INTRODUCTION:

Hunger and malnutrition are still a global problem. The World Food Program (WFP) reports that there will be an increase of more than twofold by 2023. This increase will reach 200 million people compared to before the COVID-19 infection outbreak. Based on the 2022 report of The State of Food Security and Nutrition in the World (SOFI), the number of people affected by hunger increased by 828 million in 2021 and 150 million since the COVID-19 pandemic¹.

A diet affects growth, the amount and nutritional value of food consumed, and a poor diet leads to malnutrition². In addition, malnutrition is also caused by hunger due to an imbalance of nutrients in the body³. Malnutrition manifests in four ways: wasting, stunting, underweight, and micronutrient deficiencies⁴. This state of malnutrition damages the small intestine tissue through oxidative stress⁵.

Starvation and malnutrition have been documented to cause alteration in the gut mucosa. This alteration includes mucosal atrophy, reflected as a decrease in villi height and the number of goblet cells⁶. Additionally, malnutrition can disrupt the balance of gut microorganisms, leading to alterations in gut microbiota composition and function⁷. Changes in the microbiota can contribute to inflammation, intestinal barrier dysfunction, and further damage to the villi. A decrease in goblet cells caused by malnutrition can cause infection with high morbidity and mortality⁸. Tumor Necrosis Factor-alpha (TNF-α) isinflammatory cytokine macrophages produce during the inflammatory process.

Protein is a significant food substance that contains nitrogen as an important factor for body functions such as maintaining or repairing damaged tissue⁹. Albumin is a protein produced by the liver and plays a critical role in maintaining plasma oncotic pressure and transporting various substances in the bloodstream. Providing the body with additional albumin can support protein synthesis and assist in tissue repair, including the regeneration of the intestinal lining. Channa striata extract has a higher protein content than other fish types¹⁰. Channa striata is a freshwater fish common in tropical countries like Indonesia. It contains amino acids (AAs) needed for albumin synthesis (such as lysine, arginine, and glutamic acid) and wound healing (such as aspartic acid) and has anti-inflammatory properties (such as arachidonic acid) that promote collagen formation and wound epithelialization¹¹.

Administration of Channa striata extract orally was expected to restore intestinal mucosa damage in a malnutrition state that will cause decreased inflammatory process. This study aims to observe the effect of Channa striata extract administration on villi height, number of goblet cells, and TNF-α expression in the small intestine mucosa of starving mice.

MATERIAL AND METHODS:

Research design:

The type of research is laboratory experimental research which uses models of starving mice as subjects. Twenty-four starved mice were divided into 3 groups: starved mice, starved mice with standard food, and starved mice with standard food supplemented with Channa striata extract.

Research protocol:

Starving mice models were made by giving low-protein diet for 10 days, mice were sacrificed on the 11th-day Standard food group was given low-protein diet for 10 days then given standard food on the 11th day for 5 days and sacrificed on the 16th day. The treatment group was given low-protein diet protein for 10 days then given standard food and Channa striata extract dose 30 ml/kg body weight on the 11th day for 5 days and sacrificed on the 16th day. This research has been approved by Health Research Ethical Clearance Commission Faculty of Dental Medicine Universitas Airlangga number 757/HRECC.FODM/XII/2019.

Tissue processing techniques:

At the end of the research, all mice were sacrificed, and 5 pieces of intestine were collected at a 3-5mm distance. After fixation in formalin, the tissue was processed with dehydration, clearing, and embedding to make paraffin blocks.

Staining procedure:

Paraffin blocks were sliced 5 mm thickness using a microtome, then stained with hematoxylin-eosin to evaluate villi length and goblet cell number. The immunohistochemistry technique was performed with mouse anti-TNF-α antibody cat number BZ-087661D-AM to evaluate TNF-α expression.

Villi height assessment and number of Goblet cells evaluation:

Assessment of villi height was made by measuring villi from the apical region to the basal region of the villi using a grid eyepiece graticule. The measurement unit is a micrometer (μm). Goblet cell count using a grid eyepiece graticule every 100 squares using a light microscope at 3 visual fields with 400x magnification.

RESULT AND DISCUSSION:

Villi height assessment:

The results shows that treatment group has higher villi height than negative control group and positive control group, and the standard group showed almost the same villi height as the treatment group.

Figure 1shows differences in intestinal villi height

Figure 1. The height of the small intestinal villi of mice (A) after being given Channa striata extract for 5 days, (B) when the mice were in a malnourished condition

The results of observations and calculations of the height of the small intestinal villi were found in the treatment group to have higher effects than the negative control group. The condition of the body that is experiencing malnutrition causes the intestinal villi to experience atrophy due to small food intake⁽¹²⁾.The small intestine is lined with tiny finger-like projections called villi, which play a crucial role in nutrient absorption. Villi increase the surface area of the intestinal lining, allowing for efficient absorption of nutrients from digested food.

However, in malnutrition, particularly in cases of severe protein-energy malnutrition or specific nutrient deficiencies, the villi can become damaged and atrophied.Short intestinal villi can decrease intestinal defense and make it easier for pathogens to enter the intestine, which can then cause various diseases¹³. The mechanisms underlying villi atrophy in malnutrition are complex and involve multiple factors. Malnutrition can result in a lack of essential nutrients needed to maintain and repair the intestinal lining, such as proteins, vitamins, and minerals¹⁴. Inadequate nutrient supply can impair the turnover of cells in the intestinal epithelium, leading to villi degeneration and flattening.

Observations in the positive control group had higher results than the negative control group. This is because the intestinal villi have a particular morphology that increases the intestine's surface area and can absorb fluids and nutrients from food. The height of the villi depends on the food that enters the body. The villi will atrophy in a body that lacks food intake, so their size becomes short because little nutrients are absorbed¹³. Intestine villi atrophy in malnutrition can lead to impaired nutrient absorption, decreased digestive enzyme production, and compromised gut barrier function. These changes can exacerbate malnutrition and contribute to a cycle of nutrient deficiency and worsening villi atrophy¹⁵.

It is important to note that the extent of intestine villi atrophy can vary depending on the severity and duration of malnutrition. The villi may not exhibit significant atrophy in acute malnutrition or short-term nutrient deficiencies. However, extensive villi atrophy can occur in chronic and severe malnutrition, which further compromises nutrient absorption and overall health¹⁶. Addressing malnutrition through proper nutrition, including adequate calories, proteins, and essential nutrients, is crucial in preventing and reversing intestine villi atrophy¹⁷. Channa striata contain many vitamins, minerals, proteins, and amino acids the body needs. Protein is essential for tissue growth, maintenance, and repair. In malnutrition, protein deficiency can lead to muscle wasting, impaired immune function, and compromised tissue repair processes. Adequate protein intake is necessary to synthesize new proteins, including those involved in intestinal cell turnover and the maintenance of villi structure. Increasing protein intake through dietary modification or supplementation can provide the necessary building blocks for protein synthesis and support the recovery of villi atrophy. The synergistic role of protein, amino acids, vitamins, and minerals helps accelerate and increase the process of cell regeneration or tissue repair¹⁸.

In addition, the high albumin content in Channa striata functions in repairing intestinal morphology damaged by malnutrition. Albumin plays a role in transporting small molecules that pass-through plasma and cell fluids¹⁹. Albumin is a protein produced by the liver and plays a critical role in maintaining plasma oncotic pressure and transporting various substances in the bloodstream. In cases of severe malnutrition, especially with accompanying hypoalbuminemia (low levels of albumin in the blood), administering albumin intravenously can help restore adequate protein levels and improve overall nutritional status²⁰. Providing the body with additional albumin can support protein synthesis and assist in tissue repair, including the regeneration of the intestinal lining. Improved albumin levels may contribute to restoring normal intestinal function, including recovering villi architecture.

While albumin and protein administration can positively manage malnutrition and potentially support the reversal of intestinal villi atrophy, they should be part of a comprehensive nutritional intervention²¹. The overall nutritional status, including calorie intake, macronutrient balance, and micronutrient adequacy, must be addressed to effectively restore the health of the gastrointestinal tract and promote villi recovery³.

Goblet cell number:

The results showed that the number of goblet cells in the small intestine of mice in the negative control group (starving mice without standard food nor Channa striata extract) was the lowest and the treatment group had the highest yield.

Figure 2 shows that in the treatment group, the cell repairs appeared clearer, characterized by a more robust goblet cell shape, filled with fluid, and a greater number compared to the positive control group (starving mice with standard food).

Figure 2. Description of goblet cells in the intestine of mice (a) normal group (b)negative control group (c) positive control group (d)treatment group

In malnutrition conditions, particularly severe and prolonged cases, there can be a decrease in goblet cells in the intestinal villi. Goblet cells have a function to protect the surface of the small intestine against pathogens and limit the movement or attachment of pathogens. Based on the results, the highest number of goblet cells was found in the treatment group, and this was because an increase in the food supply in the form of protein could affect the distribution of goblet cells. These goblet cells produce a mucus layer that prevents invasion and colonization of pathogenic microbes by forming the gut microbiota²². This aligns with previous studies, which stated that the mucus layer prevents microorganisms from approaching the gastrointestinal epithelial cells and moves continuously to remove waste materials. The mucus can catch pathogenic bacteria²³.

Malnutrition, especially when accompanied by deficiencies in essential nutrients and inadequate dietary intake, can negatively impact the health and function of the gastrointestinal tract. Several factors associated with malnutrition can contribute to decreased goblet cell numbers and processes. Inadequate nutrient supply or malnutrition often results in a lack of essential nutrients, including vitamins, minerals, and proteins. Goblet cell differentiation, mucus production, and the synthesis of mucin proteins can be compromised due to the insufficient availability of these nutrients. This can lead to decreased goblet cell numbers and decreased mucus production²⁴.

Malnutrition can affect the turnover and regeneration of intestinal epithelial cells, including goblet cells. Goblet cells are essential in macrophage signaling for epithelial cell differentiation and maintenance of intestinal homeostasis. Neutrophils have a role as self-defense at the start after the injury occurs, and then this role will be bound by macrophage cells as a second cellular defense. Macrophages are the primary type of phagocytic cells with a longer life duration than neutrophils. Phagocytosis, carried out by macrophages on dead cells, is a way to remove damaged cells. This wound-healing process is associated with macrophage cells and neutrophils. After macrophages are active, apart from having a phagocytic role, macrophages also secrete active ingredients that help repair wounds. The active ingredients include plasma proteins, platelet-activating factors (PAF), chemotactic, cytokines, and growth factors. The high increase in macrophages induces growth factors that increase the number of new cells and the formation of granulation tissue more quickly, so the healing process occurs more quickly²⁵.

Malnutrition can impact the composition and diversity of the gut microbiota. Alterations in the gut microbiota can disrupt the symbiotic relationship between the host and microbiota, influencing goblet cell function. A dysbiotic microbiota may change goblet cell activity and mucus production²⁶. Reduced mucus production and impaired mucosal integrity can make the intestinal epithelium more susceptible to damage, inflammation, and microbial translocation.Addressing malnutrition through appropriate nutrition and nutrient supplementation is essential in restoring goblet cell function and overall intestinal health.

Adequate intake of essential nutrients, including proteins, vitamins, and minerals, can support the regeneration of goblet cells and the production of protective mucus. It's important to note that the extent of goblet cell depletion in malnutrition can vary depending on the severity and duration of the condition²⁷. The individual's nutritional status and accompanying complications will also play a role. Nutritional intervention should be tailored to address the underlying nutrient deficiencies and promote the recovery of goblet cells and intestinal health.

Protein and albumin administration may contribute to the reversal of goblet cell depletion to some extent in malnutrition, but their impact on goblet cells is explicitly not as well-studied compared to their overall role in nutritional support. Protein administration can play a role in replenishing essential amino acids necessary for protein synthesis and tissue repair, including the regeneration of goblet cells. Adequate protein intake supports cellular functions, including producing and maintaining goblet cells²⁰. Providing the necessary building blocks for protein synthesis, protein administration may contribute to the recovery and regeneration of goblet cells.

Albumin administration, on the other hand, primarily aims to address hypoalbuminemia, which is a consequence of severe malnutrition²⁰. While albumin does not directly affect goblet cell depletion, addressing hypoalbuminemia through albumin administration can contribute to overall nutritional improvement, which may positively affect goblet cell regeneration. It is important to note that recovery of goblet cells and overall gut health is a complex process influenced by many factors, including adequate intake of essential nutrients, overall nutritional status, and resolution of underlying malnutrition because nutritional status affects the quality of a person's health²⁸. Protein and albumin administration should be part of a comprehensive nutritional intervention that addresses all aspects of malnutrition, including macronutrient and micronutrient deficiencies, to support the recovery of goblet cells and restore proper intestinal function.

TNF- α expression:

The results showed that the TNF-α positive control group showed the highest results when compared to the negative control group and the treatment group. The treatment group showed lower results compared to the negative control group.

Figure 3 shows the appearance of the brown dots in the positive control group showing the highest amount of TNF-α compared to the negative control group and in the treatment group the brown dots appeared to decrease along with the decrease in TNF-α expression.

Figure 3. Intestinal macrophage cells that express TNF-α appear brown(a) negative control group (b) positive control group (c) treatment group(d) normal group (400x magnification)

Malnutrition can disrupt the balance of the gut microbiota, resulting in dysbiosis. Dysbiosis is an imbalance in the composition and diversity of the gut microbial community. Changes in the gut microbiota can lead to the overgrowth of harmful bacteria and the reduction of beneficial bacteria.Oxidative stress that causes inflammation triggers stressors for protein secretion and reduces albumin synthesis²⁹. This microbial imbalance can stimulate the immune system and trigger inflammatory responses in the intestinal villi.

Malnutrition can compromise the immune system, including innate and adaptive immune responses. Inadequate nutrition leads to a reduction in immune cell numbers, impaired function of immune cells, and alterations in cytokine production. These dysfunctions can disrupt immune homeostasis and contribute to an inflammatory environment within the intestinal villi. The inflammatory process triggers an increase in lymphocytes, which are important in wound healing. The increase in lymphocytes releases lymphokines which affect macrophage aggregation and fibroblast production, which affects the wound healing process³⁰.

The inflammation triggered by malnutrition in the intestinal villi can further exacerbate the damage to the intestinal epithelium, disrupt nutrient absorption, and perpetuate the cycle of malnutrition. Chronic inflammation can lead to complications such as villi atrophy, impaired barrier function, and increased infection susceptibility³¹. Addressing malnutrition through proper nutrition and nutrient supplementation is essential in reducing inflammation and promoting the recovery of the intestinal villi³².

The treatment group was given additional nutrition to support the immune system and the development of granulation tissue³³. The additional nutrition provided is in the form of Channa striata extract. The advantage of Channa striata is that it has anti-inflammatory properties in the form of albumin, which can inhibit the formation of pro-inflammatory cytokines such as TNF-α³⁴. This helped reduce the expression of TNF-α in the treatment group. This research aligns with Ramadhanti et al. (2021), which stated that giving 100% snakehead fish extract significantly affected a decrease in macrophages and blood vessels in the inflammatory reaction of skin wound tissue³⁵.

Another study conducted by Ailsa et al. (2022) concluded that the content of amino acids, albumin, Zn, Fe, Cu, and unsaturated fatty acids in Channa striata is quite effective in efforts to increase albumin levels, decrease neutrophil and lymphocyte values during inflammation in hypoalbuminemia patients¹⁰. This shows that administration of Channa striata extracts over a more extended period can reduce TNF-α expression, which is more significant. It's important to note that reducing inflammation in malnutrition requires a comprehensive approach that addresses the underlying nutritional deficiencies and supports overall health³⁶. In addition to protein and albumin administration, a well-balanced nutritional plan that includes an adequate intake of macronutrients, micronutrients, and essential fatty acids is crucial. This supports the proper functioning of the immune system, promotes tissue repair, and helps restore the integrity of the intestinal barrier³⁷. It's also worth mentioning that inflammation management may require additional interventions beyond nutritional support. In cases of severe inflammation associated with malnutrition, anti-inflammatory medications or other therapeutic approaches may be necessary. The specific treatment approach should be determined by healthcare professionals who can evaluate the individual's condition and provide personalized recommendations.

Channa striata's anti-inflammatory properties are due to albumin, amino acids (arginine, lysine, aspartic acid, glutamic acid), fatty acids, and minerals. Albumin and minerals (zinc, copper, and iron) contained in Channa striata have antioxidants that act as ROS scavengers and protect cellular against oxidative stress³⁸. Antioxidants are essential substances that protect individuals from free radicals, such as reactive oxygen species (ROS)³⁹. In addition, amino acids such as arginine as substrates help form NOS, arginase enzymes as triggers for immune responses, and lysine, aspartic acid, and glutamate as antioxidants that synergize with fatty acids⁴⁰. Linoleic acid blocks inflammation by suppressing the production of leukotriene B4, which induces TNF-α. Other types, such as linoleic and arachidonic acids, inhibit the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α⁴¹. Oleic and stearic acids weaken endothelial leukocyte adhesion molecules' expression and reduce the polymorphonuclear leukocyte (PMN) activity. Reducing PMN activity can prevent the release of ROS, which causes tissue damage⁴².

Channa striata (striped snakehead fish) is rich in protein and contains albumin. Channa striata is a freshwater fish species widely consumed in various cuisines and known for its nutritional value. Protein is one of the primary components of Channa striata, and it is considered a good source of high-quality protein. Protein is essential for various bodily functions, including tissue repair, muscle growth, and immune system support. Albumin is a type of protein found in Channa striata and other animal-based food sources⁴³. Albumin is a major protein in the blood and plays a crucial role in maintaining plasma oncotic pressure, transporting substances in the bloodstream, and supporting overall bodily functions. Consuming Channa striata as part of a balanced diet can contribute to meeting the body's protein and albumin requirements.

CONCLUSION:

Administration of Channa striata extract can relieve inflammation and repair intestinal villi damage in the small intestine of malnutrition mice.

CONFLICT OF INTEREST:

The authors declare there are no conflicts of interest regarding this study.

ACKNOWLEDGMENTS:

The researchers would like to thank Wilda Fitria Rachmadina for preparing and typing this manuscript.

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Received on 23.08.2023 Modified on 09.02.2024

Research J. Pharm. and Tech 2024; 17(10):4833-4839.

DOI: 10.52711/0974-360X.2024.00743