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TABLE 17.3 (Continued)
443
Therapeutic Agent Category of
Therapeutic Agent
Resveratrol Natural product IPEC-J2 cells, increased cell viability, increased expression of TJ proteins, activities
Puerarin Natural product DSS-induced colitis mice model, diminishes pathological symptoms of colon damage
Observations Reference
of antioxidant enzymes elevated and ROS and oxidative stress generated apoptosis
is reduced, upregulated expressions of antioxidant genes under oxidative stress,
increased p-AKT/AKT ratio
inhibited inflammation, regulates the NF-E2 p45-related factor 2 (Nrf2) signaling
cascade and markers of TJ proteins elevated
Zhuang et al. (2019)
Jeon et al. (2022)
444
Further, it reduced the symptoms of acute intestinal inflammation in DSS-induced mice
(Guzman et al., 2013). Further well-known natural products quercetin and ellagic acid
are also found to be preventing intestinal oxidative damage through antioxidant and antiinflammatory pathways. Ellagic acid enhanced levels of adherence junction and TJ proteins
and further reduced liver damage brought on by the condition of leaky gut (Dong et al., 2020;
Kim et al., 2021). Another well-documented antioxidant plant flavonoid resveratrol also
demonstrated to be significantly upregulating the levels of TJ proteins and the antioxidant
signaling marker proteins. Further activity of the antioxidant enzymes superoxide dismutase-1,
catalase, and glutathione peroxidase were also elevated in oxidative stress (hydrogen
peroxide)-induced barrier injury (Zhuang et al., 2019). Isoflavon puerarin administration
improved the conditions of intestinal epithelial barrier in UC-induced test animals evident
through reduced signs of pathological colonic damage. NF-κB and proinflammatory signaling
molecules are both considerably reduced by purarin. Furthermore, the overexpression of
NF-E2 p45-related factor 2 (Nrf2) demonstrated antioxidative potential (Jeon et al., 2022).
Oxidative imbalances in the intestine cause physiological injury to the epithelial barrier and
various natural products have been explored toward the development of a therapeutic option.
However, the underlying mechanism of action of these natural products is not known as
majority of the beneficial potential documented underexplored the intracellular mechanism
of epithelial barrier protection.
17.7 TRADITIONAL MEDICINE AND NATURAL PRODUCTS UPREGULATING THE TJ PROTEINS
17.7.1 TRADITIONAL MEDICINE AND HERBAL EXTRACTS PROMOTING JUNCTION PROTEIN PROTECTION
Improvements in the TJPs’ structure and functioning as well as the maintenance of the
epithelial mucin layer have been shown to be crucial in limiting the emergence of intestinal
barrier breakdown or leaky gut syndrome. Hypoxia-inducible factor (HIF) and NF-κB
are the central regulatory factors in maintaining intestinal barrier integrity. HIF controls
the overall epithelial barrier health in the intestinal physiology through generating mucin,
regulating the microbial metabolites, and signaling the TJP expressions. Butyrate serves
as the energy source for these processes. HIF further suppresses intestinal inflammation
and reestablishes the mucosal microenvironment. On the other hand, NF-κB inhibition
also triggers the suppression of proinflammatory markers resulting in barrier protection
(Dey, 2020). Traditional herb QingBai decoction has been shown to reduce intestinal
permeability and upregulated the expression of TJP. QingBai decoction further reduced
the inflammation through the regulation of NF-κB and Notch signaling cascade (Lin et al.,
2019). Furthermore, herbal formulation Xiaoyaosan used for chronic depression, have
been reported to be significantly reversing intestinal membrane destruction and improving
membrane permeability in rat depression model. The study also establishes a relationship
between improved circumstances of moderate unexpected depression and improved intestinal environments, as seen by rising levels of 5-hydroxytryptamine (5-HT) in the brain
445
and colon (Ding et al., 2020). Li et al. studied the underlying mechanism of action of traditional medicine Tongxinluo and evaluated that oral administration improved levels of TJP.
The protective role of epithelial barrier was further extended to improved cardiovascular
protection (Li et al., 2015).
17.7.2 PHYTOCOMPOUNDS FOR JUNCTION PROTEIN PROTECTION
Natural bioactive molecules proving beneficial in improving TJP levels as well as
mucosal injury are reported to be flavonoids, polyphenols, terpene, polysaccharides,
and organic acids (Table 17.4). Flavonoids quercetin, morin, and naringenin promoted
membrane integrity and improved TJP protein expression in hyperglycemia-induced
Caco-2 cell line (Sharma et al., 2020). Further bioactive flavonoids kaempferol and
genistein improves TJP integrity and ameliorates oxidative damages in test animals
(Dey, 2020). When added in-vitro galactooligosaccharides reduced deoxynivalenolinduced disruptions of epithelial barrier function in Caco-2 cells. Expressions of TJ
assembly and cellular distribution of claudin3 were restabilized (Akbari et al., 2015).
Sulfated polysaccharides isolated from Gracilaria lemaneiformis improved physical
conditions related to colitis. Further they improved healthy colonic microstructure
reduced inflammatory markers and upregulated TJ protein expression (Han et al.,
2020). Organic acids protocatechuic acid (PCA) and ferulic acid have been tested for
their TJP-promoting activities in intestinal barrier dysfunction induced by LPS in-vivo
and in-vitro models, respectively (He et al., 2020; Hu et al., 2022). PCA-supplemented
diet when fed to LPS-induced piglet model significantly promoted the TJP expression.
Inflammatory marker levels in serum, that is, ILs and TNF-α were reduced. Dietary
PCA supplementation also balances gut microbiota population reducing the relative
abundance of Prevotella, Holdemanella, and Ruminococcus torques group while
increasing the same of Roseburia and Desulfovibrio genera. Soybean agglutinin, a
glycoprotein able to bind to intestinal receptors also maintained intestinal permeability
and prevented the progression of leaky gut conditions in piglet model in higher doses.
The increase in TJP levels in treated animals had a linear relationship with the treatment
dose (0–0.2% of total diet) with lower doses (0–0.05%) showing no significant result
(Zhao et al., 2011).
17.8 NATURAL PRODUCTS AVERTING PATHOLOGICAL CONDITIONS THROUGH MAINTAINING INTESTINAL BARRIER FUNCTION
Numerous studies have documented how natural products can help treat a variety of
metabolic and chronic disorders by strengthening the intestinal barrier and reducing
endotoxin translocation across the gut. Besides, many bioactive natural products work
through the modulation of intestinal microbiota and upregulation of proinflammatory
markers. Recent evidences showed that polyphenolic compounds can manage metabolic
diseases through the modulation of gut microbiota. The gut’s resident bacteria may
TABLE 17.4 Medicinal Plant Extracts and Natural Products Reported for Tight Junction Protein Protection toward the Prevention of Intestinal Barrier
Dysfunction
Therapeutic Agent Category of
QingBai decoction Polyherbal composition UC mice model, decreased inflammation, and the protection against colitis, reduction
Xiaoyaosan Chinese polyherbal
Tongxinluo (TXL) Chinese polyherbal
Flavonoids (quercetin,
morin, naringenin)
Galactooligosaccharides
Polysaccharide Natural product UC mice model, alleviate eating disorders, decrease endotoxin, lipopolysaccharide-
Protocatechuic acid Natural product LPS-challenged weaned piglets, increased expression of tight junction proteins,
Ferulic acid Natural product Human epithelial intestinal Caco-2 cells, mediates the PI3K/AKT pathway He et al. (2020)
⏎
Observations Reference
Therapeutic Agent
in intestinal permeability, upregulated junction complexes expression, downregulates
oxidative stress-related damage, regulation of NF-κB and Notch signaling cascade
Rat depression model, alleviated depression-like behavior, improved eating habits in
formula
formula
Natural product Human epithelial intestinal Caco-2 cells, increased cell viability, and reduced glucose
Natural products Caco-2 cells and B6C3F1 mice, improved tight junction assembly, decreased leaky gut
test animals, repaired gastrointestinal damages, increased TJPs
Human cardiac microvascular endothelial cells and angiotensinogen transgenic mice,
improved symptoms of intestinal permeability through regulating KLF5 expression
absorption in hyperglycemic Caco-2 cells, decreased ROS generation, improved TJs
protein interaction, and regulated membrane barrier function
condition, reduced overexpression of junction proteins
binding protein (LBP) and myeloperoxidase activity. Meanwhile, suppress secretion
of inflammatory markers maintain healthy colonic microstructure, enhanced tight
junction proteins expression
decreased thiobarbituric acid reactive substances in the serum, elevated firmicutes/
bacteroidetes ratio
Lin et al. (2019)
Ding et al. (2020)
Li et al. (2015)
Sharma et al. (2020)
Akbari et al. (2015)
Han et al. (2020)
Hu et al. (2022)
446
447
function as a catalyst for the polyphenols’ metabolism. The phenolic gut metabolites
are found to be significantly active against the metabolic diseases, in some cases, even
better than the parent compounds. Gut microflora has been reported to be influencing the
bioactivity and bioavailibity of many polyphenolics. Further gut microbial abundance
can also be modulated through the daily intake of plant polyphenolic compounds (Gowd
et al., 2019). Similarly, polysaccharide from Salviae miltiorrhizae Radix et Rhizoma,
brown algae-derived polysaccharides, Flos lonicera extracts have been reported to
exert therapeutic effect in obesity and metabolic diseases through modulating the gut
microbial population and preventing intestinal barrier injury (Li et al., 2022; Wang et al.,
2014; Yang et al., 2022). Bioactive natural molecules like polyphenol quercetin (Porras
et al., 2017) and marine oligosaccharide chitosan (You et al., 2022) have demonstrated
a beneficial effect in preventing diet-induced NAFLD and regulated lipid metabolism
through the activation of gut–liver axis.
Recent scientic evidence has also presented that different natural products like
alkaloids, polyphenols, terpenoids, and sulfur-containing compounds are capable of
preventing the progression of cancer-inducing chronic conditions through by modulating
the gut barrier function. The green teapolyphenol, epigallocatechin-3-gallate, is thought
to enhance the function of the intestinal immunological barrier by encouraging the
production of defensins at the mRNA and protein levels (Wan et al., 2016). Studies
on humans and animals show that polyphenols and whole foods high in polyphenols
can increase butyrate production and probiotics like Lactobacillus and Bidobacterium
that treat colitis and prevent colitis-associated cancer (Zhao and Jiang, 2021). Emerging
studies have shown that the etiology of CRC and gut microbial dysbiosis are related. Gut
microbiota dysbiosis has been linked to colorectal carcinogenesis by promoting tumor
growth, inammation, DNA degradation, and shielding tumor from immune attack (Fong
et al., 2020). According to Yi et al.’s study, Portulaca oleracea, a medicinal plant with
anti-inammatory and antioxidant properties, may also have the potential to prevent
CRC by lowering the imbalance of the gut microbiota (Y i et al., 2022). In a study by Ram
et al., it was shown that nimbolide, a signicant limonoid component of Azadirachta
indica, has the capacity to mitigate gut dysbiosis and avoid bacterial translocation
by enhancing intestinal barrier integrity and lowering inammation in hepatocellular
carcinoma (Ram et al., 2022). These investigations support the idea that phytochemicals
are crucial in preventing cancer by preserving barrier integrity and stabilizing the gut
epithelial junction.
17.9 CONCLUSION
A significant number of research have been conducted over the years to investigate the
protective effects of traditional herbal medicines, polyherbal formulations, and natural
bioactive molecules toward the protection of intestinal barrier structure, its function,
and prevention of one of the complex physiological disruptions leaky gut conditions.
It is to be noted that leaky gut could be an indication of host-specific physiological
processes as well as a result of chronic inflammatory responses and disturbances in
448
the gut microflora due to underlying different pathological conditions like metabolic
diseases, inflammatory, and oxidative injury. Notably endotoxin translocation through
a disrupted intestinal membrane can in turn lead to various diseases ranging from mild
inflammation and headache to development of chronic metabolic syndromes and also
cancer. Studies have showed the potential benefits of natural products in the management
of leaky gut and related complications; however, the underlying mechanisms of action
are still underexplored. Especially with studies involving natural products that alter the
gut microbial population, more elaborate insights are required to properly understand
microbial dependency of the therapeutic effects. Also, many of the reported studies are
conducted in in-vitro models and majority of the studies are observational in nature,
thus more investigations are required to properly understand the complex function of
the intestinal barrier and its protection through the use of traditional medicines and
natural products. It is well reported that the bioavailability and bioactivity of many
natural products are influenced by the local intestinal environment. Thus, targeting
the management of the gut barrier integrity can provide a novel therapeutic pathway
for natural product drug design and development for the prevention and mitigation
of gastrointestinal diseases, leaky gut conditions as well as metabolic and chronic
diseases.
KEYWORDS
• leaky gut
• tight junction proteins
• intestinal barrier dysfunction
• natural products
• traditional medicine
• medicinal plants
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