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. 2024 Oct 31;58(19):56–63. doi: 10.47895/amp.vi0.8005

Lactobacillus brevis BIOTECH 1766 Attenuates Oxidative Stress and Histopathological Changes following Aluminum Poisoning in ICR Mice

Gerwin Louis T Dela Torre 1,✉, Richelle Ann M Manalo 1,2, Szarina Krisha K Ko 3, Erna C Arollado 1,2, Arlene A Samaniego 4
PMCID: PMC11586292  PMID: 39600661

Abstract

Objective

The aim of this study was to investigate the protective effects of Lactobacillus brevis BIOTECH 1766 against oxidative damage in the brain, liver, and kidneys induced by aluminum (Al) poisoning in ICR mice.

Methods

Twenty mice were divided into four groups (n = 5): (I) control, (II) Al, (III) citric acid (CA), and (IV) L. brevis BIOTECH 1766 group. A 14-day treatment period was implemented, wherein groups I and II received sterile water, while groups III and IV received 10 mg/kg bw of CA and 1 x 109 cfu/kg bw of L. brevis BIOTECH 1766, respectively. On day 15, all except the control group received a single oral dose of 1438 mg/kg bw of AlCl3.6H2O. After 24 h, mice were euthanized to collect the brain, liver, and kidneys for the oxidative stress marker analyses and histopathological examination.

Results

Acute intoxication of Al led to a significant increase in tissue malondialdehyde (MDA) and a significant decrease in the tissue's reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Mice pretreated with CA or L. brevis BIOTECH 1766 have markedly reduced CAT activity in the liver, and SOD in all three organs. Extensive organ injuries were also prevented by CA and L. brevis BIOTECH 1766 pretreatment, with the latter providing better protection against liver damage.

Conclusion

The findings showed that L. brevis BIOTECH 1766 provides a protective effect against acute Al poisoning in mice by ameliorating oxidative damage in the brain, liver, and kidneys.

Keywords: aluminum poisoning, catalase, Lactobacillus brevis, oxidative stress, superoxide dismutase

INTRODUCTION

Aluminum (Al) is the third most abundant element existing throughout nature, in air, water, and plants.1 Aluminum-containing compounds are also used extensively in human products and processes. The most common form of human exposure to Al is through gastrointestinal absorption because salts of Al are used in food additives, pharmaceuticals, and in drinking water purification.2 In addition, there is the existing issue of food contamination as a result of leaching during the process of food preparation from Al cooking vessels, such as pans and Al foils.3 Human exposure to Al is therefore difficult to avoid. This is a matter of concern because biologically available Al is highly reactive and essentially toxic.4 The gastrointestinal absorption and the subsequent accumulation of Al in various organs have deleterious health effects.2 Indeed, epidemiological and experimental studies suggest that Al exposure is linked to brain, liver, and kidney diseases.5-7

In Al poisoning cases, deferoxamine has been accepted as one of the preferred treatments.8 It binds to Al forming aluminoxamine complex which is excreted by the urine.6 However, aluminoxamine may persist for long periods, especially in kidney diseases causing additional toxicity problems. Further, deferoxamine also has a high affinity with iron, increasing the risk of iron deficiency.8 Similarly, citric acid (CA) was found to reduce the concentration of Al in acute cases through fecal excretion after binding to the metal.9 Additionally, CA has been suggested as a prophylactic agent against metal intoxication.10 Prophylaxis is favored because prevention is far better than treatment of Al poisoning.11 However, the chronic use of CA may result in liver and kidney damage.12,13 Thus, the search for prophylactic agents against Al poisoning is warranted.

Lactic acid bacteria (LAB), such as Lactobacillus brevis, have been identified as candidate agents in preventing metal toxicity because they have the ability to bind metal ions including mercury, lead, and Al.14-16 Moreover, they offer an advantage as the majority are generally recognized as safe (GRAS) and are commonly used as probiotics.17 These microorganisms may produce antioxidant metabolites, and scavenge reactive oxygen species (ROS), which are important in alleviating Al toxicity.16,18 However, it is important to note, that the bioactivity of microorganisms is strain-specific and cannot be extrapolated to other microbial strains.19 Thus, assessment of activity must be applied to each candidate strain. In this study, we tested the hypothesis that pretreatment of the BIOTECH 1766 strain of L. brevis could alleviate the oxidative damages of acute oral Al poisoning in vivo.

MATERIALS AND METHODS

Microbial Strain and Culture

The BIOTECH 1766 strain of L. brevis was purchased from the Philippine National Collection of Microorganisms, National Institute of Molecular Biology and Biotechnology, University of the Philippines Los Baños. The microorganism was grown in MRS agar at 37°C for 24 h. Well-isolated colonies were suspended in sterile water and the turbidity was adjusted against a McFarland standard.

Design of Experiment

Figure 1 presents the experimental process of the study. Twenty, 6-week-old male ICR mice weighing 28-32 g were procured from the Research Institute for Tropical Medicine and were housed in the animal facility of the National Institutes of Health, University of the Philippines Manila. The mice were acclimatized for two weeks. The temperature and humidity were controlled under 12 h light/dark cycles. Animals were fed ad libitum with a standard diet and water. The protocol of the study was approved by the University of the Philippines Manila Institutional Animal Care and Use Committee (Protocol No. 2019-017).

Figure 1.

Figure 1

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Animal and experimental design (created with BioRender.com).

After acclimatization, the mice were randomly assigned to 4 groups (n = 5), namely, (I) control, (II) Al, (III) CA, and (IV) L. brevis BIOTECH 1766 group. The comparator used was CA. For 14 days, sterile water was given to mice in groups I and II, while doses of 10 mg/kg bw of CA and 1 x 109 cfu/kg bw of L. brevis BIOTECH 1766 were given to mice in groups III and IV, respectively.16,20 On day 15, all mice were given a single oral dose of AlCl3·6H2O at a concentration of 1438 mg/kg bw except for mice in group I, wherein sterile water was provided. This dose was found to induce acute toxicity in mice based on the previous study of Llobet et al.21 The mice were observed for any signs of toxicity for a period of 24 h. On day 16, all mice were chemically anesthetized with an intraperitoneal injection of tiletamine-zolazepam (Zoletil®; 10 mg/kg bw) prior to euthanasia via decapitation.22 The brain, liver, and kidneys were excised for the oxidative stress level measurement and histopathological examination.

Preparation of Tissue Homogenates

The brain, liver, and kidneys were washed with cold saline. Afterward, the organs were homogenized using cold 0.1 mol/L phosphate buffer (pH 7.4). The tissues were minced in a beaker with a pair of sterile surgical scissors. The crude tissue homogenates were centrifugated at 10,000 rpm for 15 min at 4°C and the resulting supernatants were used for the spectrophotometric determination of protein contents, tissue malondialdehyde (MDA), and reduced glutathione (GSH) levels, and tissue superoxide dismutase (SOD) and catalase (CAT) activities.

Protein Content Determination

The protein contents of the tissues were determined using the Folin-Ciocalteau method. The sample (0.5 mL) was mixed with distilled water (0.10 mL). Alkaline copper solution (3 mL), which consisted of 2% Na2CO3 in 0.1 mol/L NaOH, 0.5% CuSO4·5H2O, and 1% KNaC4H4O6·4H2O, was added followed by vortexing for 30 s. The mixture was then allowed to stand at room temperature for 10 min. Afterward, the Folin-Ciocalteau reagent was added, mixed, and left to stand in the dark for 30 min before reading the absorbance at 600 nm. A standard curve was prepared using bovine serum albumin.23

Tissue MDA Level

Lipid peroxidation in tissue homogenate was measured by estimating the formation of thiobarbituric acid reactive substances (TBARS). The sample (0.2 mL) was mixed with 20% trichloroacetic acid (1 mL) and 1.34% thiobarbituric acid (1 mL). The volume was made to 3 mL using distilled water, vortexed for 10 s, and heated at 95°C for 20 min. The mixture was cooled, followed by the addition of n-butanol (3 mL). Subsequently, the mixture was centrifugated at 10,000 rpm for 5 min, and the supernatant’s absorbance was measured at 532 nm against a reagent blank. The TBARS as MDA content of the sample was calculated using the molar extinction coefficient value of 1.56 x 105 L/mol per cm and expressed as nmol/mg protein.24,25

Tissue GSH Level

The determination of GSH level followed the method of Jollow et al.26 The sample (1 mL) was mixed with 4% sulfosalicylic acid (1 mL). The mixture was incubated at 4°C for 1 h and centrifugated at 10,000 rpm for 15 min. The resulting supernatant (0.2 mL) was mixed with 0.1 mol/L phosphate buffer, pH 7.4 (2.6 mL), and 5,5’-dithiobis(2-nitrobenzoic acid) at a concentration of 4 mg/mL in 0.1 mol/L phosphate buffer, pH 7.4 (0.2 mL). The mixture was vortexed for 10 s, after which the absorbance was read at 412 nm against a reagent blank. The GSH was calculated using the molar extinction coefficient of 1.3 x 104 L/mol per cm and was expressed as nmol/mg protein.

Tissue CAT Activity

The CAT activity was measured using the method of Hadwan with some modifications.27 The sample (0.5 mL) and 10 mmol/L H2O2 (1 mL) were mixed and incubated at 37°C for 2 min. Afterward, a working solution (6 mL) was added which contains Co2+, Na(PO3)6, and NaHCO3 solutions. The mixture was vortexed for 5 s and was kept in the dark at room temperature for 10 min. The changes in absorbance were recorded at 440 nm against a reagent blank. A standard solution was also prepared composed of distilled water, 10 mmol/L H2O2, and the working solution. The CAT activity was expressed as U/mg protein.

Tissue SOD Activity

The SOD activity in the tissue was measured using the SOD assay kit (Sigma-Aldrich 19160) which was performed according to the recommendation of the manufacturer.28 The tissue SOD activity was expressed as U/mg protein.

Histopathological Examination

The excised brain, liver, and kidneys were fixed with a 10% formalin solution. The tissues were embedded in paraffin and sectioned at 5 μm thickness. Sections were stained with hematoxylin-eosin (H&E) for light microscopy examination. The results of the histopathological examination were semi-statistically evaluated.29,30

The list of changes in the brain tissues that were observed includes the vacuolization around the neuron or perinuclear space, disruption or degeneration of neurons, neurofibrillary tangles, neuronal cytoplasm shrinkage, and plaque formation; for liver tissues, the changes include the loss of intact liver plates, chromatin condensation, cytoplasmic vacuolization, and necrosis of hepatocytes; and for kidney tissues, the changes include the loss of intact tubules and glomeruli, dilation in the glomeruli, and tubular necrosis.

Statistical Analyses

Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) 23.0. Results were reported as mean ± standard deviation (SD). Data were checked for normality and homogeneity of variance using Shapiro-Wilk and Levene’s tests, respectively. Depending on the results, data were analyzed with one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test or Kruskal-Wallis test followed by Dunn’s multiple comparison test. Values of p<0.01 were considered statistically significant.

RESULTS

Acute Al Toxicity

No mortality was observed in any of the groups up to the end of the animal experiment. However, the administration of a single oral dose of AlCl3·6H2O on day 15 caused observable signs of toxicity in the 24 h observation period, in the form of decreased locomotor activity, lethargy, and piloerection. These signs were observed in all mice of the Al group, while only three mice experienced the signs in both the CA and L. brevis BIOTECH 1766 groups.

Oxidative Stress Markers Estimation

Table 1 summarizes the estimated oxidative stress markers in the brain, liver, and kidneys of mice. In the Al group, the MDA levels were higher except in the liver, and the GSH levels were lower in all organs when compared to other groups, but the differences did not reach statistically significant values (p>0.01). No significant differences were also identified among the groups in the brain and kidney CAT activities (p>0.01). Interestingly, pretreatment of CA and L. brevis BIOTECH 1766 was effective in increasing the CAT activity in the liver and the SOD activities in all organs (p<0.01). However, when compared to CA, L. brevis BIOTECH 1766 had statistically lower SOD activities in the liver (p=0.005) and kidney (p<0.001).

Table 1.

Effects of Different Treatments on the Levels of MDA and GSH, and the CAT and SOD Activities in the Brain, Liver, and Kidneys of Mice

Group MDA level (nmol/mg protein) GSH level (nmol/mg protein) CAT activity (U/mg protein) SOD activity (U/mg protein)
Brain
 Control 250.94±23.47 10.87±2.13 116.34±0.49 91.89±1.91bc
 Al 284.48±24.67 0.58±0.30 19.06±0.40 10.52±0.20ac
 CA 250.91±47.11 3.39±1.17 63.99±0.52 51.43±3.87ab
 L. brevis BIOTECH 1766 233.72±65.38 2.90±1.28 41.07±0.61 49.05±1.36ab
Liver
 Control 187.48±58.03 1.20±0.19 129.94±3.96bc 6.95±0.23b
 Al 232.71±27.14 0.28±0.13 51.85±0.99ac 4.58±0.07ac
 CA 254.67±15.79 0.63±0.18 85.90±2.44ab 6.84±0.16b
 L. brevis BIOTECH 1766 189.02±51.25 0.47±0.16 80.84±1.27ab 6.17±0.17abc
Kidney
 Control 142.86±38.33 1.50±0.59 148.37±0.81 18.86±0.24bc
 Al 246.91±74.14 0.20±1.10 113.20±0.31 13.97±0.13ac
 CA 208.85±28.68 0.67±0.88 118.49±0.17 16.89±0.43ab
 L. brevis BIOTECH 1766 144.44±54.65 0.71±0.01 115.33±0.23 15.11±0.23abc
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Values expressed as mean ± SD. Per organ, the superscripts a, b, and c indicate statistically significant differences compared to the control, Al, and CA group, respectively at p<0.01.

Histopathological Findings

Scores of histopathological changes are summarized in Table 2. Representative brain tissue photomicrographs of mice from each group are depicted in Figure 2. The brain tissue of mice in the control group appeared normal. Histopathological changes were observed for the Al, CA, and L. brevis BIOTECH 1766 groups. In the Al group, mononuclear cell infiltrations, granulovacuolar changes, and basophilic necrotic neurons were seen. It was also noted that mononuclear cell infiltrations were found in the CA group, while neuronal disruptions occurred in the L. brevis BIOTECH 1766 group. Figure 3 shows the representative hepatic photomicrographs of mice in each group. Liver sections of mice in the control group were found to be normal, while several other histopathological anomalies were identified in other groups. In the Al group, centrilobular degeneration, focal loss of intact hepatic cords, sinusoidal dilatation, and focal perivascular infiltration of mononuclear cells were identified. In the CA group, perivascular inflammation and karyolysis were apparent, while in the L. brevis BIOTECH 1766 group, small inflammatory cell aggregates were seen. Lastly, representative renal photomicrographs of each group are shown in Figure 4. Normal histological structures were evident in the kidneys of mice in the control, CA, and L. brevis BIOTECH 1766 groups. In the Al group, focal tubular degenerations were visible.

Table 2.

Histopathological Scores of the Brain, Liver, and Kidney Tissues per Treatment Group, Based on the Indicated Signs

Tissue Indicated sign Score of groups
Control Al CA L. brevis BIOTECH 1766
Brain Vacuolization around the neuron or perinuclear space - - - -
Disruption or degeneration of neurons - ++ + +
Neurofibrillary tangles - ++ + +
Shrunken cytoplasm of the neuron - + + +
Presence of plaques - - - -
Liver Loss of intact liver plates - ++ + -
Chromatin condensation - ++ + +
Cytoplasmic vacuolization - - - -
Necrosis of hepatocytes - ++ + -
Kidneys Loss of intact tubules and glomeruli - + - -
Dilation in the glomeruli - - - -
Tubular necrosis - + - -
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(-) No change observed in the samples; (+) Changes rarely observed in the samples with an average of 1-2 changes per vision field; (++) Changes occasionally observed in the samples with an average of 8–10 changes per vision field; (+++) Changes often observed in the sample with >20 changes per vision field.

Figure 2.

Figure 2

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Representative photomicrographs of brain tissue of mice (H&E stain; 100x magnification). (A) Brain tissue of mice in the control group with normal histology; (B) brain tissue of mice in Al group with [1] irregularly shaped darkly staining neurons with neurofibrillary tangles (notched arrow), [2] central chromatolysis (fullbodied arrow) and enlarged astrocytes (arrowhead); (C) brain tissue of mice in CA group showing granulovacuolar changes (full-bodied arrow), and neuronal central chromatolysis (notched arrow); and (D) brain tissue of mice in L. brevis BIOTECH 1766 group showing basophilic irregularly shaped shrunken neurons (full-bodied arrow).

Figure 3.

Figure 3

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Representative photomicrographs of liver tissue of mice (H&E stain; 400x magnification). (A) Normal liver tissue of mice in the control group; (B) liver tissue of mice in Al group depicting centrilobular degeneration, with karyopyknosis (arrowhead), karyolysis (fullbodied arrow), and karyorrhexis (notched arrow); (C) liver tissue of mice in CA group showing centrilobular degeneration with karyorrhexis (full-bodied arrow) and karyopyknosis (arrowhead); and (D) liver tissue of mice in L. brevis BIOTECH 1766 group with karyopyknosis (full-bodied arrow).

Figure 4.

Figure 4

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Representative photomicrographs of kidney tissue of mice (H&E stain; 400x magnification). (A) Kidney tissue of mice in the control group with normal structures; (B) kidney tissue of mice in Al group showing diffused tubular degradation, loss of intact glomerulus (full-bodied arrow) and tubule (arrowhead); (C) kidney tissue of mice in CA group showing normal features; and (D) normal kidney tissue of mice in L. brevis BIOTECH 1766 group.

DISCUSSION

Earlier studies have shown that Al compounds are capable of inducing acute toxicity with high doses.21,31 The results of our present study clearly confirmed that a single oral dose of AlCl3 6H2O at a concentration of 1438 mg/kg bw caused distress in mice. On the basis of ion, the concentration is equivalent to 161 mg Al/kg bw. Observed reduced locomotor activity, lethargy, and piloerection are all attributable signs of acute Al toxicity and possible organ injuries.21 In our study, these physical signs were visually observed to be present in all mice of Al group. For both the CA and L. brevis BIOTECH 1766 groups, the absence of the physical signs was noted on two mice, which is indicative of the protective effect of the pretreatment.

It is a fact that high levels of Al accumulating in the organs can lead to toxic effects.32 Hence, preventing Al from reaching the organs is an avenue to avert tissue damage. One of the binding agents, effective in removing Al in biological systems is CA.9 However, the excessive use of CA carries its own ill health effects.12,13 Thus, there was a proposed shift in the use of the members of LAB, possessing both antioxidant and metal binding activity as an intervention to prevent metal toxicity, such as that of Al. However, the present study only focused on the evaluation of the antioxidant property of L. brevis BIOTECH 1766 in terms of oxidative stress modulation.

It is known that Al causes oxidative stress in the brain, liver, and kidney tissues.33 High MDA levels, which are the end product of the lipid peroxidation process, can serve as a reliable marker of oxidative stress. In addition, drastic amounts of ROS exhaust GSH, CAT, and SOD, leaving no protection against tissue damage.29,34 These were evident in the Al group when compared against the other groups, wherein MDA levels were highest in brain and kidneys, while GSH, CAT, and SOD were lowest in the brain, liver, and kidneys of mice following the acute Al poisoning. The findings indicate that the antioxidant defense grid was impaired. Statistically significant improvements in the oxidative stress markers were observed among mice pretreated with CA and L. brevis BIOTECH 1766, specifically the CAT activity in the liver, and SOD activity in all three organs. The protection provided by L. brevis BIOTECH 1766 against oxidative damage was consistent with previous reports using different strains of L. brevis. Noureen et al. demonstrated that administration of L. brevis MG000874 improved SOD and CAT activities in the brain, liver, and kidneys of mice subjected to a murine model of oxidative stress. Furthermore, the strain upregulated both SOD and CAT expression.35,36 Although our study found that the administration of LAB caused an insignificant improvement in MDA and GSH, other scientists reported otherwise. Han et al. showed the protective effect of L. brevis HY7401 on tert-butylperoxide-induced liver injury in mice by decreasing the MDA levels.37 Jiang et al. concluded that L. brevis 23017 relieves mercury toxicity by modulating oxidative stress which includes reducing MDA levels and increasing the activity of GSH.14 These differences may be attributed to the strains, doses, and experimental designs used. Regardless of the differences, these bioactivities may be partly related to the antioxidases and other metabolites with intrinsic antioxidant activity that L. brevis produces.

Histopathologically, we found that pretreatment of L. brevis BIOTECH 1766 minimized brain, liver, and kidney injuries. It performed better than the CA in preventing histopathological changes in the liver. The protection can be ascribed to the previously reported metal-binding trait of L. brevis.14-16 The present study did not quantify both the capacity of the BIOTECH 1766 strain to bind Al as well as the amount of deposited Al in the organs after pretreatment. These, however, must be clarified in future research to better understand the protective effect of L. brevis BIOTECH 1766. In general, Al is absorbed in the intestines finding its way to the systemic circulation wherein it can be transported to different organs.38 Findings from the histopathological analysis showed that acute oral exposure to Al caused substantial alteration in the brain, liver, and kidney structures. Looking at the brain, the toxicity of Al affects biological reactions such as axonal transport, neurotransmitter synthesis, synaptic transmission, and protein degradation.39 In the present study, degeneration of neurons and neurofibrillary tangles were observed in the brain tissue of mice in Al group. A link between Al and the appearance of neurofibrillary degeneration and of neurofibrillary tangle-like structures in the brain has been established previously.40,41 Neurofibrillary tangles are formed in the cytoplasmic regions where Al accumulates amongst aggregates of hyperphosphorylated tau.42 These abnormalities diminished in occurrence and became rare on mice pretreated with CA and L. brevis BIOTECH 1766. Moreover, our study demonstrated granulovacuolar degeneration and necrosis in the brain of mice in Al group, as a response to the oxidative stress induced by Al.42 Except for the control group, infrequent shrinkage of the cytoplasm and darkening of neurons were likewise observed. These have been reported before in the brain of rats intoxicated with AlCl3 .30 In the CA and L. brevis BIOTECH 1766 groups, basophilic or dark neurons, and white matter vacuolation were observed. However, these alterations are common artefactual findings in the rodent brain, especially in non-perfused tissues related to the prolonged fixation process.43 Hence, it is imperative to determine if Al poisoning is related to these changes in future research. Liver toxicity is also a manifestation of excessive Al exposure. It was reported that Al causes liver dysfunction due to mitochondrial oxidative damage. Specifically, AlCl3 exposure causes hepatocellular destruction and necrosis.44 In our histopathological finding, occasional necrosis of hepatocytes, chromatin condensation, and loss of intact liver plates were observed in the liver tissues of mice in Al group. These observations concurred with studies on the hepatotoxicity of Al.16,45 Results of CA pretreatment reduced chromatin condensation and hepatic necrosis, while L. brevis BIOTECH 1766 pretreatment prevented the loss of intact liver plates and necrosis of hepatocytes. Lastly, the kidneys are also vulnerable to Al-mediated toxicity. This is due to the fact that the primary route of elimination for Al is through urine, thus kidneys are exposed to Al in the normal process of renal excretion. Diffused tubular necrosis and the loss of intact glomeruli and tubules in the Al group of our study were identified which were in line with previous Al toxicity reports.46,47 Interference in glomerular hemodynamics might have occurred that resulted in the morphological changes.48 The CA and L. brevis BIOTECH 1766 groups revealed no apparent renal histopathological changes, similar to the normal histological architecture of the control. Although the present study did not evaluate the effects of L. brevis BIOTECH 1766 on the inflammatory response, prior studies involving different L. brevis strains concluded that the reduction of pro-inflammatory factors helped in alleviating pathological changes,14,49 and this mechanism can be investigated in future studies involving the BIOTECH 1766 strain.

CONCLUSION

The present study revealed that pretreatment of L. brevis BIOTECH 1766 in mice offered protection against Al poisoning by attenuating oxidative stress, specifically improving the activities of CAT in the liver and SOD in all three organs. Extensive histopathological injuries were likewise prevented by the microbial strain. Given this knowledge, L. brevis BIOTECH 1766 can be considered a potential agent in preventing Al-induced damage in the brain, liver, and kidneys. This work also calls for further studies on other protective mechanisms of L. brevis BIOTECH 1766 against Al poisoning.

Statement of Authorship

All authors certified fulfillment of ICMJE authorship criteria.

Author Disclosure

All authors declared no conflicts of interest.

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