gut barrier integrity, reducing inflammation, and regulating immune function.

The mechanism of action of butyrate involves its interaction with various receptors and pathways within the gastrointestinal tract.

One important mechanism is its role as a histone deacetylase (HDAC) inhibitor, which can regulate gene expression and influence cellular processes such as proliferation and differentiation.

Butyrate also acts on specific receptors such as GPR43 and GPR109A, which are involved in signaling pathways related to inflammation and metabolism.

SCFA: mechanisms and functional importance in the gut

  • In recent years, the importance of the gut microbiota in human health has been revealed, highlighting its role as a key component of human physiology.
  • Modern sequencing approaches have allowed for the characterization of the microbiome in healthy individuals and in disease, demonstrating a disturbance of the microbiota, or dysbiosis, associated with pathological conditions.
  • The microbiota establishes a symbiotic crosstalk with their host: commensal microbes benefit from the nutrient-rich environment provided by the gut, and the microbiota produces hundreds of proteins and metabolites that modulate key functions of the host, including nutrient processing, maintenance of energy homeostasis, and immune system development.
  • Many bacteria-derived metabolites originate from dietary sources, with an important role attributed to the metabolites derived from the bacterial fermentation of dietary fibers, namely short-chain fatty acids (SCFA), linking host nutrition to intestinal homeostasis maintenance.
  • SCFA are important fuels for intestinal epithelial cells (IEC) and regulate IEC functions through different mechanisms, modulating their proliferation, differentiation, and functions of subpopulations such as enteroendocrine cells, impacting gut motility, and strengthening gut barrier functions as well as host metabolism.
  • Recent findings show that SCFA, particularly butyrate, also have important intestinal and immuno-modulatory functions.
  • The review discusses the mechanisms and the impact of SCFA on gut functions and host immunity, consequently affecting human health.

https://pubmed.ncbi.nlm.nih.gov/32238208/

The purpose of butyrate in the body includes:

  1. Providing energy: Butyrate is a significant energy source for the cells lining the colon, contributing to their function and maintenance.
  2. Maintaining gut barrier integrity: Butyrate helps strengthen the intestinal barrier, which is crucial for preventing the entry of harmful substances into the bloodstream.
  3. Modulating inflammation: Butyrate exhibits anti-inflammatory properties, helping to reduce inflammation in the gut and throughout the body.
  4. Regulating immune function: Butyrate influences immune cell activity and helps maintain a balance between immune tolerance and response.

Ways to improve butyrate levels in the body include:

  1. Diet: Consuming foods rich in dietary fiber, particularly those that contain resistant starches and non-digestible carbohydrates, can promote the production of butyrate by gut bacteria.
  2. Probiotics and prebiotics: Certain probiotic bacteria and prebiotic fibers can stimulate the production of butyrate by promoting the growth of butyrate-producing bacteria in the gut.
  3. Butyrate supplementation: In some cases, supplementation with butyrate or butyrate-producing compounds may be beneficial, although more research is needed to determine its effectiveness and safety.

When butyrate levels are too low:

    • it can lead to various gastrointestinal issues and may contribute to conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and colorectal cancer.
    • Symptoms of low butyrate levels may include increased intestinal permeability, inflammation, and alterations in gut microbiota composition.

Low levels of butyrate and other SCFAs can lead to various symptoms and health issues due to their crucial roles in maintaining gut health and overall wellbeing.

Some additional symptoms of low SCFA production and butyrate levels may include:

  • Increased intestinal permeability:
    • SCFAs, particularly butyrate, play a vital role in maintaining the integrity of the intestinal barrier.
    • When SCFA levels are low, the gut barrier may become compromised, allowing harmful substances such as toxins, pathogens, and undigested food particles to leak into the bloodstream.
    • This condition, known as increased intestinal permeability or “leaky gut,” can trigger inflammation and immune responses, contributing to various gastrointestinal disorders and systemic health issues.
  • Digestive discomfort:
    • Low SCFA levels may lead to digestive symptoms such as bloating, gas, abdominal discomfort, and irregular bowel movements.
    • SCFAs help regulate gut motility and stimulate the secretion of mucus, which lubricates the intestinal lining and facilitates smooth passage of stool.
    • Insufficient SCFAs can disrupt these processes, leading to gastrointestinal discomfort and dysfunction.
  • Inflammation:
    • SCFAs, particularly butyrate, possess anti-inflammatory properties and help regulate immune responses in the gut.
    • Low levels of SCFAs can disrupt this balance, leading to chronic inflammation in the gastrointestinal tract.
    • Persistent inflammation may contribute to the development or exacerbation of inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, as well as other inflammatory conditions throughout the body.
  • Altered gut microbiota composition:
    • SCFAs play a crucial role in shaping the composition and diversity of the gut microbiota.
    • They provide energy and substrates for beneficial bacteria while inhibiting the growth of harmful pathogens.
    • Low SCFA levels can disrupt this balance, leading to dysbiosis (an imbalance in the gut microbiota) characterized by overgrowth of pathogenic bacteria and reduction of beneficial species.
    • Dysbiosis has been associated with various gastrointestinal disorders, metabolic disorders, and autoimmune conditions.
  • Impaired metabolism:
    • SCFAs, particularly propionate, play a role in regulating energy metabolism and glucose homeostasis.
    • Low SCFA levels may impair metabolic processes, contributing to insulin resistance, dyslipidemia, and obesity.
    • Additionally, SCFAs can influence appetite regulation and satiety, and their deficiency may disrupt these mechanisms, leading to altered food intake and weight management issues.

The underlying reasons for low SCFA production can vary and may include dietary factors, gut dysbiosis, intestinal inflammation, medication use (such as antibiotics), and certain medical conditions affecting the gastrointestinal tract.

Addressing the root causes of low SCFA levels often involves dietary modifications, probiotic supplementation, lifestyle changes, and targeted therapies aimed at restoring gut health and promoting SCFA production.

Several factors can contribute to low SCFA and butyrate production in the gut.

These factors may include:

  • Dietary factors:
    • Consumption of a diet low in fermentable fibers and resistant starches can reduce the substrate available for gut bacteria to produce SCFAs, including butyrate.
    • Diets high in processed foods, refined carbohydrates, and low in fruits, vegetables, and whole grains are often associated with lower SCFA production.
  • Antibiotic use:
    • Antibiotics can disrupt the balance of the gut microbiota, leading to reduced diversity and altered functionality of gut bacteria.
    • This disruption can impair SCFA production, including butyrate, and may take some time to recover after antibiotic treatment.
  • Gut dysbiosis:
    • Imbalance in the gut microbiota, known as dysbiosis, can affect SCFA production.
    • Dysbiosis may result from factors such as antibiotic use, dietary changes, stress, and certain medical conditions.
    • Dysbiosis often leads to a decrease in beneficial bacteria that produce SCFAs, contributing to low SCFA levels.
  • Intestinal inflammation:
    • Inflammatory conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and celiac disease can impair SCFA production.
    • Chronic inflammation in the gut may disrupt the growth and functionality of butyrate-producing bacteria, leading to decreased butyrate levels.
  • Reduced transit time:
    • Prolonged transit time in the gastrointestinal tract can reduce the interaction between gut bacteria and dietary fibers, limiting the production of SCFAs.
    • Factors such as constipation and slowed gastrointestinal motility may contribute to low SCFA production.
  • Age:
    • Aging is associated with changes in the gut microbiota composition and function, which can impact SCFA production.
    • Older adults may have lower levels of butyrate-producing bacteria and reduced SCFA production compared to younger individuals.
  • Stress:
    • Psychological stress can influence gut function and alter the composition of the gut microbiota.
    • Chronic stress may disrupt SCFA production by affecting gut motility, intestinal permeability, and microbial balance.
  • Alcohol consumption:
    • Excessive alcohol intake can negatively impact gut health and alter the gut microbiota composition.
    • Chronic alcohol consumption may reduce SCFA production and butyrate levels, contributing to gastrointestinal dysfunction.

Addressing these factors through dietary modifications, lifestyle changes, probiotic supplementation, and targeted therapies aimed at restoring gut health can help promote SCFA production, including butyrate, and support overall gastrointestinal function and wellbeing.

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