The impact of L-Arginine on the microbial community in the intestine

As a semi-essential amino acid, L-Arginine serves not only as a nutritional substrate for host intestinal epithelial cells but also as a critical nitrogen and carbon source for intestinal microbiota metabolism. Its impacts on the gut microbiota are reflected in three dimensions: microbiota structure remodeling, metabolic function regulation, and host-microbiota interaction optimization. These effects exhibit distinct concentration dependence and strain specificity.

I. Regulating the Structural Composition of Intestinal Microbiota: Promoting Beneficial Bacteria Proliferation and Inhibiting Pathogen Colonization

The balance of intestinal microbiota relies on competition and synergy among different strains. L-Arginine achieves positive remodeling of microbiota structure through differential nutrient supply and metabolic intervention.

1.  Providing Exclusive Nutritional Substrates for Beneficial Bacteria to Drive Their Selective Proliferation

Dominant beneficial bacteria in the gut (e.g., *Lactobacillus*, *Bifidobacterium*, *Faecalibacterium*) generally possess a complete L-Arginine metabolic pathway, and can directly utilize L-Arginine as a core nutrient for growth and reproduction.

In vitro culture experiments have confirmed that adding an appropriate concentration of L-Arginine to the medium increases the proliferation rate of *Lactobacillus* by 20%–40% and raises the viable count of *Bifidobacterium* by 1–2 orders of magnitude. Animal experiments also show that in the intestines of mice supplemented with L-Arginine, the relative abundance of *Faecalibacterium*—a core beneficial bacterium that secretes short-chain fatty acids—is significantly increased, and the enrichment of such strains directly enhances the repair capacity of the intestinal mucosal barrier.

The core mechanism is as follows: beneficial bacteria can convert L-Arginine into metabolic products such as ornithine and putrescine through key enzymes including arginine deiminase and ornithine carbamoyltransferase, to meet their own needs for nucleic acid synthesis and cell division. In contrast, most pathogenic bacteria (e.g., *Escherichia coli*, *Salmonella*) have incomplete arginine metabolic pathways, cannot efficiently utilize L-Arginine, and thus are at a disadvantage in nutrient competition.

2. Inhibiting the Virulence Expression and Mucosal Adhesion of Pathogenic Bacteria

L-Arginine and its metabolites can directly inhibit the pathogenicity of harmful bacteria and reduce their risk of invading the intestinal mucosa.

On the one hand, L-Arginine can downregulate the expression of virulence factors in pathogenic bacteria. For example, the activity of the type III secretion system of *Salmonella*—a key structure mediating bacterial invasion of host cells—is significantly reduced in the presence of L-Arginine, leading to a more than 50% decrease in its ability to adhere to intestinal epithelial cells. On the other hand, nitric oxide (NO) produced by L-Arginine metabolism has broad-spectrum antibacterial effects; it can damage the cell membrane structure of pathogenic bacteria through oxidative stress, inhibit the formation of their biofilms, and further weaken the colonization ability of pathogenic bacteria.

3. Enhancing the Diversity of Intestinal Microbiota

An appropriate concentration of L-Arginine can improve the nutritional microenvironment in the gut, provide living conditions for various commensal bacteria, and thus increase the α-diversity of the microbiota (species richness within the community).

Populations with long-term L-Arginine deficiency in their diet tend to have low intestinal microbiota diversity with a high proportion of harmful bacteria. After L-Arginine supplementation, the species distribution of the microbiota becomes more uniform, and the types of commensal bacteria increase significantly. Such a high-diversity microbiota structure helps enhance the gut's tolerance to environmental changes (e.g., antibiotics, dietary fluctuations) and reduces the risk of microbiota dysbiosis.

II. Regulating the Metabolic Functions of Intestinal Microbiota: Promoting the Synthesis of Beneficial Metabolites and Reducing the Accumulation of Harmful Metabolites

The metabolic activity of intestinal microbiota directly affects host health. L-Arginine promotes the shift of microbiota metabolism toward a direction beneficial to the host by interfering with microbial metabolic pathways.

1. Promoting the Synthesis of Short-Chain Fatty Acids (SCFAs)

Short-chain fatty acids (acetate, propionate, butyrate) are core products of dietary fiber metabolism by intestinal microbiota, and have multiple physiological functions such as repairing intestinal mucosa, regulating immunity, and inhibiting inflammation.

L-Arginine can increase the content of SCFAs in the gut through two pathways: first, it directly promotes the proliferation of SCFA-producing bacteria (e.g., *Faecalibacterium*, *Roseburia*), expanding the scale of functional microbiota; second, it enhances the metabolic activity of SCFA-producing bacteria—the ammonia produced by L-Arginine metabolism can serve as a nitrogen source to assist microbiota in completing dietary fiber fermentation, thereby improving SCFA synthesis efficiency. Animal experiments show that in mice supplemented with L-Arginine, the butyrate concentration in feces can be increased by 30%–60%. Butyrate is the preferred energy source for intestinal epithelial cells, and can significantly enhance the integrity of the intestinal mucosal barrier.

2. Promoting the Synthesis of Polyamines

Polyamines (putrescine, spermidine, spermine) are important products of L-Arginine metabolism by intestinal microbiota, and have functions such as inhibiting cell apoptosis, promoting intestinal epithelial cell proliferation, and regulating immune cell activity.

Beneficial bacteria in the gut such as *Lactobacillus* and *Bifidobacterium* can convert L-Arginine into putrescine through arginine decarboxylase, which is further synthesized into spermidine and spermine. L-Arginine supplementation can significantly increase the concentration of polyamines in the gut, especially spermidine, which has been proven to delay intestinal cell senescence and improve intestinal inflammatory status.

3. Reducing the Production of Harmful Metabolites

When intestinal microbiota metabolism is disrupted, harmful products such as indole, phenol, and trimethylamine are generated. These substances can damage the host's liver, kidneys, cardiovascular system and other organs after entering the bloodstream.

L-Arginine can reduce the production of indole, phenol and other substances by inhibiting the proliferation of harmful bacteria. Meanwhile, L-Arginine can regulate the trimethylamine synthesis pathway of the microbiota, reduce the concentration of trimethylamine in the gut, thereby decreasing the accumulation of its oxidation product (trimethylamine-N-oxide) in the liver, and lowering the risk of cardiovascular diseases such as atherosclerosis.

III. Mediating Host-Intestinal Microbiota Interactions: Bidirectional Regulation to Maintain Intestinal Homeostasis

The impact of L-Arginine on the gut microbiota is not unidirectional; instead, it maintains the physiological balance of the gut through bidirectional host-microbiota interactions.

1. Metabolites of L-Arginine by Microbiota Feedback to Regulate Host Intestinal Functions

Substances such as NO, polyamines, and SCFAs produced by microbiota metabolism of L-Arginine can directly act on the host gut: NO can dilate intestinal blood vessels and improve intestinal blood circulation; polyamines can promote the expression of tight junction proteins in intestinal epithelial cells and reduce intestinal permeability; SCFAs can activate immune cells in the intestinal mucosa and enhance local anti-infection ability. This pathway of "microbial metabolites → host function regulation" is an important medium for L-Arginine to exert its intestinal protective effects.

2. Host Intestinal Status Feedback to Regulate Microbiota Utilization of L-Arginine

The health status of the host gut affects the metabolic activity of the microbiota: when the intestinal mucosa is damaged, intestinal epithelial cells secrete more arginine transporters, increasing the concentration of L-Arginine in the gut, thereby promoting the proliferation of beneficial bacteria and the synthesis of reparative metabolites. When the gut is in an inflammatory state, host immune cells consume a large amount of L-Arginine, leading to a reduction in the L-Arginine available for microbiota utilization. At this time, the microbiota structure tends to shift toward a pro-inflammatory direction, and exogenous L-Arginine supplementation can reverse this trend.

IV. Key Factors Affecting the Efficacy: Concentration and Individual Differences

The effect of L-Arginine on the gut microbiota is not absolutely "beneficial"; its efficacy is significantly regulated by the supplementation dosage and the individual's baseline intestinal status.

1. Concentration Dependence

Appropriate concentration (physiological dose, 1–5 g per day): Can significantly promote the proliferation of beneficial bacteria, increase the synthesis of SCFAs and polyamines, and optimize the microbiota structure.

Excessive supplementation (more than 10 g per day): Will lead to a sharp increase in ammonia concentration in the gut. Ammonia is not only toxic to intestinal epithelial cells but also promotes the proliferation of potentially harmful bacteria such as Proteobacteria, disrupting microbiota balance. Meanwhile, excessive L-Arginine can cause intestinal microbiota metabolic disorders, resulting in gastrointestinal discomfort such as bloating and diarrhea.

2. Baseline Status of Individual Intestinal Microbiota

For healthy individuals with high intestinal microbiota diversity and a high proportion of beneficial bacteria, the regulatory effect of L-Arginine supplementation is relatively mild. For individuals with microbiota dysbiosis (e.g., post-antibiotic use, patients with inflammatory bowel disease), the intervention effect of L-Arginine is more significant, which can quickly promote the restoration of the microbiota to a healthy state. In addition, the microbiota composition varies among individuals, and their metabolic capacity for L-Arginine is different, which also leads to individual differences in the regulatory effect.

Through selectively nourishing beneficial bacteria, inhibiting pathogenic bacterial virulence, regulating microbial metabolic pathways, and mediating host-microbiota interactions, L-Arginine achieves positive regulation of the intestinal microbiota, ultimately helping maintain intestinal homeostasis. The core of its role lies in "appropriate dosage" and "precise matching"—supplementing L-Arginine within the physiological concentration range based on individual intestinal status can maximize its beneficial effects on the gut microbiota; excessive supplementation may trigger microbiota dysbiosis and instead damage intestinal health.