From Muscle to Macrophage: An Anti-inflammatory Role for the Metabolite N-lactoyl-phenylalanine in Inflammatory Bowel Disease

Aggressive tissue immune responses are a pathophysiological feature underlying all forms of inflammatory bowel disease (IBD). Macrophages make up a substantial portion of innate immunity and are recruited in large numbers to the intestine during injury, infection, and disease. Here, tissue signals polarize these cells along a continuum of states with functional roles ranging from pathogen clearance and immune amplification to tissue repair and regeneration.^1,2 In IBD, aberrant macrophage responses are predominantly skewed towards proinflammatory function; a dysregulation that contributes to disease pathology.³ Host genetics and factors in the tissue microenvironment likely underly overactive macrophage-driven inflammation, and a wealth of studies have focused on identifying how to limit the deleterious effects of these activated cells in disease.^2,4

Population studies and experimental evidence largely support the notion that exercise confers anti-inflammatory benefits on the body. Exercise is a potential lifestyle intervention for disease, with suggested beneficial effects on macrophage polarization⁵ and attenuating intestinal inflammation in IBD⁶; however, a mechanistic understanding of why this may be the case has remained scarce. In a recent issue of Cellular and Molecular Gastroenterology and Hepatology, Yu, Zhang, and Yuan et al reveal intriguing insight into this topic by identifying a potential route to connect the metabolic byproducts of muscle with reduced gut inflammation via modifying macrophage activation state.⁷ Lactate is produced as a glycolytic byproduct of muscle usage and is known to be processed with phenylalanine in various cells throughout the body to synthesize N-lactoyl-phenylalanine (Lac-Phe).⁸ Authors in this recent study found that exercise-induced production of the signaling metabolite, Lac-Phe, led to anti-inflammatory effects in experimental colitis via an immunoregulatory skewing of macrophage activation in the gut.

In a detailed series of studies combining experimental intervention in murine colitis and in vitro analyses, Yu, Zhang, and Yuan et al demonstrated that increased exercise led to elevated circulating Lac-Phe levels and a reduced severity of acute experimental colitis and inflammatory macrophage response in mice. In findings which hint towards a therapeutic application of these results, they further found that supplementation with either Lac-Phe or its pre-cursor, phenylalanine, enhanced protection against colitis. Authors clarified the direct role of Lac-Phe in inflammation by finding that phenylalanine did not confer protection in mice that were coadministered with an inhibitor of the Lac-Phe conversion process. To understand if the metabolite may be acting directly on macrophages, authors performed in vitro experiments to assess its ability to alter macrophage polarization state. These experiments revealed an anti-inflammatory effect of Lac-Phe on macrophages by regulating the activity of nuclear factor kappa B (NFκB) signaling within these cells. Lac-Phe directly limited the proinflammatory activation of these cells, thus explaining the observed reduction of macrophage-produced cytokines in mice who underwent exercise in experimental colitis. Importantly, and of direct relevance to human disease, authors made the striking finding that patients with IBD, on average, have less circulating Lac-Phe and colonic levels of its synthesis enzyme, CNDP2. This indicates a possible link to the exacerbated inflammation seen in IBD and suggests that restoring Lac-Phe levels (either via supplementation or therapeutically targeting metabolic machinery) may be a possible route to induce remission or prevent disease flare-ups.

The intriguing findings presented in this work suggest an important role for exercise and Lac-Phe in regulating tissue immunity in the gut. Future work will be essential to addressing key questions that remain. For instance, it remains to be determined precisely how Lac-Phe represses NFκB activity. Is this metabolite driving a shift in metabolic rewiring of these cells to thus alter polarization state? Metabolic shifts in macrophages have been shown to regulate the activation of macrophages; thus, could Lac-Phe be a feedback inhibition mechanism that shifts glycolytic metabolism of these cells to repress proinflammatory activation? Another question that remains is whether there is a receptor that senses this compound to elicit signaling changes that repress NFκB activity. The way in which Lac-Phe drives these changes remains unanswered. Furthermore, apart from the mechanistic questions that remain, the disease-focused question of why reduced levels of Lac-Phe and its synthesis enzyme are found in patients with IBD is still elusive. Important work remains to address these questions and to clarify whether regulation of Lac-Phe or its downstream targets could be a viable approach in disease.

Symptomatic control and tissue healing are key goals of current IBD therapeutics. The mainstay of treatment at present is controlling excessive tissue inflammation to allow healing of affected areas of disease; however, a significant proportion of patients with IBD are nonresponsive to therapy or lose responsiveness over time. Thus, identifying novel ways to specifically repress overactive immune cell subpopulations in affected tissues is of high interest. The work highlighted here provides one possible mechanistic rationale to explain why exercise has anti-inflammatory benefits by producing metabolic products that directly regulate macrophage function. These findings demonstrate a clear role for Lac-Phe on macrophage-mediated disease progression and suggest an inhibitory feedback mechanism by which exercise impacts these highly metabolic cells. As this line of study develops, it could support the notion that lifestyle approaches may provide a therapeutic benefit in combination with current biologic treatments or immune modulators. Furthermore, additional research could lead to development of targeted therapies that harness this metabolic byproduct of exercise to dampen the aggressive inflammation observed in IBD. Whether these and other metabolic products may have widespread effect on other aspects of the tissue immune response remains to be determined.