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Microbes & Immunity Sepsis and gut microbiome

cells and maintains the integrity of the gut barrier. restore gut microbiota balance and improve outcomes in
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Wu et al. demonstrated that glutamine is particularly septic patients could provide valuable insights into new
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important in preserving the intestinal mucus barrier in a therapeutic approaches.
mouse model of burn sepsis. Specifically, the researchers (C) Citrulline
found that glutamine promotes the O-GlcNAcylation of Citrulline, a precursor of arginine, has the potential
the glucose-6-phosphate dehydrogenase (G6PD). This to enhance vasodilation and increase blood flow by
modification enhances the intestinal cells’ antioxidant stimulating nitric oxide production. Numerous clinical
defenses, helping protect them from oxidative stress. At trials have investigated the impact of citrulline on
the same time, glutamine inhibits the S-glutathionylation improving the exercise performance of athletes. 93,94 It has
of the protein AGR2, essential for mucus production. also been reported to support gut health by improving
By supporting antioxidant mechanisms and mucus intestinal barrier integrity and modulating intestinal
production, these glutamine-mediated effects help preserve inflammation and can be synthesized by beneficial bacteria
the integrity of the gut barrier. This, in turn, reduces the such as Lactobacillus. A study conducted by Wang et al.
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risk of bacterial translocation and the development of revealed that Lachnospiraceae can produce L-citrulline,
systemic complications during sepsis. which, when converted into L-arginine, influences bone
(B) Arginine mechanical adaptations. During sepsis, especially in ICU
Arginine is a semi-essential amino acid in various patients, citrulline levels often decrease due to gut barrier
physiological processes, including protein synthesis, dysfunction. The damage induced by sepsis compromises
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nitric oxide production, and immune function. In the integrity of the gut lining, impairing the ability of
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the gut, arginine is produced by the enterocytes and enterocytes to generate citrulline. This reduction is closely
gut microbiota. During sepsis, the body’s demand for linked to increased gut permeability, bacterial translocation,
arginine increases significantly due to its involvement in and systemic inflammation, all of which exacerbate the
immune response modulation, vascular regulation, and severity of sepsis. Therefore, citrulline levels can serve as a
tissue repair. However, sepsis-induced dysbiosis can alter biomarker for identifying gut barrier failure and predicting
the gut microbiota responsible for arginine production, the overall prognosis of septic patients. Citrulline
leading to complications in arginine metabolism and supplementation in sepsis presents both benefits and risks,
availability. Certain gut bacteria, including Lactobacillus acting as a double-edged sword. Research by Asgeirsson
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and Bifidobacterium species, decrease in abundance after et al. has identified citrulline as an anti-inflammatory
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the onset of sepsis, and these bacteria are involved in agent. Moreover, Reizine et al. have demonstrated that
the synthesis of arginine. These probiotic bacteria can enteral citrulline administration can help alleviate sepsis-
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convert the amino acid ornithine into citrulline, which induced T-cell mitochondrial dysfunction. By restoring
is further converted into arginine through the urea arginine levels and promoting nitric oxide production,
cycle. Clinical trials have explored the potential benefits citrulline boosts T-cell functionality, enhancing immune
of arginine infusion in severe sepsis, focusing on its responses and reducing the severity of sepsis. These
effects on microcirculation and metabolic function. findings imply that citrulline may serve as a valuable
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One randomized controlled trial demonstrated that therapeutic intervention in safeguarding immune function
arginine supplementation could improve microvascular during sepsis. On the contrary, a separate study revealed
perfusion and support metabolic recovery in septic that citrulline supplementation aggravated sepsis severity
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patients. Furthermore, intravenous administration in infected preterm piglets. The early administration
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of arginine has been shown to benefit CD4+ T-cell of citrulline-induced immunosuppression, possibly
homeostasis and attenuate liver inflammation in a mouse attributed to excessive nitric oxide production, exacerbates
model of polymicrobial sepsis, thereby boosting T-cell outcomes. This underscores the dangers of immune
proliferation and function. Arginine’s role in enhancing overmodulation and emphasizes the importance of timing
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nitric oxide production helps to improve blood flow and and context in citrulline supplementation. Nevertheless,
reduce lactic acidosis, which is crucial in managing septic two clinical trials propose monitoring citrulline levels
shock. However, concerns remain regarding the balance in septic patients as a potential biomarker for predicting
between the beneficial vasodilatory effects of arginine the development of acute respiratory distress syndrome
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and the potential risk of exacerbating hypotension in and overall prognosis. A deficiency in citrulline reflects
unstable septic patients. These studies highlight the need gut barrier dysfunction, which is closely linked to the
for careful patient selection and dosing to maximize severity of sepsis and its associated complications. Future
arginine’s therapeutic potential in treating sepsis. investigations could establish citrulline monitoring as a
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Investigating how arginine supplementation might standard protocol for managing septic patients.

Volume 2 Issue 1 (2025) 9 doi: 10.36922/mi.4742