Impact of microplastics on the human digestive system: From basic to clinical

Abstract

As a new type of pollutant, the harm caused by microplastics (MPs) to organisms has been the research focus. Recently, the proportion of MPs ingested through the digestive tract has gradually increased with the popularity of fast-food products, such as takeout. The damage to the digestive system has attracted increasing attention. We reviewed the literature regarding toxicity of MPs and observed that they have different effects on multiple organs of the digestive system. The mechanism may be related to the toxic effects of MPs themselves, interactions with various substances in the biological body, and participation in various signaling pathways to induce adverse reactions as a carrier of toxins to increase the time and amount of body absorption. Based on the toxicity mechanism of MPs, we propose specific suggestions to provide a theoretical reference for the government and relevant departments.

Key Words: Microplastics; Digestive system; Oxidative stress; Metabolism; Toxicity

Core Tip: This paper is a review of the damage caused by microplastics (MPs) to human digestive system organs and the related mechanisms. As an emerging pollutant, MPs have caused irreversible damage to the environment and human body. This paper analyzes and summarizes the mechanism of action of MPs on human digestive organs, and puts forward suggestions for relevant departments to reduce MPs pollution.

INTRODUCTION

Microplastics (MPs), or pieces of plastic smaller than 5 mm, were a concept first introduced by Thompson et al[1] of the University of Plymouth, United Kingdom, in the journal of Science in 2004. As a result of human activities, such as the use of cleaning products, cosmetics and medical supplies, a large amount of plastic waste is generated[2]. Most of them have not been properly disposed of but are left to become MPs, which are mainly divided into two categories: Primary MPs and secondary MPs; the former mainly refers to the plastic particles industrial products discharged into the water environment through rivers and sewage treatment plants[3], the latter refers to the plastic particles caused by physical, chemical and biological processes of large plastic waste such as ultraviolet radiation and mechanical degradation[4-6]. MPs are ubiquitous in the environment and are often deposited in the ocean[7,8], soil[9] and freshwater systems[10] in their natural state. They damage the natural environment and make it difficult for humans active in ecosystems to escape their harm[11]. Global demand for plastics continues to grow because of their stability, durability and versatility[12]. More than 6.3 billion tons of plastic waste were produced globally in 2017[13], and a few studies have pointed out that 12 billion tons of plastic waste may be produced by 2050[13]. Human beings have to ingest approximately 39000-52000 MPs every year[14], and 20 MPs in every 10 g of feces of a normal adult[15]. Recently, MPs have been reported in the blood of human[16], which indicates that MPs have been inextricably linked with human life.

MPs enter the human body mainly through the digestive[15], respiratory system[17] and skin systems[18]. Among them, the pathways to enter the digestive system are more diverse, including various media, such as food, air, and drinking water[19]. Natural foods containing high levels of MPs are primarily seafood[20]. A survey of European food-grade sea salt showed a median MP content of 466 MPs/kg with a mean mass estimate of 4.51 ± 6.74 μg/kg[21]. Air and drinking water are also important ways for humans to ingest MPs, we ingest 4400-5800 MPs per year from tap water[12,22]. With the popularity of takeout in recent years and the widespread use of plastic packaging boxes, the MP content in the human body has significantly increased[23]. Schwabl et al[15] first discovered the presence of MPs in human feces in 2019, suggesting that MPs may accumulate in the human digestive system and pose a health threat. Nowadays, their impact on the digestive system is a growing concern. Starting at the upper end of the digestive system, MPs alter the microbiota in the mouth[23], which may induce dental caries, periodontitis, bad breath and other oral problems. They then enter the esophagus, destroy the esophageal epithelial barrier and are associated with eosinophilic esophagitis[24]. MPs affect the distribution of gastrointestinal flora and the absorption of nutrients[25] while affecting the function of the liver and pancreas, including lipid[26] and blood sugar metabolism[27].

As an important system to ensure the normal progress of human metabolism, the digestive system is one of the most important ways to ingest MPs[28], which is greatly affected by them[29]. However, current research on the impact of MPs on the digestive system mostly focuses on discussing individual organs, and lacks a systematic and comprehensive argumentation of the digestive system. This review summarizes the role of MPs in the entire digestive system from a macro perspective.

OVERVIEW OF MPS

Although there is no clear definition of the upper and lower limits of the MP size in actual research, the most commonly used is the 2008 definition by the National Oceanic and Atmospheric Administration, which states that plastic particles do not exceed 5 mm[30]. Surveys have shown serious MP pollution in soil[31]. The concentration of MPs in agricultural soil in China is 42960 MPs/kg, while the concentration of MPs in coastal sediments in India is as high as 73100 MPs/kg[32]. Researchers have confirmed that MPs can change soil properties and affect microorganisms and plant growth[33]. For example, MPs are genotoxic and cytotoxic to crops such as broad beans and onions[34], which may be related to their tendency to attach to plant roots and damage the corresponding cell structures[35]. The health of animals that consuming foods containing MPs is also at risk. Animals involved in soil decomposition such as earthworms and nematodes directly ingest MPs through their activities, causing metabolic disorders[36], genetic damage[37], neurotoxicity[38] and other adverse effects. In addition, chickens consuming plants containing MPs are associated with increased cardiotoxicity[39]. For rodents such as mice, studies have reported that MPs can cause great harm to their digestive systems, causing intestinal dysfunction, intestinal flora disorder, and even affecting the liver’s clearance function[40,41]. Moreover, MPs flow into the marine ecosystem[42,43]. Therefore, it is not surprising that MPs have been detected in corals and phytoplankton in the ocean[44]. Smaller shrimps may be more susceptible to their effects because they ingest food that is similar in size to MPs[45]. Commercial fish and crustaceans eat these organisms containing MPs, leading to further accumulation. Undoubtedly, it is difficult for humans at the top of the food chain to escape adverse effects[46,47]. Various studies have shown that they can accumulate and cause damage to the human gastrointestinal tract[28], liver[48], pancreas[49] and other organs.

Various studies have shown that MPs are unfavorable to organisms; they can affect the function of thrombin and the aggregation of platelets through the combination of coagulation factors and promote thrombosis formation[50]. They can affect digestive function by damaging gastrointestinal epithelial cells, adsorbing toxic substances and destroying the ecological balance of digestive tract microorganisms[51]. They can promote the inflammatory response in hepatocytes and the formation of liver fibrosis through the activation of signaling pathways such as the reactive oxygen species (ROS)/transforming growth factor-β (TGF-β)/Smad2/3 signaling axis[52], cGAS/STING pathway[48] and Wnt/β-catenin pathway[53].

OVERVIEW OF DIGESTIVE SYSTEM

As one of the eight major systems of the human body, the digestive system performs physiological functions, such as intake, transport, digestion of food, absorption of nutrients and excretion of waste. At the same time, digestive system diseases have a high incidence, high recurrence rate and high mortality status, which cause huge economic burdens to society and individuals[54]. With the development of society, more new pollutants have gradually entered human life and been ingested by the digestive system, causing various diseases, such as gastritis, peptic ulcers, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), pancreatitis and metabolic disorders. In the digestive system, there are various causes and pathogenesis of diseases. For example, gastrointestinal diseases are mostly caused by pollutants that damage mucosal cells and destroy the defensive barriers. The flora is disordered, the intestinal microecology is destroyed[55], the absorption of nutrients and immune defense is reduced[56] and the regulation of the brain-gut axis[57] is broken. Activation of the inflammatory pathway increases the secretion of inflammatory factors such as interleukin-1 (IL-1), IL-6, and IL-8, which can induce an imbalance of inflammatory factors/anti-inflammatory factors, persistent intestinal inflammation and barrier function impairment[58]. Another important disease, NAFLD, is caused by insulin resistance[59], inflammation and necrosis of hepatocytes, endoplasmic reticulum (ER) stress[60], liver fibrosis, intestinal flora disorders and other factors[61]. To a certain extent, MPs can induce these factors. They are mainly transported and absorbed in the gastrointestinal tract through the lymphatic follicles of the ileum into the digestive system, and harm to the human body is mainly divided into three parts: Inducing apoptosis of normal human cells or regulating gene expression through various signaling pathways[49,62], as a carrier of toxic chemicals such as di(2-ethylhexyl) phthalate (DEHP), polychlorinated biphenyls and polycyclic aromatic hydrocarbons[63], and as a foreign body to stimulate the body and induce oxidative stress reactions to destroy normal cells[64]. Even at non-cytotoxic concentrations, it can cause elevated levels of IL-6, tumor necrosis factor, and malondialdehyde, leading to adverse reactions[65], which requires further exploration.

IMPACT OF MPS ON VARIOUS DIGESTIVE ORGANS

Oral

The mouth is usually the first stop point for MPs to enter the digestive system. The daily intake of MPs for average Chinese residents can reach 0.14 items/kg bw/day[66]. Therefore, the effect of MPs on the oral cavity cannot be ignored. MPs have been observed to damage the oral cavity by altering the composition of oral microorganisms[23] and destroying the oral mucosa (Figure 1). Microorganisms in the oral cavity colonize rapidly a few hours after birth[67]. As the second largest microbiota after the intestinal flora, they are mainly composed of bacteria, such as Salivary Streptococcus, Lactobacillus and Staphylococcus, which are closely associated with oral acid-base balance, inflammation and other health problems[68]. Studies have reported differences in the oral microbial composition between occasional, frequent MP exposure and no MP exposure, and they observed a higher probability of cough and pharyngitis in the former than the latter[23]. For example, in the group with frequent exposure to MPs, Oribacterium levels were positively correlated with MPs[23], and they were strongly associated with chronic obstructive pulmonary disease (COPD)[69] and predisposed to cough and pharyngitis. In addition, MPs in the oral cavity can induce oxidative stress, leading to an imbalance in the antioxidant defense system and promoting the progression of chronic inflammation[70,71]. The increase in inflammatory factors can promote damage to the oral mucosa and increase its permeability, which in turn increases the absorption of pollutants such as MPs by the oral mucosa, creating a vicious cycle.

Figure 1 Mechanism of the damage from microplastics to oral cavity. Microplastics induce oxidative stress, which triggers an inflammatory response, releasing inflammatory factors that damage the oral mucosa and increase microplastics absorption; and change the oral flora species and cause health problems. MPs: Microplastics; TNF: Tumor necrosis factor; IL: Interleukin.

Esophagus

The concentration of MPs in the esophagus may be lower than that in the gastrointestinal tract, possibly because of the peristaltic movement of the esophagus and its smaller surface area[72]. However, the effects of MPs on the esophagus are undeniable, mainly by destroying the epithelial structure of the esophagus[24], altering the species and concentration of original bacteria in the esophagus, carrying toxic substances, and affecting the function of the brain-gut axis[73]. They can even cause eosinophilic esophagitis[67], esophageal cancer[74] and other diseases.

Gastrointestinal

The role of the gastrointestinal tract is varied. In addition to being an important organ for absorbing nutrients, it is an important immune defense barrier in the body[75]. Ibrahim et al[76] reported MPs in colon sections of 11 patients with colorectal cancer after resection, confirming that ingested MPs can remain in the digestive tract. Studies have shown that these particles accumulate over time[62] and that ingestion of MPs can damage the gastrointestinal tract, affecting their normal function[28,51]. Microorganisms in the gastrointestinal tract play an important role in nutrient absorption[77], metabolism[78] and immune defense[79]. Therefore, disrupting the balance between the gastrointestinal flora and the organism will inevitably negatively impact the gastrointestinal tract and the whole organism. Mice fed high concentrations of MPs showed a decrease in the abundance of Parabacteroides and an increase in the abundance of Staphylococcus in the gastrointestinal tract microbiota of mice[58]. Previous studies have reported that patients with ulcerative colitis and irritable bowel syndrome have reduced Parabacteroides simulants in their gut microbiota compared to healthy individuals[80]. Collado et al[81] observed that Staphylococcus overgrowth is related to inflammatory bowel disease, which may be associated with inflammation induced by Staphylococcus superantigens. Therefore, MP-induced changes in Parabacteroides and Staphylococcus have been hypothesized to contribute to intestinal inflammatory diseases[58]. MPs may be associated with intestinal inflammation and related diseases. The altered composition of the flora and dysfunctional ecological balance may be related to various factors (Figure 2). First, the expression of superoxide dismutase (SOD), catalase- and nuclear factor erythroid 2-related factor-signaling pathway-related genes was enhanced in the presence of MPs, which in turn induced an oxidative stress response[82]. The abundance of Actinomycetes and Proteobacteria increased in the oxidized state environment owing to environmental selectivity[83]. Second, MPs stimulate the body’s immune system and induce an inflammatory response of the immune system[84]. In an inflammatory environment, peroxides and nitrogenous substances in the host intestine can produce peroxynitrite, which can be rapidly converted into nitrate[85,86]. Enterobacteriaceae, which may contain enzymes that break down nitrate, proliferate massively in an inflammatory environment[87]. Ultimately, the intestinal microbial balance was disrupted. Third, MPs are difficult to absorb and utilize as inorganic substances, while they can occupy the gastrointestinal space, resulting in reduced nutrient absorption by the body[88], and the normal function of symbiotic flora is also compromised due to the lack of nutrition[89]. Fourth, MPs can act as a carriers of harmful substances owing to their large specific surface area, carrying toxins into the gastrointestinal tract and affecting the microbial composition[90]. Lastly MPs, can abrade the digestive tract and cause mechanical damage as foreign bodies[91], and the growth of bacteria is inevitably affected by the environment in which they survive. The effect of MPs on the gastrointestinal flora should not be underestimated, and its effect on gastrointestinal function should not be ignored.

Figure 2 How microplastics do harm to gastrointestine. Microplastics alter the gastrointestinal flora species and cause dysbiosis by changing the environment; reduce nutrient absorption and affect the growth of commensal flora; induce oxidative stress-mediated apoptosis of epithelial cells and increase permeability; act as a carrier to carry pathogens and plasticizers; and cause mechanical damage to the gastrointestinal tract. MPs: Microplastics; ROS: Reactive oxygen species; SOD: Superoxide dismutase; Nrf: Nuclear factor erythroid 2-related factor.

In addition to their effects on microorganisms in the gastrointestinal tract, MPs can act directly on the gastrointestinal tract. MPs induce oxidative stress to generate large amounts of ROS, mediating apoptosis in epithelial cells[62]. As the first line of defense of the immune system, apoptosis of the epithelial cells of the gastrointestinal mucosa leads to increased permeability, and large proteins and bacteria are free to pass through the intestinal tract, which may result in serious infectious conditions[92]. MPs, owing to their large specific surface area, can easily serve as a carriers to transport pathogens such as bacteria and toxic substances such as plasticizers, into the tract, causing intestinal inflammatory and structural damage[90,93,94]. Increased permeability of the gastrointestinal tract and elevated intestinal absorption of MPs, cause a vicious cycle.

Liver

The liver is the largest glandular and parenchymal organ and the most metabolically active organ in the body[95]. As an emerging pollutant, MPs have been reported to accumulate in organisms, particularly in the digestive system. MPs have been observed in liver samples from patients with cirrhosis; however, the exact mechanism is unclear[96]. Another study on MPs in mice tracked the accumulation and distribution of MPs in the liver, intestine, and kidney, and observed that MPs are hepatotoxic, affecting hepatic metabolism and posing a potential risk to mammalian health[70]. MPs have been observed to accumulate in the gills, liver, and intestine of zebrafish, and they can adversely affect the liver by inducing oxidative stress and disrupting lipid and energy metabolism in the liver[97]. These experimental results support that MPs can accumulate in organisms and cause damage, strengthening the detrimental consequences on these organs observed in the in vitro experiments. In a model simulating human exposure to MPs, MPs were reported to accumulate in the liver[98], suggesting that MPs may have an effect on it. We observed that MPs may damage the liver in various ways such as causing hepatocyte damage[99], affecting lipid metabolism processes[26], and even advancing the progression of liver fibrosis[48] through consulting literature.

Hepatocyte damage by MPs manifests in several ways. First, when liver organoids (LOs) were cultured in a polystyrene MP (PS-MP) environment, the number of apoptotic hepatocytes and the diameters of LOs were dose-dependent with PS-MP[100] (the number of apoptotic cells was positively correlated with PS-MP dose, while the diameters of LOs were negatively correlated with PS-MP dose). In addition, study has reported that in a PS-MP environment, the release of aspartate aminotransferase and alanine aminotransferase increases, but their activity decreases, suggesting that PS-MP may induce acute liver injury[100]. This may be related to various mechanisms such as hepatocyte toxicity and oxidative stress caused by MPs. MPs can induce a decrease in the activity of glutathione S-transferase and glutathione and the content of SOD, leading to an antioxidant imbalance and the generation of a large number of ROS[101], which can cause damage to cellular structures such as proteins and DNA.

The liver is the hub of fat transport and participates in the regulation of fat metabolism. NAFLD is a clinicopathological syndrome characterized by excessive fat deposition in hepatocytes caused by alcohol and other liver damage factors. Changes in various markers of UDP-glycosyltransferase and sulfotransferase in patients with NAFLD are consistent with LOs cultured in a PS-MP environment, which means that PS-MP may be involved in inducing lipid metabolism disorders[100,102,103]. We observed that the effect of MPs on lipid metabolism in the liver was related to several mechanisms (Figure 3). PS-MP has been reported to increase lipid accumulation in the liver and may act as a carrier to carry fatty acids while endocytosing into the organ and promoting hepatic steatosis[100,104]. At the same time, studies have observed that in a PS-MP environment, the expression of cytochrome P4502E1 in the liver is upregulated, which is considered the main catalyst promoting hepatic steatosis owing to its ability to promote lipid peroxidation[105]. The peroxisome proliferator-activated receptor (PPAR) is closely related to hepatic lipid metabolism, in which PPARα and PPARγ are involved in the consumption of free fatty acids and the uptake and storage of lipids[106,107]. The process of lipid metabolism is impeded by the downregulation of PPAR expression[108] and inhibition of both PPARα and PPARγ[100] in the presence of MPs. In addition, metabolic processes often require the consumption of adenosine triphosphate, while PS-MP can accumulate in mitochondria[109], induce mitochondrial autophagy through the adenosine5’-monophosphate-activated protein kinase/UNC-51-like kinase pathway, inhibit mitochondrial function[100], affect energy supply and inhibit liver metabolic activities.

Figure 3 Mechanism of how microplastics influence lipid metabolism in liver. Microplastics up-regulate the expression of cytochrome P4502E1 and promote lipid peroxidation; down-regulate the expression of peroxisome proliferator-activated receptor and affect lipid metabolism; induce mitochondrial autophagy through the adenosine5’-monophosphate-activated protein kinase/UNC-51-like kinase pathway and affect energy supply; and carry fatty acids into the liver. MPs: Microplastics; CYP2E1: Cytochrome P4502E1; PPAR: Peroxisome proliferator-activated receptor; LPO: Lipid peroxides; AMPK: Adenosine5’-monophosphate-activated protein kinase; ULK1: UNC-51-like kinase; FA: Fatty acid; ATP: Adenosine triphosphate.

As mentioned before the livers of patients with cirrhosis and other chronic liver diseases accumulated more MPs than those of healthy individuals[96] (Figure 4). The progression of hepatic fibrosis may be related to the enhancement of TGF-β and fibronectin as well as the expression of the Wnt/β-catenin and cGAS/STING pathways by MPs in rats[48,110-112]. However, it has not been fully determined whether the accumulation of MPs in the liver of patients with cirrhosis is a cause or consequence. Cirrhosis causes portal hypertension, which in turn leads to damage to the intestinal mucosal barrier[96], and MPs can pass through the intestinal wall into the liver to accumulate there. Overall, the harm caused by MPs to the liver can be summarized as hepatocyte toxicity, influence on liver metabolism, disruption of mitochondrial function, and oxidative stress.

Figure 4 How microplastics act in the liver fibrosis. Microplastics enhance the expression of transforming growth factor-β and fibronectin, as well as the Wnt/β-catenin pathway and the cGAS/STING pathway to promote the progression of hepatic fibrosis; cirrhotic complications disrupt the intestinal barrier and increase the absorption of microplastics. MPs: Microplastics; TGF: Transforming growth factor.

Pancreas

Studies have shown that exposure to MPs increases sugar levels in the blood[27]. The pancreas is an important organ for regulating blood sugar; therefore, we speculate that MPs may have certain effect on the pancreas. MPs were observed to accumulate and cause damage to the pancreas of mice that received MPs orally, accompanied by elevated blood glucose levels[27]. Ducks, such as waterfowl, are at a higher risk of exposure to MPs, which induce inflammation and fibrosis in the pancreas[113]. After reviewing the literature, we have summarized the mechanism of damage to the pancreas by MPs. First, as a type of nanoscale particle, the accumulation of MPs in organs can induce oxidative stress and generate large amounts of ROS[114], which cause direct oxidative damage to pancreatic cells. When exposed to 1 mg/L of MPs, the normal structure of pancreatic tissue disappeared and areas of acinar degeneration necrosis appeared[115]. Second, ROS can cause insulin resistance by interfering with the phosphatidylinositol 3-kinase/protein kinase B pathway, leading to elevated blood glucose[27,116]. Lastly, MPs can activate the gluconeogenic enzyme gene pck1, which reduces the expression domains of insulin-related genes, decreasing insulin levels and increasing blood sugar[117]. MPs can produce synergistic effects, which include promoting ER oxidative stress in pancreatic cells, activating the glucose-regulating protein 78 (GRP78)/C/EBP homologous protein (CHOP)/Bcl-2 pathway, enhancing the expression of mitochondrial apoptosis-related genes such as Bax, caspase3, caspase9 and inducing apoptosis in pancreatic cells (Figure 5)[49]. In addition, because of the large specific surface area of MPs, it is easy to absorb hazardous substances such as DEHP, which is used as a plasticizer of polyvinyl chloride[118]. Pancreatic β-cells are important for insulin secretion, and their DNA can be destroyed by DEHP[119], resulting in impaired function and glucose metabolism[120].

Figure 5 Mechanism of the damage from microplastics to pancreatic cells. Microplastics induce oxidative stress causing oxidative damage; adsorb di(2-ethylhexyl) phthalate and act synergistically with it to promote oxidative stress in pancreatic intracellular endoplasmic reticulum and induce apoptosis in pancreatic cells; di(2-ethylhexyl) phthalate damage pancreatic β-cells’ DNA and reduce insulin secretion. MPs: Microplastics; ROS: Reactive oxygen species; DEHP: Di(2-ethylhexyl) phthalate.

DIFFERENT SIGNALING PATHWAYS OF MPS ACTING IN THE DIGESTIVE SYSTEM

cGAS/STING pathway

Liver fibrosis refers to the process of hyperplasia and repair of connective tissue caused by various pathogenic factors. If the injury factors persist for a long time, fibrosis will develop into cirrhosis. As an important signaling pathway that can regulate the inflammatory response by controlling the secretion of pro-inflammatory cytokines from cells, the inflammatory repair process is closely related to the cGAS-STING pathway[121]. Figure 6 shows that MPs can penetrate the lipid layer of the cell membrane[122], weaken the barrier effect, facilitate MPs to enter the cell to induce oxidative stress and produce a large amount of ROS[101]. ROS can damage DNA in the nucleus and induce mitochondrial autophagy through the adenosine5’-monophosphate-activated protein kinase/UNC-51-like kinase pathway[100,111], and the damaged DNA fragments enter the cytoplasm. The double-stranded DNA (dsDNA) sensor cGAS interacts with cytoplasmic free dsDNA to catalyze guanosine triphosphate and adenosine triphosphate to form a secondary messenger 2’,3’-cyclic GMP-AMP. Cyclic GMP-AMP binds to the ER receptor protein STING homologous diploid to activate the downstream pathway, and at the same time, the expression of transcription factors interferon regulatory factor 3 and phosphorylated nuclear factor-kappaB increased[48,121,123]. As a transcriptional regulator, nuclear factor-kappaB can amplify the role of cGAS/STING signaling and enhance the inflammatory response[121]. MPs can damage the DNA structure by inducing oxidative stress, and then the free dsDNA activates the cGAS-STING pathway to promote the inflammatory process and liver fibrosis.

Figure 6 The role that microplastics play in the cGAS/STING pathway. Microplastics induce oxidative stress, produce a large number of reactive oxygen species, damage DNA in the nucleus, and induce mitochondrial autopahgy. Damaged DNA enters the cytoplasm and interacts with double-stranded DNA sensor cGAS to catalyse guanosine triphosphate and adenosine triphosphate to form cyclic GMP-AMP. Cyclic GMP-AMP binds to STING homomeric diplosomes to activate downstream pathway and induce increased expression of transcription factors interferon regulatory factor 3 and phosphorylated nuclear factor-kappaB. Phosphorylated nuclear factor-kappaB, in turn, amplifies the action of the cGAS/STING signal. MPs: Microplastics; ROS: Reactive oxygen species; AMPK: Adenosine5’-monophosphate-activated protein kinase; ULK1: UNC-51-like kinase; IRF3: Interferon regulatory factor 3; p-NFκB: Phosphorylated nuclear factor-kappaB; cGAMP: Cyclic GMP-AMP; ATP: Adenosine triphosphate; GTP: Guanosine triphosphate.

Wnt/β-catenin pathway

Organ tissue damage often leads to repair, that is, fibrosis processes such as liver fibrosis and myocardial fibrosis. Many studies have shown that fibroblast activation and proliferation are related to the Wnt pathway[124]. As a classic Wnt pathway, it is closely related to the inflammatory process of organ and tissue injury and repair[110,111]. Studies have shown that absorbed MPs accumulate easily in the digestive system[11]. MPs induce oxidative stress, producing a large amount of ROS[125], which can cause cell and tissue damage[126]. Oxidative stress can activate the Wnt signaling pathway[127], and experiments have shown that the expression of Wnt, β-catenin, TGF-β and fibronectin in the pathway increases with enhancement of the oxidative stress response[110,111]. Therefore, we believe that MPs can activate the Wnt/β-catenin pathway by inducing oxidative stress and thus promoting fibrosis.

GRP78/CHOP/Bcl-2 pathway

As plasticizers of polyvinyl chloride, DEHP and MPs often occur together harm organisms. The toxicity of DEHP combined with MPs is higher than that of DEHP or MPs alone[49]. DEHP and MPs can reduce SOD activity and glutathione content in pancreatic cells, leading to an imbalance in the oxidation and antioxidant systems, inducing oxidative stress and producing a large amount of ROS[49]. Acetylcysteine, vascular endothelial growth factor A, curcumin and other substances can cause ER stress via ROS[128-130]. As Figure 7 shown, GRP78, a highly conserved chaperone, is mainly located in the ER and combines with inositol-requiring enzyme 1, PKR-like ER kinase and activating transcription factor 6 to form a complex, which disintegrates and then becomes activated after ER stress[131,132]. Disintegrated products promote the activation of CHOP protein[133]. At the same time, ER stress itself can stimulate the activation of CHOP protein[133], while aggravating oxidative stress and promoting the accumulation of ROS[134]. Previous studies have shown that the CHOP protein can decrease the expression of the anti-apoptotic gene Bcl-2 and increase the expression of the pro-apoptotic gene Bax[135,136]. This effect increases mitochondrial membrane permeability, releases Cyt-c into the cytoplasm, activates the caspase pathway, and promotes apoptosis[137]. In other words, the combination of MPs and DEHP can activate the GRP78/CHOP/Bcl-2 pathway to promote the apoptosis of pancreatic cells by inducing oxidative stress.

Figure 7 Damage from the combination of microplastics and di(2-ethylhexyl) phthalate to pancreatic cells through glucose-regulating protein 78/C/EBP homologous protein/Bcl-2 pathway. The combination of di(2-ethylhexyl) phthalate and microplastics can induce oxidative stress and produce a large number of reactive oxygen species. Endoplasmic reticulum stress can be caused by various intracellular substances through reactive oxygen species. After stress, complexes formed by glucose-regulating protein 78, inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 on the endoplasmic reticulum can be disintegrated, thus promoting the activation of C/EBP homologous protein. Activation of C/EBP homologous protein can aggravate oxidative stress, but also promote the expression of apoptotic genes and induce apoptosis. MPs: Microplastics; SOD: Superoxide dismutase; DEHP: Di(2-ethylhexyl) phthalate; GSH: Glutathione; ROS: Reactive oxygen species; VEGF-A: Vascular endothelial growth factor A; ER: Endoplasmic reticulum; CHOP: C/EBP homologous protein; GRP78: Glucose-regulating protein 78; ATF6: Activating transcription factor 6; IRE1: Inositol-requiring enzyme 1; PERK: Protein kinase RNA-like ER kinase.

CLINICAL DIAGNOSIS AND TREATMENT

The most fundamental solution for reducing the impact of MPs on human health is to reduce the intake of MPs. However, owing to the good stability of plastics, low production cost, and good plasticity[138], the production of plastics worldwide is still increasing year by year[139]; thus, the resulting plastic waste is increasing. Therefore, there is an urgent need to develop new environment-friendly materials and suitable degradation methods. At the same time, we should minimize the use of products containing MPs, such as eating more fresh fruits and vegetables and reducing the consumption of processed foods. The principles of prevention and treatment of MP-induced digestive system diseases are the same as those of conventional environmental pollution and digestive system diseases. The diagnosis is based mainly on clinical symptoms and various laboratory and imaging diagnostic techniques. Treatment principles mainly include: Removal of etiology, that is, reducing exposure to and intake of MP products; specific site injury targeted administration to control and improve symptoms; and improving lifestyle, such as smoking cessation, alcohol restriction, active exercises, and eating more fresh food, which can prevent recurrence and improve prognosis.

In addition to the accumulation of MPs in the digestive system, they can easily accumulate in the respiratory system[17], inducing inflammation of lung epithelial cells, which secrete a large number of inflammatory factors such as IL-6 and IL-8, leading to COPD, asthma and other lung diseases[65]. Studies have reported that COPD is highly correlated with α(1)-antitrypsin deficiency[140], and experiments have observed that the expression of α(1)-antitrypsin is significantly reduced by MP exposure[65], further confirming the impact of MPs on the respiratory system. In recent years, studies have been conducted on the presence of MPs in the blood[16]. MPs can enter various tissues and cells through the blood and cause adverse effects, as well as play a role in blood vessels. For example, in 2023, Wu et al[141] first detected MPs in thrombosis. Animal experiments have shown that MPs are related to thrombosis, and different group modifications have different effects[142]. For example, amine group modification can promote thrombosis[143], which may be related to the effect of the amine group and the membrane on the surface of platelets, and then platelets can be connected through the “amine group - MPs” chain[144]. Carboxyl group modified MPs did not promote thrombosis in this study[142]. In addition to causing system-specific effects, small MPs can enter cells through the blood and induce apoptosis and oxidative stress[63,145], which can lead to DNA fragmentation and the production of a large number of ROS, respectively, which may be associated with the cancer development[146]. However, there are currently few studies of MPs in specific cancers at various sites, and we expect that this can be further explored in the future to discover more intrinsic mechanisms and help scientists understand the production of disease.

FUTURE EXPECTATION

To better investigate the mechanism of MPs injury to the human digestive system, we should explore more appropriate monitoring methods. For example, we can try to label MPs, observe and record the process of MPs entering the human body through the food chain, and extract parts of the body fluids to understand the distribution of MPs in the human body[19]. Developing and improving existing in vitro simulated organs simulating real-life environments where MPs are exposed and analyzing the physiological process of accumulation and damage in organs[100]. Clarify the toxicity of MPs by identifying their effects on organisms and the compounds to which they are bound[147].

We observed that MPs are a double-edged swords for organisms. The toxic effect of MPs is size-dependent; the smaller the particles, the more toxic they are to organisms[148]. This may be due to the stronger reaction between small-sized MPs and antioxidant enzymes[148], as well as the increased accumulation of organic pollutants, heavy metals and microorganisms in the body[149]. Conversely, larger MPs can act as carriers, carrying harmful substances out of the body and reducing the amount of time they remain in the body[150,151]. In addition, we observed that exposure to MPs alone leads to intestinal damage, but co-exposure to certain antibiotics (e.g., chlortetracycline) reduces intestinal damage by altering the intestinal microbiota[150]. Shang et al[148] reported that the effect of MPs on organisms is biphasic in dose (both low and high concentrations of MPs are less harmful to the organism), and the specific mechanism needs to be further studied. These findings provide new insights for reducing the harmful effects of MPs on the human body.

Minimizing the harm caused by MPs is an important topic that needs to be solved urgently. First, given the size-dependent toxicity of MPs[148,150], we can consider using materials to aggregate MPs; as a result, they are no longer “micro” and the harm caused by the oxidative stress induced by MPs can be reduced. At the same time, large particles can be used as carriers to carry toxic substances (e.g., heavy metals, organic pollutants, and harmful microorganisms) out of the body, reduce their residence time in the gastrointestinal tract[151,152], and minimize hazards to the human body. Second, reasonable and feasible ways to degrade MPs, such as using earthworms to degrade them and the soil environment can be improved after they digest MPs and convert them into organic matter[153]. However, considering the decomposition efficiency and treatment cost issues, it is currently challenging to implement[154], but biodegradation is one area that warrants further exploration, as it is more environmentally friendly and sustainable. Exploring the mechanism of MPs injury and reducing the harm of MPs to human beings requires a lot of time and effort; therefore, it is more half-hearted to solve the problem at the source. Governments in various countries (regions) have begun to gradually improve the relevant laws and regulations on restricting MPs to reduce the reckless discharge of MPs into the natural environment. As early as 2015, the United States passed a law prohibiting the use of microbeads[155]. The European Commission adopted a regulations on September 25, 2023, further amending the restrictions on MPs under the Registration, Evaluation, Authorization, and Restriction of Chemicals Finding new materials that can replace MPs is a topic that deserves our attention, as new environmentally friendly materials can avoid the harmful effects of MPs on the human body. Finally, from each person, we can eat more fresh food and minimize the consumption of take-out and other fast-food products to reduce the intake of MPs[156]. In addition, canvas bags can be used instead of plastic bags to live a green and low-carbon life.

CONCLUSION

The harmful effects of MPs have been discussed since their discovery in recent years. Although there is a lack of specific mechanisms for the toxic effects of MPs on the human body for ethical reasons, we can conclude that MPs are harmful to the digestive system based on various experiments on marine organisms and mice. In summary, these include damaging the epithelial barrier of the digestive tract, disturbing the ecological balance of the bacterial flora, damaging parenchymal organs such as the liver and pancreas, affecting their normal functioning, and acting as a carrier for toxins to enter the human body, exerting a poisonous effect.