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Corresponding author. Address: Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Tel.: 419 383-4130, fax: 419 383-2871.
Hepatocyte growth and proliferation depends on membrane phospholipid biosynthesis. Short-chain fatty acids (SCFAs) generated by bacterial fermentation, delivered through the gut-liver axis, significantly contribute to lipid biosynthesis. We therefore hypothesized that dysbiotic insults like antibiotic treatment not only affect gut microbiota, but also impair hepatic lipid synthesis and liver regeneration.
Major surgeries often entail a high-risk of life-threatening nosocomial infections that can severely impact recovery and even lead to death. To mitigate against the risk of infection, prophylactic antibiotics are prescribed as part of standard perioperative care.
However, recent advances in surgical techniques have minimized the need for antibiotic intervention. Instead, antibiotics are strictly administered only during surgery and then discontinued within 24 hours.
Such clinical practice aligns with initiatives led by the World Health Organization to curb the emergence of antibiotic-resistant microbes that have plagued healthcare facilities around the world.
Despite this, extended use of postoperative antibiotics is still practiced for hepatectomy (alias liver resection) due to the inevitable cutting of portal veins, which carry blood containing unprocessed gastrointestinal contents, including microbial products and metabolites.
The necessity for such practice, however, has been called into question based on a lack of postoperative benefits seen in several randomized controlled trials.
paints a different picture on prophylactic antibiotic use, i.e., it delays liver regeneration (Fig. 1). Of note, the liver is bestowed with an extraordinary regenerative capability, and complete liver regeneration can be achieved after partial hepatectomy. The authors found that oral broad-spectrum antibiotics can severely impede liver regeneration following 70% partial hepatectomy and this resulted in increased post-surgical mortality in mice. An immediate question that came to mind is whether this was due to the known hepatotoxic effects of antibiotics.
noted that there were no histologic signs of liver injury, hepatocyte death or hepatic inflammation; this led the authors to contend that these factors may not be the main contributors to the loss of liver regeneration. Instead, the authors attributed antibiotic-mediated impediment of liver regeneration to a significant reduction in hepatocyte proliferation and a delay in the activation of critical cell cycle regulators (e.g., cyclins A2, B1, D1, E1 and cell-cycle dependent kinase 1).
Fig. 1Gut microbiota promotes de novo lipogenesis that fuels liver regeneration. Fermentation of dietary fibers by the gut microbiota releases acetate that upregulates hepatic expression of SCD1. SCD1 bioactivity provides raw materials such as palmitoleate (C16:1) and oleate (C18:1) for phospholipid biosynthesis which in turn serve as building blocks for membrane biogenesis and promote liver regeneration. Ablation of gut bacteria in mice either via administration of broad-spectrum antibiotics or maintained in a germ-free condition severely impede liver regeneration, resulting in increased mortality after partial hepatectomy. SCD1, stearoyl-CoA desaturase 1.
homed in on the casualties devastated by antibiotics: the gut microbiota. The gut microbiota denotes a consortium of bacteria, fungi, and viruses residing in the gastrointestinal tract. This assemblage of microbes is predominated by two dominant bacterial phyla, Firmicutes and Bacteroidetes, alongside other minor phyla such as Proteobacteria.
The authors found that the antibiotic regimen (i.e., ampicillin, vancomycin, metronidazole and fluconazole) given to mice depleted Firmicutes and Bacteroidetes but allowed the overgrowth of Proteobacteria.
Such a shift in microbial composition is a hallmark of ‘gut microbiota dysbiosis’, i.e. a state of imbalance, that has been implicated in the pathogenesis of many disorders including liver diseases.
The finding that gut microbiota are important for liver regeneration may not be surprising, considering the prior work that had attested to this notion more than three decades ago.
employed germ-free mice, which are devoid of microorganisms, and examined their recovery from partial hepatectomy. Similar to what was seen in mice given antibiotics, germ-free mice also had significant defects in liver regeneration and increased post-surgical mortality. Remarkably, the authors were able to rescue liver regeneration in germ-free mice by colonizing their gut with a defined minimal microbiota comprised of 12 select bacterial strains. Such elegant use of axenic mice underscored that neither Proteobacteria overgrowth per se nor the emergence of antibiotic-resistant bacteria was the cause of delayed liver regeneration following antibiotics treatment; rather the problem was broadly due to the loss of key bacterial taxa. A depleted gut microbiota could have deprived the liver of microbial metabolites or growth factors that are needed to nurse the regenerating liver. Indeed, when the authors employed metabolic tracing with stable isotope-labelled precursors, they found hepatic de novo lipogenesis, specifically phospholipid biosynthesis, to be notably impeded in both hepatectomized germ-free and antibiotic-treated mice. The question then became: How does the gut microbiota dictate lipid biosynthesis in the liver?
Liver regeneration is metabolically demanding and requires an adequate supply of fatty acids for membrane biogenesis via de novo lipogenesis. In this setting, stearoyl-CoA desaturase 1 (SCD1; alias delta-9 desaturase, EC 1.14.19.1) is a rate-limiting, lipogenic enzyme in the biosynthesis of monounsaturated fatty acids (MUFAs) such as palmitoleate (C16:1 n-7) and oleate (C18:1 n-9) from palmitate (C16:0) and stearate (C18:0), respectively.
Notwithstanding the importance of SCD1, several studies have reported its pathologic role in obesity, type II diabetes, chronic inflammation, and cancers; this is due to MUFAs also serving as excellent substrates for pro-steatogenic neutral lipids such as triglycerides and cholesterol esters.
Despite their potential to cause harm when in excess, the participation of SCD1 and SCFAs in hepatic de novo lipogenesis is nourishing, perhaps even coveted, for the regenerating liver, which requires a constant supply of phospholipids for cell membrane biogenesis.
Gut bacterial fermentation of dietary fibers generates millimolar quantities of SCFAs (i.e., acetate, butyrate and propionate) with acetate being the most abundant.
The same authors from the current study have previously shown that gut microbiota can direct de novo lipogenesis by (i) providing acetate as a substrate and (ii) upregulating SCD1.
found that both SCD1 and acetate levels are well-correlated, whereby both were decreased in germ-free and antibiotic-treated mice. The hypothesis on the acetate-SCD1 link is thought-provoking and, if ascertained, would advance our understanding of the intricate dialogue between the gut microbiota and its host. To further test such a link, the authors used hepatocyte organoid and cell line models. Indeed, acetate was found to upregulate Scd1 transcripts and increase cell proliferation in vitro, where the latter could be blocked by SCD1 inhibitors. Oral supplementation of acetate to mice likewise elevated Scd1 transcripts in vivo. Finally, to show clinical relevance, the authors corroborated the association between Scd1 expression and hepatocyte proliferation using biopsies from humans with liver metastasis who underwent partial hepatectomy as part of a procedure to increase liver size prior to tumor resection.
From the authors’ findings, there is clearly an interaction between acetate and SCD1 in hepatic de novo lipogenesis. With that being said, the molecular mechanisms underpinning such interactions still remain an enigma. On one hand, the enzymes in de novo lipogenesis are modulated by a family of transcription factors, i.e., sterol regulatory element binding proteins (SREBPs); for instance, Scd1 expression is regulated by SREBP-1c.
It is tempting to speculate that these pathways may interact in some way and thus warrant further study. Further, the epigenetic effects of acetate, e.g. in inducing histone acetylation at the promoters of lipogenic genes,
it is also important to consider measuring the delta-9 desaturation index or product/precursor ratio (C16:1/C16:0 and C18:1/C18:0) in tissues as a better surrogate marker for SCD1 activity. One should take note that sexual dimorphism has been observed with regards to SCD1 activity;
as the study by Yin et al. (4) employed only female mice, future studies should determine whether the findings are applicable to male mice as well.
In summary, the study by Yin et al. is certainly elegant in illustrating the significance of a healthy gut microbiota for proper liver regeneration, thus cautioning against antibiotic use in this context. However, there are still some surgeries, such as those in the gastrointestinal tract, for which antibiotics will be needed to avoid a leaky gut situation, which can result in bacterial dissemination and metabolic infection. The authors’ findings also have clinical considerations that could be used to potentially improve recovery post-liver surgery. For instance, perhaps patients convalescing from liver resection would benefit from an increased intake of dietary fiber and/or SCFA supplementation. In line with this, avoidance of foods that can dampen SCD1 activity, such as those rich in polyunsaturated fatty acids,
Dietary polyunsaturated fatty acids mediate the inverse association of stearoyl-CoA desaturase activity with the risk of fatty liver in dyslipidaemic individuals.
should also be considered in postoperative care. Last but not least, the study by Yin et al. serves as a reminder that, though personalized medicine remains a far-cry in clinical practice, approaches that account for individual microbiota disposition should be considered. Inspecting the microbiota could be an important next step for improving liver health, not only in the setting of hepatectomy, but for a spectrum of liver diseases.
Financial support
M.V–K. is supported by National Institute of Health (NIH), National Cancer Institute (NCI) grant R01 CA219144.
Conflict of interest
The authors declare no conflict of interest.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
B.S.Y. and M.V–K. prepared the original draft, reviewed and edited the manuscript.
Supplementary data
The following are the supplementary data to this article:
Dietary polyunsaturated fatty acids mediate the inverse association of stearoyl-CoA desaturase activity with the risk of fatty liver in dyslipidaemic individuals.
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