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Bacterial diarrhea is a global health concern, particularly in developing countries like Mexico, where high morbidity and mortality rates persist, especially in children under five years of age. While antibiotics like ciprofloxacin, ceftriaxone, and azithromycin are effective, increasing bacterial resistance has led to the search for alternatives. Tea tree essential oil (TTEO) has been proposed as a potential treatment, but research, especially in vivo, remains limited due to oil composition variability and a lack of standardized protocols. This review compiles current data (2000-2024) on the epidemiology, diagnosis, treatment, and antibiotic resistance of critical dia- rrhea-causing bacteria (E. coli, Shigella spp., Campylobacter spp., and Salmonella spp.) and evaluates TTEO’s antibacterial potential. In vitro studies show its bactericidal and bacte- riostatic effects, while in vivo studies assess its therapeutic impact on animal models. In conclusion, TTEO holds promise as an alternative or adjuvant to antibiotics for treating bacte- rial diarrhea. However, further in vivo studies are required to confirm its efficacy and optimize its clinical application.
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Universidad de Sonora
ISSN: 1665-1456
Journal of biological and health sciences
http://biotecnia.unison.mx
1
Volume XXVI
*Author for correspondence: Luis Quihui-Cota
e-mail: lquihui@ciad.mx
Received: February 27, 2023
Accepted: October 8, 2024
Published: November 7, 2024
Bacterial resistance in diarrhea and tea tree oil
as a potential alternative treament: a review
Resistencia bacteriana en diarrea y aceite esencial de arbol de té
como potencial tratamiento: revisión
Javier Nicolás González-González, Ildefonso Guerrero-Encinas, Gloria Guadalupe Morales-Figueroa,
Gustavo A. González-Aguilar, Jesus F. Ayala-Zavala, Humberto F. Astiazarán-García, Marco A. López-
Mata, Raymundo R. Rivas-Cáceres & Luis Quihui-Cota*
1 Centro de Investigación en Alimentación y Desarrollo, A.C. (CIAD, A.C.) Carretera Gustavo Enrique Astiazarán Rosas No. 46.
Col. La Victoria 83304. Hermosillo, Sonora, México.
2 Departamento de Ciencias de la Salud, Universidad de Sonora, Campus Cajeme, Blvd. Bordo Nuevo S/N, A.P. 85040, Antiguo
Providencia, Cd. Obregón, Sonora, México.
3 Universidad Autónoma de Ciudad Juárez, Ave. Plutarco Elías Calles No. 1210, FOVISSSTE Chamizal Cd, Juarez C.P. 32310,
México.
ABSTRACT
Bacterial diarrhea is a global health concern, particularly in
developing countries like Mexico, where high morbidity and
mortality rates persist, especially in children under ve years
of age. While antibiotics like ciprooxacin, ceftriaxone, and
azithromycin are eective, increasing bacterial resistance has
led to the search for alternatives. Tea tree essential oil (TTEO)
has been proposed as a potential treatment, but research,
especially in vivo, remains limited due to oil composition
variability and a lack of standardized protocols. This review
compiles current data (2000-2024) on the epidemiology,
diagnosis, treatment, and antibiotic resistance of critical dia-
rrhea-causing bacteria (E. coli, Shigella spp., Campylobacter
spp., and Salmonella spp.) and evaluates TTEO’s antibacterial
potential. In vitro studies show its bactericidal and bacte-
riostatic eects, while in vivo studies assess its therapeutic
impact on animal models. In conclusion, TTEO holds promise
as an alternative or adjuvant to antibiotics for treating bacte-
rial diarrhea. However, further in vivo studies are required to
conrm its ecacy and optimize its clinical application.
Keywords: Diarrhea, Antibiotics, Antibiotic-resistant, Essen-
tial oils, Tea tree.
RESUMEN
La diarrea bacteriana es un problema de salud pública mun-
dial, especialmente en países en desarrollo como México,
donde persisten altas tasas de morbilidad y mortalidad,
sobre todo en niños menores de cinco años. Aunque los an-
tibióticos como la ciprooxacina, ceftriaxona y azitromicina
son efectivos, el aumento de la resistencia bacteriana nos
ha forzado a buscar alternativas. El aceite esencial de árbol
de té (TTEO) ha sido propuesto como tratamiento potencial,
pero la investigación, especialmente in vivo, es limitada de-
bido a la variabilidad en la composición del aceite y la falta
de protocolos estandarizados. Esta revisión recopila datos
actuales (2000-2024) sobre la epidemiología, diagnóstico,
tratamiento y resistencia a antibióticos de bacterias clave
que causan diarrea (E. coli, Shigella spp., Campylobacter spp.
y Salmonella spp.), y evalúa el potencial antibacteriano del
TTEO. Los estudios in vitro muestran sus efectos bactericidas
y bacteriostáticos, mientras que los estudios in vivo evalúan
su impacto terapéutico en modelos animales. En conclusión,
el TTEO tiene potencial como una alternativa o complemen-
to a los antibióticos para tratar la diarrea bacteriana, pero se
necesitan más estudios in vivo para conrmar su ecacia y
optimizar su aplicación en la práctica clínica.
Palabras clave: Diarrea, Antibióticos, Resistente a los anti-
bióticos, Aceites esenciales, Árbol de té.
INTRODUCTION
One of the leading health problems worldwide is malnutri-
tion and infection. Both conditions have been associated with
high morbidity and mortality rates in children and adults,
resulting in intestinal alterations and a negative impact on
nutrient absorption (FDA, 2023). In addition, the indiscri-
minate or inappropriate use of antibiotics in animals and
humans has contributed to the increased bacterial resistance
to multiple drugs (van den Bogaard, 2000; Bouarab-Chibane,
2019). Pathogen bacteria such as Escherichia coli, Shigella
spp., Campylobacter spp., and Salmonella spp. (Hirose and
Sato, 2011) are on the list of the highest epidemiological
surveillance worldwide, causing mild symptoms to severe
diseases (WHO, 2017). Thus, they negatively impact on the
host’s nutritional status and are associated with alterations in
the intestinal mucosa, resulting in a low absorption capacity
of nutrients (Fagundes-Neto and Aonso-Scaletsky, 2000).
Natural alternatives with antibacterial properties have
been sought, and they may be an appropriate adjuvant for
conventional antibiotics (Calo et al., 2015). Essential oils (EOs)
of some plants have shown antibacterial properties in vitro,
producing inhibition percentages ranging from decient (13
%) to very satisfactory (96 %) against some pathogenic bac-
DOI: 10.18633/biotecnia.v26.2270
Review
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González-González et al:/ Biotecnia 26:e2270, 2024
2
teria (Kon and Rai, 2012; Chouhan et al., 2017). In addition,
EO’s components can exert antioxidant eects (Miguel, 2010;
Yang et al., 2019), which may positively impact the host’s
nutritional status since they act as functional foods for both
animals and humans (Firmino et al., 2020).
Search strategy
This review was conducted by retrieving data from reputable
scholarly databases, including Google Scholar, PubMed,
Springer, Science Direct, and Wiley Online Library. The search
used keywords pertinent to the ecacy of tree tea essential
oil against Shigella, Salmonella, Campylobacter, and Escheri-
chia coli, encompassing both in vitro and in vivo evaluations
at the gastrointestinal level. The inclusion criteria for selected
studies encompassed publications from 2000 to 2023. Fur-
thermore, an investigation into plant extracts’ safety prole
and compositional characteristics demonstrating ecacy
was undertaken to provide a holistic perspective on their
potential applications.
Shigella spp.
Shigella is a Gram-negative bacterium from the Enterobacte-
riaceae family and causes approximately 125 million diarrhea
cases and 160,000 deaths annually, and a third of this gure
are children. One of the important clinical aspects of Shigella
is that even a low infectious dose is associated with aggressi-
ve watery diarrhea or bloody diarrhea (Baker and Chung-The,
2018). In addition, this bacterium is the third most isolated
pathogen by clinical laboratories in the United States. Shige-
lla is subdivided into four major species: Shigella dysenteriae,
Shigella boydii, Shigella exneri, and Shigella sonnei (Bowen,
2018).
Shigellosis is a disease that occurs once the bacteria
settle in the intestine. Shigella spp. can tolerate the acidic pH
of the stomach, colonizing the digestive tract, generating
pores in the membrane of epithelial cells, and invading their
cytoplasm. Shigella spp. can then multiply in adjacent cells
without moving through the extracellular medium (Barran-
tes-Jiménez and Achí-Araya, 2009). Although all Shigella spp.
can cause bloody diarrhea, S. dysenteriae can produce Shiga
toxin, which causes hemolytic uremic syndrome, associated
with blood in the urine and, occasionally, clots in blood ves-
sels of the kidneys (Lampel, 2012). To prevent this infection,
hand washing, food care, precautions in drinking water
(especially in developing countries), use of alcohol-based
sanitizers, and avoiding fecal exposure in the sexual act
are more often recommended (Bowen, 2018). On the other
hand, special attention must be paid to fulll those measures,
particularly to children under ve years old. In addition, when
an infant is infected, special care must be taken so that there
is no person-to-person transmission, especially if the child’s
diaper must be changed (CDC, 2023c).
To diagnose properly, a doctor must suspect shigellosis
based on its usual symptoms such as pain, fever, and watery
or bloody diarrhea. Subsequently, conrmation is carried out
with serological or molecular methods (Lampel, 2012).
Salmonella spp.
Salmonella is a Gram-negative bacterium belonging to the
Enterobacteriaceae family. Salmonella strains can cause two
types of illnesses: typhoid fever and non-typhoid salmone-
llosis. Although both cause fever, the former is more severe
and has a higher mortality rate (Hammack, 2012). However,
globally, non-typhoid salmonellosis is one of the four leading
causes of diarrheal illness, with around 153 million cases of
gastroenteritis and 57,000 deaths (Hunter and Francois-
Watkins, 2018). There are 2,500 serotypes of the two main
species, Salmonella bongori, and Salmonella enterica, the
second being the most relevant clinically and in public health
(WHO, 2019).
Most Salmonella strains are pathogenic due to their
ability to invade and survive in host cells. When Salmonella
enters the digestive tract, it can penetrate epithelial cells
by injecting eectors through the membrane into the cyto-
plasm, or some adhesion systems, detected in strains such
as S. enterica (Shu-Kee et al., 2015). Within these systems,
adhesins, invasins, exotoxins, and endotoxins have been
identied to ensure its survival in low pH. These properties
give specicity to the dierent serotypes to adapt to the host,
promoting the advancement of the disease (Jajere, 2019).
Therefore, since it has been reported that salmonellosis
is the most signicant foodborne infection worldwide, its
prevention is a concern for public health (Jajere, 2019), so
risk prevention is focused on primary production to food
transportation (WHO, 2019). In addition, the usual safety
measures, such as hand washing and precautions when in
contact with farm or domestic animals, are recommended.
On the other hand, greater caution is recommended in chil-
dren under ve years old, who are the most susceptible to
salmonellosis (Hunter and Francois-Watkins, 2018).
Regarding diagnosis, coprological analysis is the selec-
tion technique for timely detection. Similarly, this can be
detected in cultures from samples of blood, urine, abscesses,
and cerebrospinal uid (Hunter and Francois-Watkins, 2018;
CDC, 2022b). In addition, in countries such as the United
States, it is important that the laboratories responsible for
clinical diagnosis report to the Center for Disease Control and
Prevention (CDC) for proper epidemiological surveillance
(CDC, 2019).
Campylobacter spp.
Campylobacter is a Gram-negative, spiral S-shaped bacteria
belonging to the family Campylobacteriaceae. It causes
diarrhea and is one of the most prevalent enteric pathogens
in developing and developed countries. In the United States,
1.3 million are infected every year (CDC, 2023a). Although the
disease by this bacterium is considered mild, in populations
under ve years of age, it may be fatal (WHO, 2020), where
Campylobacter jejuni is the most common agent found asso-
ciated with diarrheal disease, in Argentina (30.1 %), Peru (23
%) and Colombia (14.4 %) (Fernández, 2011).
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C. jejuni is competitive in the intestine of the host, taking
DNA from the environment, allowing recombination bet-
ween strains, and favoring its genetic diversity (Young et al.,
2007), which allows it to adapt to adverse acidic and aerobic
environments. Through agella and union factors, C. jejuni
can attach to epithelial cells of the intestine, colonizing the
host’s intestine and causing severe diarrhea, fever, and blood
in the stool (Dasti et al., 2010).
There are no vaccines to prevent infection, but preven-
tion is achieved by applying basic hygiene recommendations,
such as hand washing, correct cooking of food, and proper
treatment of contaminated water (Geissler et al., 2018). In
addition, some organizations emphasize disease control with
timely hygiene measures at all stages of the food chain, from
farms to homes (WHO, 2020).
The diagnosis of C. jejuni is made with unique isolation
and growth conditions due to its microaerophilic characteris-
tics. The stool or rectal samples are inoculated in a selective
medium, and the culture is kept at an ideal temperature (42
°C) for 72 h, with 5 % oxygen (Foley, 2012). On the other hand,
microscopic visualization has been recommended, where the
spiral S shape of the bacterium can be observed to establish
an opportune diagnosis. A relevant issue is that laboratories
analyze the sample in no more than 2 hours, taking advan-
tage of the unique bacterial characteristics (Geissler et al.,
2018).
Escherichia coli
E. coli is a group of Gram-negative bacilli and facultative
anaerobes belonging to the Enterobacteriaceae family (Vila
et al., 2016). E. coli strains are predominant in the intestinal
microbiota of mammals and, specically, in humans, showing
a prevalence higher than 90 % (Denamur et al., 2021). At the
epidemiological level, the diarrheagenic E. coli (DEC) sub-
group is the leading cause of diarrhea, a condition that kills
infants in developing countries (Hebblestrup, 2014). Around
6 DECs have been identied, including Enteropathogenic E.
coli (EPEC), Enterotoxigenic E. coli (ETEC), Shiga-toxigenic E.
coli (STEC), Enteroinvasive E. coli (EIEC), Enteroaggregative E.
coli (EAEC) and diusely adherent E. coli (DAEC) (O’Reilly et
al., 2018).
Diseases associated with DEC had a 30–40 % preva-
lence in Asia, the Middle East Africa, Central America, South
America, and Mexico, especially within children populations
(Gomes et al., 2016; O’Reilly et al., 2018). In Mexico, these
bacteria represent the top pathogens that cause diarrhea in
children, with 30.9 %, followed by S. enterica (11.4 %), Shigella
spp. (10.8 %), and Campylobacter spp. (5.6 %) (Rios-Muñiz et
al., 2019). For example, EPEC has been known to cause 17 to
19% of childhood diarrhea (Vidal et al., 2007). On the other
hand, ETEC and EAEC, which produce “traveler’s diarrhea,
aect both children and adults, with prevalences ranging
from 5.1 to 12.2 % in Northwest Mexico. The rest of the DEC
seems less frequent, with prevalences ranging from 0.2% to
1.4 % (Rios-Muñiz et al., 2019).
The pathogenesis of DEC depends on the pathotype
and the specic strains. However, most of them mainly aect
the small or large intestine, with an incubation period ran-
ging from 8 hours to 10 days, mainly causing watery diarrhea
(Gomes et al., 2016; O’Reilly et al., 2018; Rios-Muñiz et al.,
2019). Specically, ETEC, EIEC, EAEC, and STEC adhere to the
intestinal mucosa, releasing enterotoxins and cytotoxins that
promote inammation, triggering diarrhea (Vidal et al., 2007;
O’Reilly et al., 2018). In addition, EPEC adheres to the intes-
tinal mucosa, causing a attening of villi and inammatory
changes, leading to conformational changes and reduction
of hydrolysis and absorption of nutrients (Morales-Cruz and
Huerta-Romano, 2010). Finally, although little is known about
its pathogenicity, DAEC is believed to form a diuse adheren-
ce that induces protruding structures protecting its colonies
and allowing disease development (O’Reilly et al., 2018).
Some strategies have been proposed to prevent infec-
tion by DEC, among which general hygiene in food prepara-
tion, hand washing, and food cooking (62.6 °C) stand out. In
addition, it is recommended to avoid consuming foods such
as raw milk and dairy products and unpasteurized juices
(CDC, 2023b). This type of prevention may be impractical for
humans since there are dierent pathogenic strains with di-
erent transmission routes. Therefore, the most widely used
strategy worldwide is the epidemiological surveillance of
specic strains that can contaminate food and infect humans.
This strategy includes the detection of potential hazards of
specic groups such as STEC, estimation of risk of food con-
tamination, counts of viable organisms to trigger the disease,
and timely diagnosis (Newell and La Ragione, 2017).
A diagnosis of EPEC can be carried out using a copro-
logical analysis to conrm the presence of these bacteria.
However, diagnostic tests that only detect a subset of STEC,
known as enterohemorrhagic E. coli (EHEC), and recently for
ETEC, are usually performed in most hospitals due to its pre-
valence and clinical importance (O´Reilly et al., 2018). In the
case of EHEC, detection of specic physiological markers pro-
duced by the EHEC O157:H7 strain are performed since this
is the primary bacterium of this pathotype. Similarly, some
tests to detect ETEC are performed by culturing the sample in
selective media, such as eosin agar and methylene blue, fo-
llowed by serotyping or the use of molecular techniques for
serotype identication (Morales-Cruz and Huerta-Romano,
2010; Newell and La Ragione, 2017).
Conventional treatment
The usual treatments for gastrointestinal diseases caused by
these bacteria, especially diarrhea, are based on uid and
electrolyte replacement (WHO, 2020b). However, in some
cases of immunocompetent patients with bloody diarrhea,
patients who are immunocompromised, or in contact with
another infected patient, antibiotic treatment is recommen-
ded (Shane et al., 2017). The prescription of these drugs va-
ries depending on dierent factors, such as the patient’s age
or the pathogenic bacteria that causes the disease (Cohen et
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González-González et al:/ Biotecnia 26:e2270, 2024
4
al., 2017). Among the most important and the rst choices to
treat infections by E. coli are azithromycin, ceftriaxone, and
ciprooxacin.
Azithromycin is a second-generation broad-spectrum
macrolide antibiotic. Guidelines for treating gastrointestinal
diseases, especially diarrhea, recommend this antibiotic to
treat Campylobacter, Shigella, and DEC infections (Shane et
al., 2017). Its primary mechanism of action is based on bacte-
rial protein synthesis by interfering with their 50S ribosomal
subunits (Parnham et al., 2014). On the other hand, eective
doses vary depending on age, reaching doses of 500 mg (Co-
hen et al., 2017). However, this antibiotic is not recommen-
ded in patients with STEC, especially children, since it can
cause hemolytic uremia syndrome, characterized by kidney
damage, hemolytic anemia, and thrombocytopenia (Tarr et
al., 2018).
Ceftriaxone is a third-generation cephalosporin prescri-
bed for treating Salmonella and Shigella infections (Lamb et
al., 2002). The main action of this antibiotic lies in its ability
to inhibit the synthesis of mucopeptides in the bacterial
cell wall. In addition, it has been shown that ceftriaxone
establishes bonds with the enzymes responsible for cell wall
synthesis and cell division, such as carboxypeptidases and
endopeptidases, which cause bacterial cell death. Doses
range from 20-50 mg/kg for standard treatment, and up to
80 mg/kg in the case of severe infections (Schleibinger et al.,
2015).
Finally, ciprooxacin is a uoroquinolone eective aga-
inst Salmonella, Shigella, and E. coli (Shane et al., 2017; Hunter
and Francois-Watkins, 2018). The antimicrobial mechanism
is based on inhibiting the DNA gyrase enzyme, a DNA to-
poisomerase involved in bacterial cell replication. It causes
bacterial DNA breaks and suppresses the division of the
target cell (Campoli-Richards et al., 1988; Ojkicet al., 2020).
Doses range from 20 mg/kg/day in children to a maximum of
500-1000 mg in adults for 3-5 days (Shane et al., 2017; Cohen
et al., 2017). However, in recent years, the loss of eectiveness
of antibiotics against bacteria was reported.
Antibiotic resistance
Drug-resistant diseases currently cause 700,000 deaths
per year, and estimations are that by 2050, there will be
around 10 million deaths per year (WHO, 2022b). Although
antibiotics are the drugs of choice for treating gastrointes-
tinal illnesses caused by bacteria, antibiotic resistance is an
increasing problem. This natural phenomenon is observed
in some medications, but their indiscriminate use in humans
and animals has aggravated this problem (CDC, 2023c).
It has been reported that Shigella spp. strains have
acquired resistance to antibiotics, including ciprooxacin
(8.9 %) and ceftriaxone (9.3 %) (Puzari et al., 2018; Hussen et
al., 2019). On the other hand, Campylobacter spp. strains have
developed resistance with prevalences of 45% and 89.9 % to
azithromycin and ciprooxacin, respectively, at their usual
doses (Yang et al., 2019). In the case of non-typhoidal Salmo-
nella, a resistance increase from 12.3 % to 19.2 % in children
has been reported in China within a 4-year period (Wu et al.,
2021). Finally, dierent E. coli strains have presented resis-
tance of up to 14.2, 9, and 20 % to ciprooxacin, ceftriaxone,
and azithromycin, respectively (Eltai et al., 2018; Xiang et al.,
2020).
The WHO and CDC have developed several recommen-
dations and strategies, among which, are the prescription of
antibiotics only when necessary, and investing in the deve-
lopment of new antibiotics and vaccines, which are the ones
that stand out (WHO, 2022e; CDC, 2023c). Recently, work
has been done on developing these new strategies, among
which the tea tree essential oil (TTEO) can be found. This
essential oil has been proven eective in vitro and in vivo to
inhibit the growth of some bacteria. It may be an alternative
or natural adjuvant in treating human and animal bacterial
infections (Chouhan et al., 2017).
Tea Tree essential oil as alternative treatment
Antimicrobial compounds and preservatives have delayed
food spoilage (Perricone et al., 2015). EOs have been an alter-
native since ancient times, gaining relevance in recent years
for their antimicrobial properties. In addition, studies have
conrmed their dierent antioxidant and anti-inammatory
properties (Dagli et al., 2015). EOs are volatile secondary
metabolites produced by plants and are responsible for
their aromatic properties (Bakkali et al., 2008). In general,
EOs are liquid, volatile, and soluble compounds in lipids and
organic solvents, which are obtained from dierent parts of
plants (e.g., owers, seeds, leaves, grouts, and bark) through
dierent extraction techniques (Aziz et al., 2018). Among
their components stand out the terpenoid and non-terpenic
compounds raised by the phenylpropanoid pathway of
eugenol, cinnamaldehyde, and safrole (Dhi et al., 2016). The
concentration of these components depends on dierent
factors, such as the source of extraction, geographical loca-
tion, season, and maturity of the plant from which they are
extracted (Dagli et al., 2015).
TTEO, obtained from Melaleuca alternifolia, has been
used for almost 100 years in countries such as Australia, due
to its properties as a complementary and alternative medi-
cine (Carson et al., 2006). This EO contains oxygenated cyclic
monoterpenes and hydrocarbons, such as terpinen-4-ol,
ƴ-terpinene, α-terpinene, and 1,8-cineol (Dagli et al., 2015).
Among them, the predominant is terpinen-4-ol (30-40%),
to which most of its bioactivities are attributed (Groot and
Schmidt, 2006).
TTEO has shown some in vitro antimicrobial properties,
for example, as antifungal, especially against Candida albi-
cans the leading cause of vaginal infections, with minimum
inhibitory concentrations (MIC) ranging from 0.06 to 8.0 %.
TTEO seems to alter the properties of the membrane and
inhibit the respiration of the fungus at MICs from 0.25 % to
1.0 % (v/v) and reaching minimal bactericidal concentration
(MBC) (Carson et al., 2006). Also, TTEO has shown some eect
against viruses that cause herpes, which is better when com-
bined with eucalyptus EO (Gavanji et al., 2016). On the other
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5
hand, in vitro studies show that TTEO reduce by 50 % of the
growth of protozoa such as Leishmania major and Trypano-
soma brucei, and it has inhibited all Trichomonas vaginalis at
300 mg/mL (Carson et al., 2006).
In summary, TTEO exhibits various antimicrobial proper-
ties in vitro, supporting its potential application in treating
infections caused by various microorganisms. However, it is
essential to consider that results from in vitro studies may not
always translate directly to clinical ecacy, highlighting the
need to explore these eects in animal models.
Tea tree oil against bacteria: in vitro and in vivo assays
Regarding antibacterial properties, concentrations from 0.78
to 50 mg/mL have been tested against bacteria that cause
urinary tract infections. This demonstrates the TTEO in vitro
and in vivo ability to reduce bacterial load (Loose et al., 2020).
Table 1 summarizes some studies reporting their MBC and
MIC in vitro against E. coli, Shigella spp., Campylobacter spp.,
and Salmonella spp. On the other hand, in vivo assays with
TTEO (1000 mg/kg), resulted in an increased count of Lacto-
bacillus colonies within the cecal contents in Partridge Shank
chickens (n = 144) at 50 days of supplementation. Terpinen-
4-ol, the primary constituent of TTEO, has been identied to
possess selective antimicrobial properties against intestinal
pathogens in vitro, which results in the modulation of the
cecal microbiota composition through the enhanced Lacto-
bacillus population because of TTEO supplementation (Qu et
al., 2019).
Additionally, TTEO as a dietary supplement, at concen-
trations ranging from 50 to 150 mg/kg in broiler chicken diets,
exhibited notable eects. A signicant enhancement in daily
weight gain (7% approximately) was observed as a reduction
in both morbidity and mortality rates (Bakkali et al., 2008).
Also, the same concentrations described above (50 mg/kg to
150 mg/kg) of TTEO supplementation resulted in an increa-
sed average daily feed intake and a tendency of daily gain
in weanling piglets (n = 120) after 21 days (Aziz et al., 2018).
This study suggested that the passage of these compounds
through the gastrointestinal tract might not aect the native
microbiota of an organism; however, information is limited,
and additional studies exploring its eects in dierent living
organisms may provide more precise information.
On the other hand, the consumption of TTEO encapsu-
lated with n-hexane lactulose, gum Arabic, and maltodextrin
for 28 days seems to modulate the microbiota in weanling
pigs (n = 144) and reduced the E. coli in the intestine and
diarrhea episodes (Wang et al., 2021). However, despite the
evidence about its eective activity against Shigella, Salmo-
nella, Campylobacter, and E. coli, additional in vivo studies are
still required to test the ecacy of a TTEO oral administration
against these bacteria in infected animal models.
Some studies administer TTEO orally for other purposes
in dierent animal models. It was observed that the con-
sumption of 0.2 mg/kg of TTEO (60 days) added to the diet
of goats (n = 24) improved intestinal immune function (Lv et
al., 2022). Likewise, using TTEO integrated into the chickens’
diet also improved immune function (Abo Ghanima et al.,
2021). Therefore, these ndings indicate that the treatment’s
potential eects go beyond its antimicrobial activity.
While existing studies have investigated the antibac-
terial properties of TTEO, a critical research gap exists in
understanding its ecacy through oral administration
against specic gastrointestinal pathogens in infected
animal models. In vitro studies have demonstrated TTEO’s
ability to reduce bacterial load. However, a comprehensive
exploration of its eectiveness in vivo against critical bacteria
such as Shigella, Salmonella, Campylobacter, and E. coli must
be explored. Current research indicates positive outcomes,
such as increased Lactobacillus colonies in Partridge Shank
chickens and notable eects on growth rates and morbidity
in broiler chickens and weanling piglets when supplemented
with TTEO in their diets. Nevertheless, the passage of TTEO
through the gastrointestinal tract and its impact on native
microbiota remains misunderstood. Additionally, despite
encapsulation studies showing promise in modulating mi-
crobiota and reducing E. coli in weanling pigs, more research
needs to be done on the oral administration of TTEO, spe-
cically targeting other bacteria in infected animal models.
Bridging this gap will provide valuable insights into the
practical ecacy and safety of TTEO as an oral therapeutic
intervention against gastrointestinal pathogens, informing
potential applications and advancing our understanding of
microbial communities’ impact on dierent organisms.
Mechanisms to support the TTE biological activities
The mechanisms proposed to explain the TTEO eects are
diverse and will depend on the doses used and the analyzed
pathogen characteristics. It is suggested that modifying
the cell membrane structure is most important, reducing
the membrane potential (Swamy et al., 2016). In addition,
it has been reported that TTEO can aect potassium ion
channel homeostasis and interfere with glucose-dependent
respiration, aecting bacterial membrane integrity, e.g., E.
Table 1. In vitro eect of Tea Tree essential oil on dierent bacteria associa-
ted with diarrhea.
Tabla 1. Efecto in vitro del aceite esencial de Árbol de Té sobre diferentes
bacterias asociadas a la diarrea.
Bacteria
Inhibition
zone
(mm)
MBC
(L/
mL)
MIC
(%) Reference
Shigella spp - - 0.25 Harkenthal et al.,
1999
Campylobacter spp 26.7-30 - 0.001 Kureckci et al.,
2013
Salmonella spp 37.4 4 - Swamy et al.,
2013
E. coli 17.0-35.03 4 0.03-
0.5
Bučková et al.,
2018; Kureckci et
al., 2019
MBC: Minimum Bactericidal Concentration; MIC: Minimum Inhibitory
Concentration.
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González-González et al:/ Biotecnia 26:e2270, 2024
6
coli (Yadav et al., 2016). Also, TTEO can improve intestinal
development, cytokine secretion, gene expression of tight
junction proteins, and Notch2 signaling to some extent,
surpassing the eect of some antibiotics. The integrity of
tight junctions is a crucial indicator of intestinal well-being,
and any disturbance in their structure and function is often
linked to intestinal stress injury. Perturbations in critical tight
junction proteins, including occlusions, claudins, ZOs, and
MUC2, can result in augmented intestinal permeability and
compromised nutrient transport. In addition, the disrup-
tion of tight junctions has been implicated in developing
inammatory bowel disease, irritable bowel syndrome, and
infectious diarrhea (Dong et al., 2019).
On the other hand, previous works have report the
toxicity of TTEO in epithelial-like cells (Hela), at IC50 of 2.7 ±
0.07 g/L (Carson and Riley, 1995). Likewise, toxicity tests were
also reported in ICR male mice using nano TTEO emulsions
in agreement with the guidelines drawn up by the Organi-
zation for Economic Co-operation and Development. In this
context, it was shown that TTEO nanoemulsions showed
lower toxicity (oral LD50 1656 mg/kg) compared to TTEO alo-
ne (oral LD50 854 mg/kg). Similarly, the antibacterial activity
against Salmonella typhimurium and E. coli has been tested
in vitro, concluding that TTEO can be used as a potential oral
antimicrobial agent (Wei et al., 2021). Emulsions have been
proposed as a strategy to make ecient use of TTEO. This sys-
tem allows for the encapsulation and protection of bioactive
compounds in droplets, with sizes ranging from micrometers
to nanometers (Singh and Pulikkal, 2022).
The mechanisms underlying the eects of TTEO are
multifaceted and contingent, on both the administered do-
ses and the specic characteristics of the studied pathogen.
These ndings endorse TTEO’s suitability as a potential oral
antimicrobial agent. Moreover, the adoption of emulsions
as a delivery strategy for TTEO is proposed, presenting an
ecient means to encapsulate and safeguard bioactive
compounds, oering potential applications in antimicrobial
interventions.
Challenges in the development of treatments based on
essential oils
Eective implementation of essential oil-based antibacterial
treatments faces multifaceted challenges that require careful
attention in development and clinical application. The varia-
bility in the composition of these oils raises questions about
the identication of essential compounds, and determining
optimal concentrations for consistent antibacterial activity.
Furthermore, addressing technical challenges in formulation
and administration, along with the need to achieve clinical
acceptance, completes the picture of challenges that must
be overcome to fully exploit EO’s therapeutic potential in
treating bacterial infections.
On the other hand, regulation of the consumption of
essential oil-based products varies signicantly depending
on the jurisdiction and the specic purpose of the product. In
general, EOs are commonly used in dietary supplements and
cosmetic products, and regulations cover aspects such as
labeling, allowable concentrations, and safety requirements.
When used for medicinal purposes, some countries may sub-
ject these products to more rigorous regulations. Regulation
on alternative therapies can be diverse, from limited to more
detailed, depending on local laws. Safety and toxicity are key
considerations, with regulatory agencies evaluating the safe-
ty of EO and setting limits to protect consumers. Additionally,
in the marketing of dietary supplements, specic regulations
regarding content and health claims may apply. Given the
constant evolution of the EO industry, consumers and ma-
nufacturers should stay informed about local regulations
and consult with relevant authorities to ensure regulatory
compliance, empowering them with the knowledge to make
informed decisions.
The acceptance of products based on EO is diverse and
depends on several factors. In recent years, there has been a
rise in the popularity of these products, driven by increasing
attention towards natural and alternative approaches to
wellness. Acceptance may be inuenced by factors such as
knowledge and education about the associated benets and
risks, personal experience with positive results, cultural and
traditional attitudes towards natural medicine, and the ge-
neral perception of eectiveness. However, acceptance may
also vary depending on individual perceptions of alternative
medicine and preference for more conventional approaches.
Considering EO as an oral treatment for gastrointestinal
bacterial infections involves several key factors. Although in
vitro studies suggest antimicrobial properties, the transition
to clinical ecacy requires further investigation. Local regu-
lations and safety should be considered, as some EOs can be
toxic in large quantities in clinical practice. The diversity of
gastrointestinal infections and the variability in ecacy aga-
inst dierent pathogens are important to evaluate. Finally,
using EOs in this context requires not just consideration but
also careful evaluation and medical supervision to ensure
safety, ecacy, eectiveness, and consideration of individual
circumstances, thereby reassuring patients and healthcare
professionals about the thoroughness of the treatment pro-
cess.
CONCLUSIONS
As described, public health concerns about antibiotic-
resistant bacteria are growing worldwide. So, essential oils
may oer an alternative or adjuvant solution to establish
new treatment strategies. Essential oils such as TTEO can po-
tentially be used to treat gastrointestinal diseases associated
with bacteria, because of their excellent antimicrobiological
properties. However, the eects reported in the literature are
primarily in vitro studies. So, further studies in animal models
are required to investigate the TTEO properties.
ACKNOWLEDGMENTS
The author thanks CIAD and CONAHCYT for supporting this
review.
Volume XXVI
González-González et al: Bacterial resistance in diarrhea and tea tree oil as a / Biotecnia 26:e2270, 2024
7
CONFLICTS OF INTEREST
The authors declare no conict of interest.
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