An expanding body of research implies that intestinal microbiota are essential in the onset and advancement of obesity [27]. Lactobacillus spp, such as L. gasseri, have been effectively utilized in in vivo studies on obesity [28]. However, there are limited studies on the biological impacts of bacteriocins produced by Lactobacillus gasseri, such as gassericin A. A bioinformatics study revealed that this bacteriocin may contribute to weight gain [14]. The present research team employed an in vivo model to evaluate the effects of gassericin A on the culture medium of 3T3-L1 preadipocyte cell line, both before and after they differentiated into mature fat cells. They assessed the morphology and viability of the cells, as well as the expression levels of specific genes related to obesity, including SCD-1, UCP-1, GLUT4, Zfp423, TNF-α, and Fabp4. The results indicated that gassericin A may increase the number of adipocytes and contribute to hyperplastic obesity, while also offering protection against obesity-related complications [22]. However, there are currently no reports utilizing an in vivo model in this context.
The current research investigated the effects of gassericin A on obesity and its associated biomarkers in mice fed an HFS diet. The results indicated that specific doses of the peptide may increase weight gain and abdominal fat content when administered through intraperitoneal injection. Bioinformatics studies on Lactobacilli, as opposed to experimental evaluations of the peptide, indicated that gassericin A may have weight-protective effects [14]. Similar outcomes have been observed in meta-analyses of clinical trials or experimental models involving the impacts of Lactobacillus gasseri on both animals and humans [13]. However, these findings contradict the results of the present report. It is important to note that the previous studies cannot be directly compared to the current one, as none of them evaluated the effects of the bacteriocin itself under in vivo conditions.
Adipose tissue has two influential metabolic processes related to fat storage in its cells: hypertrophy, in which the cell volume is increased by storing fat particles, and hyperplasia, in which the fat cells multiply through cell division. In general, cell hyperplasia is not linked to metabolic or morphological disorders. In contrast, an increase in cell size may be associated with conditions such as local hypoxia in adipose tissue and various cellular disorders [29]. In the present research study, gassericin A decreased the size of fat cells, which is consistent with the previous findings in 3T3-L1 cells [22]. Smaller adipocytes are associated with a greater resistance to metabolic disorders, such as diabetes. Conversely, larger adipocytes are linked to a reduced production of anti-inflammatory adipokines like adiponectin, increased lipolysis, and heightened release of inflammatory cytokines [29]. These results indicate that gassericin A may offer protection against obesity-related complications by promoting hyperplastic fat cells. However, further research is necessary to monitor the levels of adipokines and inflammatory cytokines in this context.
In this study, gassericin A increased the expression of the Fabp4 gene in fat tissue. This gene, also known as 422/ap2, encodes the adipocyte fatty acid-binding protein 4. This finding is consistent with the increased abdominal fat and body weight in the mice treated with gassericin A. This result is also consistent with previous findings on cultured 3T3-L1 cells, both before and after their differentiation into adipocytes [22]. Adipocyte fatty acid-binding protein 4 is expressed in adipocytes following the activation of genes specific to adipose tissue, such as peroxisome proliferator-activated receptor (PPAR) γ, C/EBPα, and C/EBPβ [30]. The expression of the Fabp4 gene rises during the transformation of preadipocytes into adipocytes [31]. In fact, genetic deletions of Fabp4 and Fabp5 provide greater protection against fatty liver disease, type 2 diabetes, insulin resistance, and obesity. Furthermore, these deletions are associated with decreased hepatic expression of SCD-1 gene [32]. However, the overexpression of the Fabp4 gene in the present study did not coincide with obesity-related disorders. The discrepancy observed in these findings necessitates further studies using additional distinct markers of fully developed adipocytes.
The additional gene of focus, Zfp423, encodes a zinc finger protein which is crucial for preserving the characteristics of white adipose tissue (WAT). Disruption of this gene has led to a significant reduction in adipose tissue [33]. White adipocytes are responsible for energy storage and resistance to thermogenesis. The Zfp423 gene is a critical regulatory factor in white adipocytes. It modulates the levels of PPARγ in preadipocyte mural cells and guides them during the process of adipogenesis. It is also found in fully developed white adipocytes. Genetic deletion of Zfp423 in white fat cells results in the development of beige adipocytes. Zfp423 is crucial for preserving the characteristics of white adipocytes by inhibiting the expression of thermogenic genes. White adipocytes show a higher expression of Zfp423 compared to brown adipocytes. This gene is downregulated upon exposure to cold [34]. Therefore, by reducing the expression of this gene, gassericin A may disrupt the process of fat whitening, leading to the formation of brown or beige adipocytes. Furthermore, gassericin A may reduce the overall size of white adipocyte tissues by decreasing the expression of this gene in the abdominal fat cells of mice. However, more studies are needed in this area. A previous in vitro study from the present team suggested that gassericin A may be capable of inducing changes in the characteristics of white or beige adipocytes by decreasing the expression of the Zfp423 gene in the culture media of both preadipocytes and mature fat cells [22].
As there are no existing studies on the biological effects of gassericin A under in vivo conditions, the present study conducted a preliminary investigation into its biological impacts, including those related to obesity. Accordingly, gassericin A decreased RBC, hematocrit, hemoglobin, and platelet counts, whereas the leukocyte count remained unaffected. The underlying mechanisms and their potential physiological and therapeutic significance remain unclear. Although the decreases in RBC, hematocrit, and hemoglobin levels were mild, prolonged exposure to or higher doses of gassericin A may result in normocytic-normochromic anemia, primarily due to impaired RBC production. The concurrent decline in platelet levels may be attributed to bone marrow suppression, a condition that can be induced by certain medications and toxins [35]. The current research was preliminary; therefore, further studies are necessary to conduct a more comprehensive investigation in this field.
Healthy nutrition is one of the primary measures for managing diabetes. An HFS diet leads to the buildup of fat in the body, the onset of metabolic syndrome, and impaired glucose tolerance, which is a precursor to diabetes [36]. Diabetes is among the most prevalent endocrine disorders and is defined by an increase in blood glucose levels resulting from a disorder in glucose metabolism [37]. Lactobacillus fermentum strain RS-2 has demonstrated the ability to prevent the onset of diabetes under certain conditions. This probiotic reduces oxidative stress by minimizing inflammation and enhancing the performance of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase in diabetic rats [38].
Oxidative stress and the damage it causes contribute to various pathological processes in numerous diseases, including diabetes. Given the beneficial effects of probiotics and their capacity to lower glucose levels, their therapeutic potential in the management of diabetes is not surprising [37]. Feeding an HFS diet resulted in a remarkable rise in fasting glucose levels in the present study. However, the administration of gassericin A effectively mitigated this increase. Mosallami et al. (2020) investigated the effects of Lactobacillus plantarum on various biochemical parameters in diabetic rats. The administration of Lactobacillus plantarum suspension to diabetic rats led to a notable decline in their fasting blood glucose levels [39]. In a study investigating the impact of intestinal microbiota modulation on metabolic syndrome in mice, Lactobacillus reuteri significantly reduced blood sugar levels [40]. Despite the observed similarities, these findings cannot be directly compared to the current results due to the differences between the studies.
The present study revealed that gassericin A significantly decreases serum levels of LDL, HDL, and cholesterol. Recent research suggests that probiotics can lower cholesterol levels and help prevent atherosclerosis [41]. The administration of Lactobacillus gasseri MG4524 to obese rats led to a decline in serum cholesterol levels [42]. These observations align with the findings of the current study, despite the differences between the two treatment protocols. In the previous study conducted by the present team on 3T3-L1 cells, gassericin A resulted in a decrease in the expression of the SCD-1 gene during the differentiation of adipocyte precursor cells [22]. Consequently, the reduction in the lipid profile induced by gassericin A may be linked to its effects on cholesterol esterification pathways, lipoprotein transporters, and SCD-1 gene expression. Reducing the expression of this gene may improve various metabolic disorders and is also associated with a reduction in obesity-related complications, such as an improved lipid profile [43]. SCD-1 reduces the production of single-chain monounsaturated fatty acids, leading to a decrease in the synthesis of triglycerides and essential blood lipids. Therefore, the decrease in SCD-1 expression caused by gassericin A may be the reason for the improvement in the lipid profile in mice [44].
In the present study, the HFS diet resulted in a decrease in BUN levels. However, this parameter was not influenced by gassericin A. Urea and creatinine are well-established biomarkers of kidney damage, and elevated serum levels of these substances are frequently associated with renal dysfunction [45]. Certain species of Lactobacillus have been demonstrated to lower serum BUN levels [46, 47]. Nevertheless, the current results obtained through parenteral injection of gassericin A cannot be directly compared to those achieved with oral probiotics.
Abnormalities in peripheral metabolism caused by obesity and weight gain can result in hepatic dysfunction. Liver enzymes are crucial biomarkers for detecting liver injury [48]. Liver diseases are linked to significant rises in ALP, AST, and ALT enzyme levels in the bloodstream. A diet rich in fat and the buildup of fat in liver cells increase the sensitivity and vulnerability of this tissue to other damaging factors. Consequently, this may cause fatty liver disease to advance to hepatic fibrosis and cirrhosis [49]. Given that the liver is essential for the metabolism of fatty acids, glucose, and energy [50], abnormal peripheral metabolism caused by obesity and weight gain can lead to the buildup of lipids in this tissue. In this study, the HFS diet resulted in substantial rises in ASP, ALP, and ALT enzymes. In contrast, treatment with gassericin A significantly inhibited the elevation of these enzymes. In a 2021 study examining the impacts of Lactobacillus acidophilus on hepatic tissue, serum levels of ALT and AST enzymes decreased in rats treated with this probiotic, resulting in improved liver function [51]. Probiotics, including Lactobacillus species, have shown similar beneficial effects in nonalcoholic fatty liver disease [52]. Additionally, SCD-1 activity has been reported to increase in obese mice with hepatic steatosis. The level of hepatic saturated fatty acids exhibits an inverse relationship with liver SCD-1. This indicates that a reduction in SCD-1 leads to the buildup of saturated fatty acids in the cytosol of cells. Consequently, the transfer of cytosolic fatty acids to the mitochondria is impeded, resulting in increased fatty acid oxidation [53]. Therefore, the decrease in liver enzyme levels and the improvement in liver steatosis may be linked to the suppression of SCD-1 gene expression by gassericin A [22]. Gassericin A appears to offer protective effects against hepatic damage induced by an HFS diet.
Comparisons with other studies: what does the current work add to the existing knowledgeDespite numerous studies examining the effects of gut microbiota on metabolism and fat accumulation, only limited number of reports have addressed the impact of bacteriocins synthetized by the same bacteria on obesity and its associated complications. To the authors’ knowledge, this team is the first to provide experimental evidence regarding the potential therapeutic effects of gassericin A on obesity. In a previous study, this research team demonstrated the beneficial effects of gassericin A in 3T3-L1 cells [22]. By employing an in vivo model of obesity, the present study confirms the former in vitro results.
Study strengths and limitationsThe most important advantage of this study is its novelty, as there are very few similar studies, even concerning other bacteriocins. Consequently, this study is preliminary, and one of its main limitations is the lack of prior research in this field. It remains unclear whether gassericin A is absorbed from the intestine under physiological conditions. Additionally, the pharmacokinetics and pharmacodynamics of the peptide are not well understood. Although three doses of the peptide were examined, the optimal effective dose has yet to be determined. Western blotting should also be conducted to assess the effects of gassericin A on protein levels. If the absorption of this bacteriocin from the intestine is feasible, potential physiological effects can be anticipated. However, the correlation between the doses administered in this study and the physiological concentration of this peptide is a subject that requires further investigation. Finally, gassericin A is not commercially available and must be produced in the laboratory in small quantities, which is both time-consuming and costly.
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