Insights into Short Chain Fatty Acids and Gut Microbiota

The interplay of short-chain fatty acids and the microbiota in the gut is of great importance in the field of personalized nutrition and gut health.

• Short chain fatty acids (SCFAs) are important for our digestive system.
• SCFAs come from dietary fiber.
• They have various roles in maintaining health.
• They influence microbiome diversity.
• They affect how our body responds to food.

Main Findings

• Short-chain fatty acids (SCFAs) are crucial for gut health, produced by the microbiota from dietary fiber.
• SCFA production and metabolism vary significantly between individuals due to genetic and environmental factors.
• The relationship between dietary fiber, SCFAs, and gut microbiota influences various health outcomes.
• Different gut microbiota compositions, or enterotypes, affect the body’s response to dietary fiber and SCFA production.
• Genetic variations (genotypes) influence how the gut microbiota interacts with dietary components and metabolizes SCFAs.
• SCFAs play a role in immune regulation, with implications for chronic diseases like obesity, diabetes, and heart disease.

The Basics of Microbiota and SCFAs

The Impact of Short-Chain Fatty Acids on Human Health

In the intricate world of our bodies, there’s a hidden community of microbes known as the microbiota, including bacteria, fungi, and more ¹.

This microbiota, residing mainly in our colon, collaborates with us in ways we’re just beginning to understand, akin to an ancient partnership.

This fascinating synergy is the foundation of the holobiont theory ².

Recent research has unveiled the microbiota’s pivotal role in regulating metabolic, immune, and endocrine functions, while also shaping our response to diseases ³.

Imbalances in the gut microbiota have been linked to various chronic health issues, including obesity ⁴, cardiovascular disease ⁵, diabetes ^{6 7}, autoimmune disorders ^{8 9}, and even neurodegenerative diseases ^{10 11} like Parkinson’s ¹² and Alzheimer’s ¹³.

Dietary habits have emerged as a powerful influencer of our gut health and overall well-being ^{14 15 16 17 18 19 20 21}.

The decline in dietary fiber (DF) consumption, for example, has raised concerns.

DF, found in foods like fruits, vegetables, and grains, serves as a bridge between our gut microbiota and our health ^{22 23 24 25 26 27 28}.

It’s a unique substance that our digestive enzymes can’t fully break down but can be utilized by our gut microbes.

They turn DF into short-chain fatty acids (SCFA), such as butyrate, acetate, and propionate ²⁹.

SCFA, particularly butyrate, plays a crucial role in nourishing the cells lining our colon and supporting our immune system ^{30 31 32 33 34 35}.

Additionally, SCFA act as powerful immune regulators, affecting different tissues and systems throughout our body ^{36 37 38}.

The importance of SCFA in maintaining our health cannot be overstated ^{39 40 41 42 43 44}.

But it’s not just our diet that influences our gut microbiota.

Various factors, including genetics, age, medication, and exposure to pathogens, also play significant roles ^{45 46 47 48 49 50}.

Genetic variations, like single nucleotide polymorphisms (SNPs), can impact how our body responds to DF intake and SCFA production ^{51 52 53 54 55}.

Furthermore, genes associated with SCFA receptors and transporters, as well as genes involved in mucus production and antioxidant defense mechanisms, can have far-reaching effects on our health outcomes ^{56 57}.

Short Chain Fatty Acids and Gut Microbiota

Understanding Dietary Fiber (DF)

DF refers to the indigestible carbohydrates found in foods like fruits, vegetables, grains, and legumes ^{58 59}.

It’s the stuff that passes through our digestive system relatively unchanged.

The recommended daily intake for DF varies but generally falls between 25-35 grams for adults, depending on the country and dietary guidelines ⁶⁰.

Some health-conscious voices, like the Physicians Committee for Responsible Medicine (PCRM), even advocate for a higher intake of around 40 grams per day ⁶¹.

DF plays a critical role in our digestive health.

It’s associated with improved bowel function, including regularity and reduced constipation ⁶².

More importantly, it’s linked to a lower risk of non-communicable diseases (NCDs), such as cardiovascular disease, type 2 diabetes, and colorectal cancer ⁶³.

DF and Precision Nutrition

Interestingly, where you get your DF matters.

The source of DF in your diet influences the composition of your gut microbiota.

For instance, a low-fat diet and a low-carbohydrate diet can lead to different types of DF intake ⁶⁴.

The former may emphasize whole grains and fruits, while the latter might rely more on vegetables and plant protein sources.

These dietary adaptations can impact your gut microbiota and potentially shape your health outcomes.

Defining Dietary Fiber

DF is a diverse group of compounds, but there’s consensus on its definition ^{65 66}.

It includes carbohydrate polymers with three or more monomeric units that human enzymes can’t digest.

This definition encompasses various types of DF, from insoluble fibers that add bulk to the stool to soluble fibers that serve as fermentation substrates for our gut microbes.

Beyond Carbohydrates

Interestingly, DF isn’t limited to carbohydrates alone.

It can also include non-carbohydrate compounds like lignin and polyphenols.

These compounds, along with resistant proteins, can be substrates for beneficial gut bacteria, leading to the production of metabolites like SCFA.

The Complex World of Fiber Fermentation

Fiber fermentation is a complex process influenced by the chemical and physical structure of DF, as well as the makeup of our gut microbiota.

Some DF types, like oligosaccharides, resistant starches, and pectins, are more likely to contribute to SCFA production.

Others, like lignin and cellulose, tend to pass through our system largely unchanged.

Recent research has spotlighted the significance of Short Chain Fatty Acids (SCFA) in the context of dietary fiber (DF), gut microbiota (GM), and probiotics.

SCFA serve as essential messengers, bridging the communication between the gut microbiota and the host.

This article dives into the multifaceted implications of SCFA metabolism for human health, while staying true to the original citation style ⁶⁷.

SCFA: The Communicators Between GM and Host

SCFA, characterized as volatile fatty acids with fewer than six carbon atoms, can take straight or branched-chain forms.

The primary SCFA—acetate (C2), propionate (C3), and butyrate (C4)—contribute to the majority (90–95%) of total SCFA produced by the gut microbiota, primarily through carbohydrate fermentation ^{68 69}.

Recently, it has been unveiled that caproate and valerate, once considered dietary components, also stem from the gut microbiota and are notably increased in individuals with severe obesity ⁷⁰.

Branched-chain SCFA (BCFA), including isobutyrate, isovalerate, and 2-methylbutanoate, make up a smaller portion (up to 5%) of total SCFA production, originating from the metabolism of specific amino acids ^{71 72}.

Interestingly, BCFA levels in fecal samples exhibit an inverse connection with fiber intake, particularly insoluble fiber.

Elevated BCFA levels have been associated with depression and other psychiatric conditions, potentially mediated through vagal afferent nerve signaling.

Additionally, BCFA, especially isobutyrate, have been linked to unfavorable serum lipid profiles in subjects with hypercholesterolemia ⁷³.

Such higher BCFA levels may correspond to increased protein consumption and reduced dietary fiber intake, factors known to contribute to negative health outcomes and age-related complications ⁷⁴.

DF Fermentation Products: Post-biotics

Recent nomenclature labels the byproducts of DF fermentation as “post-biotics.”

In adults, the primary products of DF fermentation include SCFA and certain gases like CO2, CH4, and H2, which can be absorbed by the host or excreted ⁷⁵.

SCFA production in the colon coincides with the consumption of ammonia, hydrogen sulfide (H2S), and BCFA by gut bacteria in the synthesis of microbial cell components.

Consequently, the reduction of these metabolites may partly account for the health benefits attributed to SCFA ⁷⁶.

Notably, ammonia has been associated with negative health outcomes, including neurotoxicity and hepatotoxicity, as well as increased intestinal permeability, loss of tight junction proteins, and elevated pro-inflammatory cytokines, as observed in animal studies ⁷⁷.

H2S, hydrogen disulfide, when abnormally produced, has been linked to neurological, cardiovascular, and metabolic diseases ⁷⁸.

How Individual Differences in Gut Microbiota

Dietary fiber (DF) impacts people differently, but understanding this variation is challenging.

Various factors, including genetics and food matrix properties, contribute to the diverse responses observed in nutritional studies ⁷⁹⁸⁰.

Bioavailability of DF-derived metabolites, like vitamins, is influenced by the SLAMENGHI factors (molecular species, linkage, amount, matrix, absorption effectors, nutrition status, genetics, and host-related factors) ⁸¹.

Inconsistencies also arise from differing DF definitions across studies.

To address this complexity, a systems analysis approach is recommended, similar to clinical oncology ⁸².

It’s crucial to recognize the baseline variation in the effects of DF consumption on health outcomes, related to individual gut microbiota (enterotype) ⁸³⁸⁴.

The impact of DF on metabolism and health outcomes varies based on one’s unique gut microbiota composition ⁸⁵.

While DF is generally beneficial, it may lead to discomfort in those with low prior DF intake.

The following sections delve into three layers of inter-individual variability (enterotypes, genotypes, and phenotypes) among healthy adults ⁸⁶⁸⁷.

Gut Microbiota and Factors Influencing It

Gut microbiota composition is shaped by numerous factors.

Host-related aspects like age, genetics, immune status, and medication use, along with environmental elements such as geography, diet, and pollutants, influence the gut microbiota ⁸⁸⁸⁹⁹⁰.

Microbial factors, including substrate competition, metabolic collaboration, and species interactions, also play a pivotal role, as do the microbial environment’s local pH, redox potential, and quorum sensing.

The gut microbiota mainly comprises Firmicutes, Bacteroidetes, Proteobacteria, Verrucobacteria, Actinobacteria, and Fusobacteria, with Bacteroidetes and Firmicutes making up 70% of the total composition in adulthood ⁹¹.

Early in life, Proteobacteria and Actinobacteria dominate, influenced by delivery and feeding methods in infancy.

Approximately 6.6% of microbial taxa are heritable, while around 48.6% are influenced by cohabitation ⁹².

Specific bacteria are involved in the production of short-chain fatty acids (SCFA) through dietary fiber fermentation.

SCFA impacts gut microbiota and health outcomes ⁹³.

Glycans and GOS have been shown to increase Bifidobacterium and Lactobacillus abundance, as well as faecal butyrate concentration ⁹⁴.

Bacteroidetes mainly produce acetate and propionate, while Firmicutes tend to generate butyrate, which may influence the host’s inflammatory state.

Enterotypes, which represent compositional gradients rather than discrete clusters, have been proposed, highlighting distinct genus-level compositions ⁹⁵.

Prevotella, a key player in one enterotype, is associated with various health outcomes, including inflammation and colitis ⁹⁶.

However, its role in diseases like autism, rheumatoid arthritis, and HIV remains inconclusive ⁹⁷.

Akkermansia muciniphila, a mucin-degrading bacterium, contributes to mucus layer regulation ⁹⁸.

Akkermansia’s abundance decreases with age and has been associated with various health conditions, such as type 1 diabetes ⁹⁹.

Dysbiosis, an imbalanced gut microbiota, can develop from an early age and may lead to inflammatory or hypotrophic dysbiosis ¹⁰⁰.

Hypotrophic dysbiosis can predispose individuals to inflammatory states and diseases like Giardia lamblia infection-induced diarrhea ¹⁰¹.

Genes and Gut Microbiota

The relationship between the human genome and the microbiome is intricate and ever-changing ¹⁰².

While the composition of the gut microbiome can shift during a lifetime, influenced by factors like diet, lifestyle choices, and location ¹⁰³¹⁰⁴, the human genome remains relatively stable, with potential epigenetic changes due to environmental exposure ^105106107.

In the realm of nutrigenetics, the focus is on how an individual’s genetic makeup, including copy number variations (CNVs) and single nucleotide polymorphisms (SNPs), can impact the fate of different foods in terms of absorption, distribution, metabolism, or excretion (ADME) patterns (Table 3).

Recent discoveries have identified CNVs and SNPs in various regions of the genome as drivers of differences in individuals’ physical traits and health outcomes.

Polygenic risk scores, which combine multiple genetic factors, have been linked to a wide range of human conditions ¹⁰⁸¹⁰⁹.

When we consider homeostasis at the holobiont level, where the host genome and microbiome interact ¹¹⁰¹¹¹, polygenic risk becomes particularly relevant ¹¹².

Twin studies have suggested that specific SNPs can influence microbiota colonization from the earliest days of life, acting as a foundation for achieving optimal homeostasis in an ever-changing environment ¹¹³¹¹⁴.

Certain SNPs, such as those related to G-protein coupled cellular receptors (GPCR41, GPCR43, GPCR109A), transporter genes like MCT and SMCT, effector genes like MUC2 (involved in mucus layer production), and regulatory genes like NRF2 (which regulates antioxidant defense proteins), may individually or collectively predispose individuals to various health outcomes.

Exploring elderly populations, researchers have identified genes associated with inflammatory responses (IL-6, IL-10, and the IL-1 cluster), genes involved in the insulin/IGF1 pathway, and genes related to oxidative stress management (PON1) as correlated with extreme old age ¹¹⁵.

While bacterial colonization in early life is crucial for various aspects of immune development, the host’s genetic background can modulate the impact of bacteria.

For example, certain genetic modifications, like programmed cell death (PD1) knockout in mice, can lead to changes in microbiota profiles, affecting the abundance of specific bacterial genera ¹¹⁶.

The secretion of immunoglobulin A (IgA) is crucial for the colonization of beneficial bacteria and defense against pathogens.

This highlights the intricate interplay between the host genome and the microbiome, where commensal bacteria require IgA coating for colonization, while the same coating triggers immune responses against pathogenic bacteria ¹¹⁷¹¹⁸.

Microbial acetate in the gut even regulates IgA reactivity to commensal bacteria, influencing microbiota species and colonization in the colon ¹¹⁹.

Antimicrobial peptides (AMPs) produced by intraepithelial cells (IEC) in the gut are another piece of the puzzle.

These peptides, like α-defensins and β-defensin 1, are rapidly activated by IL-22 and IL-17 to inactivate invading microorganisms.

AMPs not only help maintain the separation between the host and microorganisms but also affect microbial composition ¹²⁰.

Studies with mice deficient in genes like MYD88, NOD2, or those transgenic for α-defensin 5 have shown altered microbiota compositions ^121122123124.

When examining Alzheimer’s disease, the APOε4 allele has been linked to higher levels of pro-inflammatory bacteria, while the protective APOε2 allele correlates with SCFA-producing bacteria ¹²⁵.

SCFAs have even been found to inhibit the aggregation of amyloid β (Aβ), a hallmark of Alzheimer’s disease, in vitro.

Mutations in MEFV, associated with familial Mediterranean fever, have also demonstrated the host’s ability to modulate microbial composition.

This suggests that the host genome and microbiome structure are functionally linked, impacting responses to dietary fiber both directly (via SCFA metabolism) and indirectly (via microbiome modulation) ¹²⁶.

Genetic Symphony of Short Chain Fatty Acids and Gut Microbiota

In the intricate world of nutrigenomics, where nutrients orchestrate gene expression, Short Chain Fatty Acids (SCFAs) take center stage.

SCFAs can directly influence genetic expression by modulating histone deacetylases ^{127 128 129 130}.

Over time, these epigenetic changes can shape an individual’s observable characteristics, known as their phenotype.

Phenotypes are often measured through various parameters, like age, body mass index (BMI), or blood counts, and their interpretation can vary depending on the type of study, be it epidemiological, clinical, or mechanistic ^131132133.

This variability is influenced by genetic predisposition and the individual’s ability to maintain balance in the face of environmental stressors ^134135136.

It’s essential to understand that these associations at the phenotype level, such as the link between BMI and metabolic issues or glycated hemoglobin levels and diabetes progression, are influenced by a complex interplay of genetics, microbiome, and diet.

Some genotypes may lead to increased inflammatory function, which is beneficial in defending against infections.

However, when a low-grade chronic inflammation becomes undesirable, as in Non-Communicable Diseases (NCDs) and aging, these genotypes can have detrimental effects ^137138139.

Even genes unrelated to immune function can play a crucial role in achieving holobiont homeostasis, with implications for NCDs and aging progression, as seen with genes like FUT-2 and AMY1 ¹⁴⁰¹⁴¹.

Centenarians, individuals who live beyond 100 years without significant chronic diseases, offer intriguing insights.

Studies suggest that centenarians have distinctive gut microbiome signatures compared to both young adults (20-40 years old) and the general elderly population (60-80 years old) ^142143144.

These variations could be attributed to specific gene polymorphisms.

For instance, the FUT2 gene, responsible for regulating glycans in mucosal tissues, has links to conditions like Crohn’s disease ¹⁴⁵.

Enterotyping has shown that the secretor phenotype, associated with Firmicutes, Akkermansia, and Ruminococcus spp., may be influenced by certain genes ¹⁴⁶.

This underscores the idea that genes not directly linked to immune function can significantly impact health outcomes, including NCDs and survival into old age ¹⁴⁷.

In mice, genotype plays a recognized role in microbial colonization ¹⁴⁸.

The timing of meals, known as chrononutrition, can also lead to significant changes in gut microbiome composition, immune responses, and metabolic conditions, including Type 2 Diabetes (T2D), Cardiovascular Disease (CVD), and psychological well-being ^149150151152.

Recent research highlights the interplay between diet, genetics, and gut microbiota in conditions like neurodegeneration, cancer, menopause symptoms, and Non-Alcoholic Fatty Liver Disease (NAFLD), all characterized by chronic inflammation ^{153154155156157}.

Studies have shown that microbiota heritability exists in humans, particularly in twins ¹⁵⁸¹⁵⁹.

This suggests that the host can benefit from the intricate interactions between their genetic makeup and microbiome composition, influenced by factors like dietary patterns and environmental exposures ¹⁶⁰.

However, there’s a degree of variability in SCFA production among individuals.

For example, while acetate is typically the most abundant SCFA in feces, some individuals may exhibit substantial differences in propionate and butyrate levels.

This variability is an intriguing aspect of the SCFA story ¹⁶¹.

How Our Bodies and Gut Bacteria Work Together

Host-Microbe Interface: Where It All Begins

Imagine your gut as a dynamic landscape.

The stomach’s quick passage time and low acidity initially keep bacterial numbers low.

But as you progress into the small intestine, the scene changes ^{162 163}.

Bacterial populations increase substantially, setting the stage for the grand performance in the colon, where anaerobic bacteria thrive ^{164 165}.

One significant factor shaping this drama is pH levels ¹⁶⁶.

The rise in pH from gastric acid neutralization and pancreatic secretions in the small intestine opens doors for specific bacteria.

The type of food you eat also matters, as it influences the fermentation products produced in your gut.

Diverse Diet, Diverse Microbiota

The availability of dietary fiber (DF) depends on what you eat.

DF serves as a substrate ^{167 168}, and its composition influences the fermentation products generated.

In the colon, DF promotes the growth of diverse microbial species that engage in “substrate cross-feeding” ^{169 170} and “metabolic cross-feeding” ¹⁷¹.

These interactions enhance microbial diversity and create a harmonious environment in your colon.

One remarkable collaboration is between Faecalibacterium prausnitzii (F. prausnitzii) and Bacteroides thetaiotaomicron (B. thetaiotaomicron).

F. prausnitzii derives butyrate from acetate produced by B. thetaiotaomicron ¹⁷².

Butyrate, in turn, boosts intestinal barrier function and mucin production, fortifying your gut’s defenses ^{173 174}.

SCFA: Heroes of the Proximal Colon

Short Chain Fatty Acids (SCFA) are the stars of the show in the proximal colon ¹⁷⁵.

Acetate, propionate, and butyrate are the primary SCFA, absorbed by colonocytes ¹⁷⁶ and entering the bloodstream.

Their absorption and impact on crypt proliferation depend on luminal pH levels.

Butyrate, in particular, is a key player.

It serves as a major energy source for colonocytes, influencing their proliferation, differentiation, and mucus production ¹⁷⁷.

Butyrate’s protective role against colorectal carcinoma is well-documented, making it a vital component in gut health ^{178 179}.

Digestive Enzymes

Our genes also influence our gut microbiota.

For instance, the AMY1 gene, which encodes salivary α-amylase, affects the oral and gut microbiota composition ¹⁸⁰.

Individuals with low AMY1 copy numbers digest carbohydrates differently from those with high copy numbers, impacting their microbiomes and SCFA production.

Variants in the LCT gene ¹⁸¹, responsible for lactase production, are correlated with Bifidobacterium abundance in the gut.

Lactase persistence can affect dairy consumption and medication responses, making genetics an essential factor in our gut’s story.

Genetic Diversity and Barriers

The gut microbiota has a role in regulating our physical barriers, such as mucin production ¹⁸².

Mucin is a vital component of the mucus layer separating enterocytes and microbiota.

Polymorphisms in mucin genes are associated with gastric cancer risk, emphasizing the interplay between genetics and gut health ¹⁸³.

Maintaining Barrier Integrity

Short Chain Fatty Acids (SCFA) play a crucial role in maintaining the integrity of our gut barriers.

They upregulate tight junction proteins ¹⁸⁴, ensuring the gut remains impermeable.

This is especially important in preventing pathogen invasion, inflammation, and diseases like obesity and insulin resistance ¹⁸⁵.

Immune Responses and Gut Health

Butyrate influences immune cell populations in the gut.

It promotes the differentiation of intestinal macrophages into tolerant macrophages, reducing pro-inflammatory responses ¹⁸⁶.

Natural killer (NK) cell differentiation ¹⁸⁷, essential for an impermeable intestinal barrier ¹⁸⁸, is also influenced by SCFA ^{189 190 191}].

Antibiotic exposure in early life ¹⁹² can predict the risk of conditions like asthma.

Conversely, early exposure to diverse microorganisms may reduce the risk of asthma, allergies, and other disorders ^{193 194}.

Prebiotics, such as GOS, increase beneficial bacteria, boost immune responses, and reduce inflammation ¹⁹⁵.

Transporter Genetics: The SCFA Highway

Monocarboxylate transporters (MCTs) ^{196 197} are the highway for SCFA uptake by colonocytes.

Fourteen transporters, including MCT1 and MCT4, are responsible for SCFA transportation.

These transporters are influenced by genetic variations and play crucial roles in energy supply to different tissues.

MCTs are pleiotropic, meaning they have various downstream effects in different tissues ^{198 199}.

For example, MCT2 is upregulated in neurons following food deprivation and ischemia recovery ²⁰⁰, while MCT4 is reduced in response to fasting ²⁰¹²⁰².

These transporters also impact drug delivery, making them essential in therapeutic strategies.

SCFA Metabolism

SCFA are known to contribute significantly to human energy needs, comprising approximately 10% of our energy requirements²⁰³.

Among the various SCFA, butyrate stands out as the primary energy source for colonocytes, while propionate can be partially converted to glucose in the liver²⁰⁴²⁰⁵.

The GM plays a pivotal role in producing SCFA, generating an estimated 500–600 mmol/d of SCFA daily.

Of this, approximately 60% is acetate, 20% is propionate, and the remaining 20% is butyrate ²⁰⁶.

These numbers translate to around 37 mmol/kg body weight of acetate, 13 mmol/kg body weight of propionate, and 12.4 mmol/kg body weight of butyrate²⁰⁷.

In the human descending colon, SCFA concentration can reach 69–91 mmol/kg luminal content, with acetate accounting for 60–75% of total fecal SCFA.

One notable player in this complex interplay is Methanobrevibacter smithii, found in 70% of humans, and a significant methane producer in the GM.

Studies suggest that methane production is linked to higher BMI scores in obesity, as well as conditions like constipation and antidepressant use²⁰⁸.

Additionally, in the presence of methane, propionate can be elongated to produce valerate²⁰⁹.

Although less is known about valerate and caproate, they exist in small amounts in the gut and may impact health over time by altering the balance of acetate, butyrate, and propionate reaching human cells ²¹⁰.

Colon: A Hub of SCFA Activity

The colon plays a pivotal role in SCFA utilization, with more than 95% of the SCFA produced by the GM being absorbed here.

Butyrate, in particular, takes the spotlight as it accounts for over 70% of colonocyte energy production^211212213.

Butyrate and propionate have been observed to increase cellular proliferation rates, while acetate does not share this effect^214215216217.

Butyrate’s significance extends to enterocyte differentiation, primarily driven by factors like FoxO3 and hypoxia-inducible factor α (HIF-α).

FoxO3 is associated with cellular homeostasis and longevity, suggesting a role for SCFA in epigenetic modulation and potential links to cancer development and tissue healing ²¹⁸.

Butyrate also plays a role in inhibiting DNA-damaged cell proliferation via p53.

In intestinal crypts, a diffusion gradient allows butyrate to be metabolized by mature enterocytes, which, in turn, enhances intestinal permeability and immune function.

This process results in a reduction in intestinal permeability, an increase in TGB-β production promoting Treg differentiation, and a shift towards a more tolerogenic immune profile with increased levels of circulating IL-10²¹⁹.

Furthermore, butyrate may directly and indirectly improve intestinal permeability and immune function, potentially suppressing pro-inflammatory factors such as TNF-α and IL-6 ²²⁰.

Interestingly, studies have shown relatively indifferent usage of SCFA by colonic tissue in arterio-venous studies ²²¹.

Acetate, on the other hand, appears to be a potent stimulant of intestinal blood flow and plays a role in regulating the brain-pancreas axis regarding insulin release regulation ²²².

Propionate, another SCFA, is gaining attention for its role in regulating colonic motility, and high doses of SCFA have been found to inhibit smooth muscle cell proliferation ²²³²²⁴.

Genetic variations in MCT1 and MCT2, which are responsible for SCFA absorption in the gut, may affect colorectal cancer outcomes ²²⁵.

Additionally, ketone bodies produced from SCFA β-oxidation serve as precursors for lipid synthesis in human cells, with glucose and glutamine oxidation being more relevant for energy production in the small intestine and proximal colon^226227228.

Liver and Adipose Tissue: SCFA in Action

Studies in humans have revealed that butyrate ratios decrease from 20% in the gut lumen to 8% in portal blood²²⁹.

SCFA are taken up by the portal circulation and used as energy substrates by hepatocytes, with propionate being a primary player in the liver²³⁰.

Specific transporters, MCT1 and MCT2, are predominantly expressed in cells using lactic acid for lipogenesis and gluconeogenesis, such as the liver, kidney tubules, and adipose tissue²³¹.

Acetate is the only SCFA found in substantial amounts in the systemic circulation, reaching approximately 200 μM in venous serum²³².

Arterial concentrations of acetate, propionate, and butyrate have been reported as 173, 3.6, and 7.5 mmol/l, respectively, for acetate, propionate, and butyrate, further underlining the hepatic clearance of SCFA²³³.

Research indicates that propionate plays a role in gluconeogenesis in the liver, while acetate and butyrate are utilized for fatty acid and cholesterol synthesis²³⁴.

The impact of SCFA on the tricarboxylic acid (TCA) cycle and energy production varies depending on cell membrane receptors.

MCTs regulate the influx and efflux of SCFA, lactate, pyruvate, and ketone bodies, influencing nutrient access to different cell tissues²³⁵.

Studies have shown that MCT4, more abundant than MCT1 in glycolytic cells, regulates the transport of lactate from glycolyzing cells to respiratory cells, impacting cellular functions²³⁶.

Systemic Metabolism: A Complex Web of Effects

The effects of SCFA on the body are intricate, diverse, and sometimes indirect, with potential synergistic interactions.

Acetate and pyruvate, close relatives of SCFA, continually feed the TCA cycle, highlighting the ability to convert and reconvert between SCFA and the importance of acetate in energy production²³⁷.

Propionate controls the TCA through its conversion to succinate, while butyrate, after β-oxidation, enters the TCA as acetate.

The impact of SCFA on the TCA and energy production is further regulated by cell membrane receptors, with MCTs playing a central role in the transport of SCFA, lactate, pyruvate, and ketone bodies²³⁸.

Recent research has shown that plasma levels of acetate, rather than fecal levels of SCFA, are linked to inflammatory markers and lipid subclasses in the blood, highlighting the importance of absorption²³⁹.

Another study suggests that circulating SCFA, particularly propionate, is associated with fasting GLP-1 levels and lipid metabolites, which could have implications for insulin sensitivity and metabolic health ²⁴⁰.

The intricate interplay of SCFA in the body extends to the brain, where acetate, propionate, and butyrate can cross the blood-brain barrier, potentially influencing neurological functions ²⁴¹.

Key Takeaways and Future Horizons in Gut Health Research

Current dietary fiber (DF) intake in Europe falls below recommended levels.

Increasing DF intake could reduce Non-Communicable Diseases (NCDs) by 15-30%.

SCFA, primarily produced from dietary fiber, has significant systemic effects.

They act as a crucial link between diet, gut microbiome, and health.

However, the causality of microbiota-derived metabolites in human disease remains unclear.

Research should prioritize human studies over in vitro findings.

The enterotype, which clusters gut bacterial communities, can have substantial health impacts.

SCFA effects are dose-dependent and vary among different types.

Colonocytes utilize SCFA for energy, influencing various metabolic pathways.

Future Perspectives:

Studies show that the gut microbiota can shift with dietary changes but remains resilient.

Precision dietary interventions, fecal microbiota transplantation, and synbiotics hold promise for addressing various diseases.

Environmental changes, like increased consumption of ultra-processed foods and decreased DF intake, may contribute to the rise in NCDs.

Complex interactions between the host, GM, and dietary patterns require further research, emphasizing the need for individualized approaches.

Investigating associations between dietary patterns, GM, and host genetics holds potential, but specific mechanisms behind phenotypic differences remain unknown.

Future research may pave the way for personalized therapies based on SCFA measurement, without disrupting overall wellbeing.

Review date not set.