CHAPTER NO.

01

INTRODUCTION

1.1 PROBIOTICS

The term "probiotics" is derived from the Greek word "pro bios," which means "for life."
The internationally recognised definition of probiotics is "live microorganisms that when
administered in adequate amounts, confer a health benefit on the host". Probiotics are viable
microorganisms and have multiple beneficial side effects. (WHO 2000)(Bodke et al., 2022).

Probiotics are foods and/or supplements that contain non-pathogenic microbes like
bacteria and yeast that colonise the gut and may have a number of health benefits. Their ability to
alter the host's immune response, oppose pathogenic microbes, or compete with pathogenic
microorganisms for adhesion sites is related to their action against microorganisms(Gupta et al.,
2009).

1.1.1 STRAINS OF PROBIOTICS

1.1.1.1 Lactobacillus species
 L.acidophilus
 L.crispatus
 L.brevis
 L.delbreukii
 L.gasseri
 L.reuteri
 L.casei
 L.plantarum
 L.rhamosus

1.1.1.2 Bifidobacterium species

 B.bifidum
 B.longum
 B.lactis
 Basilus subtilus
1
 B. infantis
 B.breve
 B.animalis
 B.adolescentis

1.1.1.3 Others

 Enterococcus faecalis
 Streptococcus cremoris
 Basilus subtil
 Escherichia choli
 lactococcus lacticus
 Saccharomyces boula
 Streptococcus thermophilius (Kesen et al., 2018).

1.1.2 APPEALING FEATURES OF PROBIOTICS

 A supply of nutrients, such as proteins, fatty acids, and vitamins, which are necessary for
healthy cell development.
 Prevent IBS by maintaining a healthy composition of gut microbiota.
Endogenous and exogenous pathogen suppression and eradication, i.e., preventing food
poisoning and infection.
 The development of the colon epithelium improves nutrition absorption by producing
vitamins and short-chain fatty acids.
 Lower colon cancer risks, which include the gut's metabolism of toxins and mutagens.
 Immunomodulation, which includes elevated macrophage activity, antibody immunity,
inflammatory bowel syndrome, food allergies, and innate immunity.
 Bile salt sequestration, or lowering of blood cholesterol.
 Curing lactose intolerance with lactose hydrolysis (Kesen et al., 2018).

1.1.3 HEALTH ISSUES ADRESSED BY PROBIOTICS

2
  Probiotics can be used to treat acute infectious diarrhoea
 Prevent antibiotic-associated diarrhoea
 Treat Helicobacter pylori infection
 Treat irritable bowel syndrome
 Treat ulcerative colitis
 Treat pouchitis
 Treat diverticular disease of the colon
 Treat infantile colic
 Treat radiation enteritis
 Treat necrotising enterocolitis
 Treat gastrointestinal cancer
 Treat fatty liver disease, and more(Valdovinos-García et al., 2019).
1.1.4 BASIC CRITERIA FOR ASSESSING THE PROBIOTIC EFFECTIVESS

1. That when germs are supplied, they must be alive in sufficient quantities.
2. Strains need to be recognised genetically, categorised using the most recent
nomenclature, and assigned names, numbers, or letters.
3. To identify a strain as a probiotic and use the strain or strains on the host to whom the
probiotics are intended (human, livestock, companion animal, etc.), investigations of a
suitable size and design must be conducted.
4. Strains that have been demonstrated to be beneficial for one ailment might not be
probiotic for another.
5. It is important to precisely identify strains utilised in animal investigations as human
probiotics undergoing experimental testing (Reid et al., 2019).

1.1.5 CRITARIA FOR SELECTION OF PROBIOTICS

Probiotics need to have specific qualities in order to be effective. Probiotics are chosen
based on their capacity to attach to the gastrointestinal mucosa, their competitive exclusion of
pathogens, and their tolerance to gastrointestinal conditions (bile and stomach acid).
It has long been suggested that a beneficial probiotic should have the following
requirements:
 A proven positive impact on host.
3
  Have no serious negative side effects, be non-toxic, and not be pathogenic.

 Have the capacity to endure both in vitro and in vivo via the gastrointestinal tract (GIT).

 Exist in the product in a sufficient quantity of living cells to provide the desired health
effect.

 Must be appropriately branded and suitable with the product matrix, processing, and
storage conditions to preserve the intended qualities(Fontana et al., 2013).

1.1.6 SOURCES OF PROBIOTICS

FOOD COUNTRY INFREDIEN MICROORGANISMS BENEFITS

TS
Acidophilu Various cow milk Lactobacillus acidophilus, Itestinal
s milk countries Lactobacillus. conditions
deLactobacillus rueckii such as
subsp. persistent
bulgaricus, diarrhoea,
Lactobacillus. helveticus, constipation,
Lactobacillus. paracasei sprue, colitis
subsp.
paracasei,
Lactobacillus. paracasei
subsp.
pseudoplantarum
Butter milk Various Cow milk Lactobacillus. bulgaricus, Stimulates the
(various countries Lactococcus. lactis subsp. power of
local lactis, digestion,
names) Lactococcus. lactis subsp. treating
cremoris, hemorrhoids,

4
 Lactococcus. lactis subsp. IBS and other
lactis biovar abdominal
diacetylactis, disorders.
Leuconostoc. mesenteroide
s subsp.
cremoris
Cheese Various cow milk, or Lactococcus. lactis subsp. It creates a
countries goat milk, or lactis, buffer against
sheep milk Lactococcus. lactis subsp. the high
cremoris, acidic
Sterptococcus environment
Thermophilus,
Lactobacillus. helveticus,
Lactobacillus.
deLactobacillus rueckii
subsp.
bulgaricus, yeasts, molds
Caplis Japan Cow milk `Lactobacillus. helveticus, The source of
Saccharomyces cerevisiae proteins, fat,
vitamins and
minerals.
Dahi India, Cow mil or Lactococcus. lactis subsp. Intestinal
( yogurt) pakistan buffalo milk cremoris, disorders
Lactococcus. lactis subsp. (dyspepsia,
lactis, dysentery,
Sterptococcus diarrhoea,
Thermophilus, etc);
Lactobacillus. improved
deLactobacillus rueckii digestion,
subsp. antibacterial
bulgaricus effects in gut
5
 Lactobacillus acidophilus,
Lactobacillus. helveticus,
Lactobacillus. fermentum,
Lactobacillus. casei,
Lactobacillus. Plantarum
Sour milk Egypt , Cow milk Lactococcus. lactis subsp. Promote
Pakistan lactis, gastrointestin
Staphylococcus. kefir, al digestion
Staphylococcus.
cittrovorus,
Lactobacillus. casei,
Lactobacillus. plantarum,
Lactobacillus. brevis,
micrococci, coliforms
Yogurt Various cow milk Lactobacillus bulgaricus, Relieve
(also countries primarily, Lactobacillus acidophilus, lactose
known as sheep milk, Lactobacillus. casei, intolerance,
dahi, leben, goat milk, Sterptococcus constipation,
goidu, dahi) buffalo milk Thermophilus, diarrhea,
Lactococcus. lactis subsp. inflammatory
Lactis bowel
disease, etc.

(Zhao et al., 2019).

1.1.7 FUNCTIONAL PATHWAY OF PROBIOTICS

Although the precise process by which probiotics achieve their therapeutic benefits is not
fully understood, a number of hypothesised mechanisms have been proposed to account for
many of their positive effects.

6
 One of these mechanisms is a competition for adhesion sites, meaning that probiotics
compete for cellular attachments. While many pathogenic organisms need to attach to the GIT
tract epithelium in order to colonise successfully, some strains of bifidobacteria and lactobacilli
can adhere to the epithelium and function as "colonisation barriers" by preventing pathogens
from adhering to the mucosa. This effect was demonstrated with the lactobacillus plantarum and
Lactobacillus rhamnosus strain GG, both of which exhibit the capacity to inhibit Escherichia
coli's attachment to the human colon cell.

Modification of microbial flora by the production of anti-microbial chemicals is another

potential mode of action. Bacteriocinsor and other antimicrobial substances are produced by a
variety of lactobacilli and bifido bacteria. "Compounds produced by bacteria that have a
biologically active protein moiety and a bactericidal action" is the definition of bacteriocins. The
lactic acid bacteria also create short-chain fatty acids, di-acetyl, and hydrogen peroxide, among
other physiologically active substances. The microflora is advantageously modified as a result of
pro-biotic organisms releasing these chemicals. Some strains of bifidobacteria or lactobacilli,
however, create antimicrobial chemicals that are very non-specific in their action, which may
have an adverse effect on both pathogenic organisms and helpful bacteria. Additionally,
probiotics have been shown to boost the immune system. The immunological response might
manifest as increased immunoglobulin-A discharges, a rise in natural killer cells, or increased
macrophage phagocytic activity. Increased IgA secretions may improve the composition of
microflora by reducing the number of harmful organisms in the gut. Because of their immune-
modulating properties, pro-biotics may help treat illnesses including inflammatory bowel
disease, pouchits, food allergies, and as an adjuvant to vaccinations in addition to fighting
intestinal and urogenital infections. Additionally, probiotics could compete with infections for
nutrients that they would otherwise need. The case involves the potentially harmful bacteria
Clostridium difficile, which grows only on monosaccharides. When there are enough probiotic
organisms, they can use up the majority of the available monosaccharides, which inhibits C.
difficile (Khalighi et al., 2016).

1.1.8 AVAILABLE PROBIOTIC FORMULATIONS

7
 Probiotic organisms can be consumed in two main forms: supplements and fermented
meals. Dairy and vegetable-based fermented foods are both possible; the most well-known of
these are yoghurt and sauerkraut, respectively. Freeze-dried bacteria are included in probiotic
supplements in the form of powder, capsules, and tablets. Products containing probiotic
organisms must include enough live organisms to provide therapeutic benefits, regardless of the
manner in which the microbes are taken. This is possible with both fermented foods and
supplements.
The following lists the benefits and drawbacks of popular probiotic delivery methods:

8
Delivery system Pros Cons
Fermented dairy  Cost-effectiveness and  Contains lactose (
accessibility and dairy proteins. K
 Simplicity in  Taste may be h
integrating into problematic a
everyday routines  Vegetarians l
 Improved bacterial shouldn't use it. i
survival g
 Good for the upper h
gastrointestinal tract  i
Capsules  Simple to administer  May include
 Does not include a excipients that
binder cause allergies
 Not therapeutic in
the upper
gastrointestinal tract
 More expensive
Tablets  Simple to use  May include
 Beneficial for the excipients and
upper gastrointestinal binders that are
tract allergic or otherwise
troublesome.
 More expensive
Powders  Easily adjustable
dosages
 Suitable for use in
meals and beverages
 Effective in the upper
gastrointestinal tract

et al., 2016).
1.2 RATIONALE OF THE STUDY

9
 The emergence of various diseases in recent times can be ascribed to several elements,
like as inadequate healthcare facilities, limited knowledge, low literacy rates, and an
underdeveloped health system. These challenges highlight the urgent need for innovative
approaches to improve health outcomes. This research attempts to assess how well probiotics
work in managing different complications as an alternative to conventional therapies, which
often come with significant adverse effects. By focusing on the potential benefits of probiotics,
this research seeks to overcome the existing healthcare challenges and provide a safer, more
effective treatment option. Probiotics, with their lower incidence of adverse effects, offer a
promising solution to enhance patient care and address the healthcare gaps prevalent in our
current system.

1.3 SIGNIFICANCE OF THE STUDY

The significance of an assessment of probiotic usage in different complications is

multifaceted. Probiotics An evaluation of probiotic use in maintaining and restoring gut health,
which is intricately linked to the various physiological systems and disease processes.
Understanding their impact on different complications can lead to innovate treatment strategies,
potentially reducing the reliance on conventional therapies that may have adverse effects. This
study could provide critical insights into optimizing probiotic intervention, enhancing patient
outcomes and contributing to the body knowledge in integrative and preventive medicine.
Moreover, the findings may inform clinical guidelines and public health polices, promoting a
broader adoption of probiotics as a complementary approach in managing complex health
conditions.

1.4 OBJECTIVES OF THE RESEARCH

 To evaluate probiotics' efficacy in various clinical complications.
 To determine Probiotics' safety profile when use in different patient populations in
various health conditions.
 To optimize the dosage and administration routes of probiotics for maximum
therapeutic benefit in various complications.
 To create evidence-based recommendations that can inform clinical rules and
practices in order to use probiotics in managing different complications.

10
 CHAPTER NO.02

LITERATURE REVIEW

2.1 BACKGROUND

11
 The word "probiotic," which comes from the Greek and means "for life," has taken on
several connotations over time. The ancient Greeks and Romans were the first to consume
fermented foods, which is how probiotics got their start. According to Genesis 18:8, which states
that "Abraham owed his longevity to the consumption of sour milk," fermented milks were likely
the first meals to contain live bacteria. Even now, people continue to consume fermented milks
in a variety of ways. Early in the 20th century, scientists identified the health benefits of yoghurt.
Nobel Prize laureate Ilya Ilyich Metchnikoff (1908, 1910), who worked at the Pasteur Institute in
Paris, France, was the first to suggest that fermented milk was good for human health. He also
believed that the microbiota in the lower intestine had a negative impact on an adult's health. He
proposed the idea that consuming helpful bacteria may lessen the impact of harmful germs in the
digestive system. Metchnikoff further proposed that the eating of yoghurt made by fermentation
with Lactobacillus bulgaricus (formerly known as the Bulgarian bacillus) was responsible for the
lifespan of the Bulgar mountain people (Anadón et al., 2021).

Lilly and Stillwell coined the word "probiotic" in 1965 to refer to compounds released by
one organism that promote the development of another. The German scientist Werner Kollath
coined the term "probiotic" in 1953 to refer to "active substances that are essential for a healthy
development of life." The phrase comes from the Latin pro and the Greek "βιoσ," which literally
means "for life." Lilly and Stillwell used this phrase in 1965 to refer to "substances secreted by
one organism which stimulate the growth of another" in a different context. More precisely,
Fuller (1992) described probiotics as "a live microbial feed supplement which improves the
intestinal microbial balance of the host animal in a positive way."(Santacroce et al., 2019).

Beginning in the early 1900s, Russian scientist Elie Metchnikoff, who would go on to
win the Nobel Prize, conducted groundbreaking research on probiotics at the Pasteur Institute in
Paris. While Metchnikoff first sought to determine the potential impact of these germs on human
health, Louis Pasteur discovered the microorganisms that drive fermentation. He linked the
frequent eating of fermented dairy products like yoghurt to the longer lifespans of Bulgarian
rural residents(Khalighi et al., 2016).

2.2 LITERATURE STUDIES

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 To assess the use of Bacillus clausii (Enterogermina)® at Italian community
pharmacies among self-medicating patients, their treatment habits, and perceived benefits, a
multicenter, prospective, non-interventional study was carried out at 18 pharmacies across
various geographical zones of Italy between October 2019 and April 2021. Two visits were
included in the study: one at screening (T0) and one at the end (T1), when symptoms were
decreased and the time frame was less than 30 days from T0. At T0 and T1, patients who were
previously predisposed to purchase B. clausii were enrolled and given questionnaires to fill out.
Evaluating the rationale of taking this probiotic species was the main goal. Secondary goals were
determining the length of therapy, perceived efficacy, quality of life, treatment satisfaction, and
safety results. The findings of the study showed that diarrhoea was the most frequent cause of
usage, with B. clausii showing a high degree of perceived efficacy and patient satisfaction. Those
who had diarrhoea or stomach discomfort received treatment for a shorter period of time than
those who experienced constipation and abdominal tension. Over 90% of people said their
symptoms had significantly improved. Approximately 90% of patients expressed satisfaction,
high satisfaction, or intense satisfaction with their therapy. There were no recorded negative
incidents(Giua et al., 2024).

The two researchers, G.V. and C.S., conducted the systematically reviewed study in
accordance with the preferred reporting items for systematic reviews (PRISSMA) guidelines.
They searched the PubMed database on December 31, 2021, for observational and randomised
studies that looked at the potential role of probiotics in causing and sustaining remission in
ulcerative colitis and Crohn's disease. One study was from Canada, India, Belgium, and Portugal;
five were from the UK and Italy; four were from China; two were from France, Germany,
Turkey, and Denmark; and six were from Japan. An initial search of the PubMed database
yielded 6237 articles, of which 16 were found following a study of the references. The results of
the study showed that probiotics are a practical treatment option for ulcerative colitis patients,
particularly when paired with conventional therapy. While bifidobacterium spp. was the only
strain that had favourable outcomes in Crohn's disease, symbiotic treatment and formulations
based on lactobacillius spp. and bifidobacterium spp. were the most successful alternatives for
individuals with ulcerative colitis(Vakadaris et al., 2023).

13
 A meta-analysis and systematic review A research based on clinical trials was conducted
in May 2021 to assess the impact of probiotics on problems following surgery for colorectal
cancer (CRC).Out of the 2518 studies that were included, 13 were used in the meta-analysis and
16 underwent in-depth reviews. Probiotic supplements have been shown to lower the risk of
surgical site infections, sepsis, pneumonia, diarrhoea, ileus, and abdominal collection. In
particular, the most successful strategies for lowering surgical site infections included lower
probiotic dosages, longer supplementation durations, and beginning probiotics a few days prior
to surgery and continuing long after(Chen et al., 2022).

To assess the impact of probiotic and symbiotic use on glycaemic control in women with
gestational diabetes, a study based on a systematic review and meta-analysis was conducted at
Sakarya 54050, Turkey, in compliance with the Preferred Reporting Items for Systematic
Review and Meta-analysis (PRISMA-2020) statement. Of the 719 papers retrieved up to june
2022, 12 possibly suitable research were selected. A meta-analysis was conducted using eight of
these randomised controlled studies. Probiotic usage is a promising prospective therapy to help
with glycaemic management in gestational diabetes mellitus, as the data showed that it lowered
fasting plasma glucose and fasting serum insulin in women with GDM (gestational diabetes
mellitus) but had no effect on HbA1c(Özdemir et al., 2022).

Between November 2019 and May 2020, a randomised, double-blind, placebo-controlled

trial was carried out in Poland to assess the safety and efficacy of multi-strain probiotics in adults
with diarrhea-related diagnosed irritable bowl syndrome. The Helsinki Declaration's ethical
guidelines for sound clinical practice were followed in the conduct of the study. The Children's
Memorial Health Institute's institutional bioethical committee gave its approval to the trial. Male
and female patients over the age of 18 to 70 who were diagnosed with IBS-D based on the Rome
III criteria—that is, who had at least one stool evaluated on the Bristol stool scale as type 5, 6, or
7 for at least two days per week—were included in the study. Coexisting serious conditions such
diabetes mellitus, uncontrolled hypertension, and cancers were excluded. According to the study,
probiotic preparations containing lactobacillus, Bifidobacterium, and Streptococcus thermophilus
strains and given at a dose of 5 billion CFU for 8 weeks had better effects than a placebo. The
probiotic was safe, well-tolerated, and improved both general IBS symptoms and specific

14
symptoms related to pain intensity and quality of life. This demonstrated that multi-strain
probiotic preparations are beneficial for adults with IBS-D (Skrzydło-Radomańska et al., 2021).

In order to determine who uses probiotics and why, a cross-sectional study was carried
out in the endoscopy suite of an academic hospital in New York between June and October 2019.
Multiple-choice, free-text, and Likert scale items were all included in the anonymous surveys.
The characteristics of probiotic users and non-users were compared using multivariable logistic
regression modelling and descriptive statistics. According to the study's findings, probiotic usage
is widespread among patients with general gastroenterology, and many of them think that
probiotics have broad rather than particular advantages for their health. Probiotic usage seems to
be motivated by symptoms, particularly bloating(Lynch et al., 2021).

Dixon and colleagues at Griffith University in Australia carried out a comprehensive

review and meta-analysis in 2020 to look into the effectiveness of probiotics in lowering risk
factors for cardiovascular disease. The study concentrated on variables that are important
predictors of CVD risk, including high blood pressure, cholesterol, glucose levels, and body
mass index. 34 randomised controlled studies with 2177 individuals that were published between
1990 and 2020 were considered in the study. The outcomes showed that the probiotic
intervention significantly decreased total cholesterol, systolic and diastolic blood pressure,
HbA1c, and BMI. Tryglycerides showed no discernible changes, whereas HDL cholesterol levels
rose. Subgroup analysis showed that the kind of formulation, length of therapy, and patient
demographic—such as diabetic patients—all had an impact on how beneficial probiotics were.
Probiotics worked better with longer courses of therapy, larger dosages, and particular
formulations like kefeir and powder(Dixon et al., 2020).

Using the Appraisal of Guidelines, Research and Evaluation (AGREE) II criteria, a

comprehensive literature analysis was carried out to find placebo-controlled randomised
controlled trials (RCTs) assessing the impact of probiotics on lower gastrointestinal (GI)
symptoms. In order to grade the evidence and reevaluate previously developed statements, an
expert panel used the Delphi method to reach a consensus on studies published between January
2012 and June 2017. A total of 70 studies were included, divided into the following disorders:
diarrhoea related to antibiotics (13 studies), Helicobacter pylori eradication therapy (7 studies),

15
irritable bowel syndrome (34 studies), and other conditions (16 studies). Eight of the fifteen trials
that evaluated global IBS symptoms as a main outcome found that probiotics significantly
outperformed a placebo.Consensus statements with 100% agreement and classified as having a
"high" level of evidence showed that certain probiotics can, while maintaining favourable safety
profiles, reduce the duration and severity of diarrhoea in patients receiving antibiotic treatment or
H. pylori eradication therapy, as well as the overall symptom burden and abdominal pain in some
IBS patients. Certain probiotics may also lessen bloating and distension and improve the
frequency and regularity of bowel movements in certain IBS patients, according to statements
with 70% to 100% agreement and classified as having "moderate" evidence(Hungin et al., 2018).

Using the PubMed, MEDLINE, and Cochrane databases, a systematic review was
conducted in 2018 to determine the mechanisms underlying the effectiveness of probiotics and
synbiotics in reducing the rates of SSIs/SRCs in patients undergoing various surgical treatments.
The study found that probiotics and synbiotics significantly decreased inflammation markers
(CRP and IL-6) and increased beneficial acids in the gut, as well as reducing surgical
complications such as abdominal distention, diarrhoea, pneumonia, sepsis, surgical site
infections, urinary tract infections, and shorter hospital stays. By boosting short-chain fatty acids
and enhancing the gut-immune response, probiotics and synbiotics are beneficial(Skonieczna-
Żydecka et al., 2018).

In order to examine the relationships between the usage of probiotic-containing food

items or supplements and several health indicators in a sizable sample of people with type 1
diabetes, cross-sectional research was carried out in a hospital environment as part of the
FinnDiane cohort. Numerous metabolic abnormalities were often seen in people with type 1
diabetes, which may have had a detrimental impact on their long-term health. In other
populations, probiotic usage has been positively linked to a number of these risk factors.1039
people with type 1 diabetes who did not have end-stage renal disease were included in the
research; Probiotics yes and Probiotics no are the names of persons who utilised and did not use
them, respectively. During the research visit, a number of common health indicators were
examined using information from food records and diet questionnaires, including weight, waist
circumference, blood pressure, blood lipids, and HbA1c.403 (39%) of the participants said they
used probiotics. Individuals in the Probioticsno group showed greater rates of
16
overweight/obesity, body mass index, and waist-to-hip ratio after controlling for possible
confounders. Furthermore, individuals who did not take probiotics had a greater chance of
developing metabolic syndrome and its constituent parts, such as triglycerides, blood pressure,
waist circumference, and HDL cholesterol. Probiotic use was linked to noticeably improved
glycaemic management in people of normal weight. The analysis found that several of the
conventional risk variables for diabetes complications may have been positively impacted by the
usage of probiotic-containing dietary items or supplements. Randomised controlled studies,
however, are necessary to confirm these findings(Ahola et al., 2017).

Between June 2013 and February 2014, 50 volunteers with type II diabetes who had been
diagnosed for at least a year participated in a double-blind, randomised, placebo-controlled study
in Ceara, Brazil. They were given either probiotics or ordinary fermented milk every day for six
weeks. While the control group drank regular fermented milk, the probiotic group drank
fermented milk that included Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp
lactis BB-12 (each at 109 colony-forming units per day). At the start and finish of the
investigation, blood and faecal samples were collected, together with measurements of body size
and composition The results confirmed that taking probiotics helped T2D patients' glycaemic
management, although fermented milk consumption seemed to be linked to further metabolic
alterations such a drop in inflammatory cytokines and an increase in acetic acid(Tonucci et al.,
2017).

The function of probiotics in the 21st century for recurrent UTIs was the subject of a
thoroughly researched study in 2022. Every English-language paper that reported on cohort
studies and randomised trials was chosen, and patients with neurogenic bladders and those under
the age of eighteen were not included. Nine publications in all, with a mean age of 34.2 years
(range: 18–65 years) and a range of probiotics utilised, satisfied the inclusion criteria. Studies
have repeatedly demonstrated that probiotics may lower the risk of rUTIs. Additionally, it was
shown that the patient's tolerance and side effect profile are restricted, allowing for high patient
compliance(New & Theivendrampillai et al., 2022).

The Korean National Health and Nutrition Examination survey conducted a cross-
sectional analysis between 2012 and 2016 to assess the relationship between probiotic food

17
intake and depression status in the country. Between 26 and 118 people between the ages of 19
and 64 made up the study population. Consumption of probiotic foods was measured using a
food frequency questionnaire. A patient health questionnaire (PHQ-9) and self-reported clinical
diagnosis were two of the approaches used to identify depression state. The findings suggest that
eating foods high in probiotics may help reduce depression, especially in males. However,
further research is needed to determine the precise mechanisms behind the relationship between
probiotics and depression(Kim et al., 2019).

A thorough research examined the efficacy of probiotics in treating individuals with irritable
bowel syndrome (IBS) from September 2007 to December 2013. 1793 IBS patients were
included in the meta-analysis, which found that probiotics significantly outperformed placebos.
In particular, probiotics significantly reduced overall symptoms (RR 2.43) and stomach
discomfort (RR 1.96). They also showed significant improvements in overall symptoms (RR
2.14) over the course of seven trials. Furthermore, with a standardised effect size of -2.57 when
compared to placebos, probiotics shown a substantial advantage in reducing symptoms such
distension, bloating, and flatulence. The findings supported the hypothesis that probiotics, as
opposed to a placebo, are beneficial for IBS patients.(Didari et al., 2016).

Prior to 2015, a study based on randomised controlled trials was conducted in China to
assess the effectiveness of probiotics in treating non-alcoholic fatty liver disease (NAFLD) in
both adults and children. Numerous databases, including the Cochrane Library,
PubMed/MEDLINE.EBSCO, OVID, SCI, CNKI, and VIP, were searched for this study. The
meta-analysis was conducted using RevMan 5.3 software.A total of 535 NAFLD cases from nine
randomised controlled trials were included. Probiotics improved the outomes of homeostasis
model assessment, total cholesterol, high density lipoprotein, and tumour necrosis factor-a in all
NAFLD patients, as well as triglycerides in Italian and Spanish patients, according to the study's
findings. However, probiotics had no effect on BMI, glucose, or insulin in adult NAFLD
patients. The information provided was insufficient to compare the effects of probiotics on
NAFLD patients in children and adults(Gao et al., 2016).

Between June 2022 and October 2020, a cross-sectional online survey was conducted in
the Netherlands to find out how women with recurrent UTIs and vaginal infections used

18
alternative medications and self-care techniques, as well as how successful they felt. Nutrition
and dietary supplements are examples of self-care, and the CM has been defined for this study as
a collection of various medical and healthcare experts. Online recruitment was used to find
female volunteers over the age of 18 who had a history of UTIs. The replies were assessed using
descriptive statistics, including measures of proportions, frequencies, and central trends. The
results of the study provided empirical support for the significant impact of VI and UTIs on
everyday and sexual activities. The indications for perceived success appear to be crucial for
future, carefully planned research to support the use of nonantibiotic/antifungal treatments in
practice, in addition to usage frequency(Witteman et al., 2021).

In accordance with the consolidated standards of reporting trials guidelines, a four-month

prospective randomised double-blinded clinical trial was carried out to assess the impact of
probiotic supplementation on the clinical and paraclinical findings of multiple sclerosis in
patients with a documented diagnosis of relapsing remitting multiple sclerosis who were referred
to the outpatient specialised and subspeciality clinics of Emam Reza hospital of Tabriz
University of Medical Sciences between June 2021 and March 2022. Following a two-week
washout period, the qualified patients were randomised to probiotic and placebo group.
According to the study's findings, the probiotic group's serum antioxidant capacity was
noticeably higher than that of the placebo group. Malondialdehyde, a measure of oxidative stress,
decreased in both the probiotic and placebo groups, although there was no discernible difference
between them. In comparison to the placebo group, the probiotic group had a substantial
reduction in both the level of pain and the degree of exhaustion. The results of the study
indicated that oxidative stress indicators and inflammatory markers could benefit from the
saccharomyces boulardii probiotic supplement. MS sufferers' pain, exhaustion, and quality of
life(Asghari et al., 2023).

In order to determine whether a food supplement containing two probiotic strains—

Limosilactobacterium reuteri and Bafidobacterium breve—could help 33 healthy adults working
at a university manage their stress following COVID-19, a double-blind, cross-over, placebo-
controlled clinical study was conducted in the pharmacy department of the University of
Calabria, Italy, between March 2021 and June 20211. Men and women in good health were the
study's subjects. 20–60 years old. The study's objective was to increase mood and sleep quality
19
by lowering perceived stress throughout the epidemic. The trial lasted for ninety days. The
results gathered confirmed that the probiotic group significantly reduced their overall mood score
and sleep quality when compared to the placebo group(Nobile et al., 2023).

One institution, the Division of Periodontology at the Bolu Abant Izzet Baysal University
Faculty of Dentistry, carried out a study to assess the frequency of probiotic use and fermented
food intake as preventative measures against per-implant illnesses in 2023. There were 126
implants in all. Using Chicago's Classification of Peridontal and Peri-implant Diseases and
Conditions, the health state of the peri-implant was evaluated. The consumption habits of
fermented and probiotic foods and products were assessed using a questionnaire. The results of
the study demonstrated that peri-implant health may be linked to increased consumption of
fermented and probiotic foods. Probiotics and fermented foods may help patients with implants
avoid developing peri-implant illnesses(Sahin et al., 2024).

In June 2017, the European Paediatric Association convened an expert panel to examine
and synthesise the position papers, guidelines, recommendations, and high-quality research, as
well as to identify the pertinent clinical questions for the use of probiotics in paediatric health
care. The panel discovered that a particular strain of probiotic was useful in treating acute
gastroenteritis, avoiding antibiotic-associated and nosocomial diarrhoea, and curing infantile
colic in breastfed babies. However, those with central nervous catheters, heart valvular disease,
short-gut syndrome, immunocompromised and severely unwell patients, and preterm newborns
were advised to exercise extra caution. It shown that probiotic effectiveness varies by
strain(Hojsak et al., 2018).

In 2017, a systematic review-based study was conducted in Denmark to evaluate the

advantages and disadvantages of using probiotics in an outpatient environment to prevent
antibiotic-associated diarrhoea (AAD). Following a search of the PubMed database, 17 RCTs
with 3631 participants were found and added to the review. The incidence of AAD, the main
outcome, was the subject of a meta-analysis. AAD was determined to be 8.0% in the probiotic
group and 17.7% in the control group, according to the pooled data. The species-specific results
for the probiotic strains L. rhamnosus GG and S. boulardii were comparable. There were no
statistically significant changes in the incidence of adverse events between the intervention and

20
control groups, according to a meta-analysis of the 10 studies that reported adverse events. The
results let people realise that using probiotics might help outpatients avoid developing AAD.
Additionally, probiotic usage seemed to be safe (Blaabjerg et al., 2017).

The effect of probiotics and synbiotics on the gut microbiota of patients with colorectal
cancer is examined in a comprehensive review titled "Role of probiotics in modulating Human
Gut Microbiota Populations and Activities in patients with Colorectal Cancer." Randomised
control studies with a median age of 65.4 years and 457 patients, mostly from Europe and Asia,
were included in the study. These trials were published up to 2021. These studies assessed the
benefits of probiotics, including Lactobacillus and Bifidobacterium species, during timeframes of
6–78 days. The findings showed that the makeup of the gut microbiota had significantly
improved, with a rise in beneficial bacteria such as Lactobacillus and Enterococcus. Probiotic
treatments have also been connected to improved surgical outcomes, decreased inflammation,
and enhanced gut barrier function in CRC patients(Wierzbicka et al., 2021).

Probiotics have been shown to have a beneficial effect on lowering the length and
severity of acute diarrhoea in children, especially in those who are dehydrated, according to a
systematic review and meta-analysis on the subject. This study, which was conducted across
several randomised controlled trials, concentrated on children under the age of 18 who
experienced diarrhoea brought on by infectious agents. The findings consistently demonstrated
that probiotic medication decreased the number of bowel movements and, on average, shortened
the duration of diarrhoea by one day. Although advantages were also reported for other forms of
gastroenteritis, children with rotavirus-induced diarrhoea showed the most impact.(Wu et al.,
2021).

An open-label, randomised controlled trial called "a combination of three probiotic

strains for treatment of acute diarrhoea in hospitalised children" was carried out in Chengdu,
China, with the goal of determining how well probiotics work to shorten the length of diarrhoea
in kids. 194 children with acute watery diarrhoea, ages 1-3, who were admitted to the hospital
were included in the experiment. According to the results, children who received probiotic
treatment experienced diarrhoea for a noticeably shorter period of time than those in control
groups. Additionally, a greater proportion of the probiotic group saw symptom alleviation within

21
24 to 48 hours, compared to 79.6% in the control group, and hospital stays were decreased by an
average of 1.2 days. Additionally, the probiotic group saw a considerably decreased incidence of
constipation(Chen et al., 2020).

Ahole et al. carried out a cross-sectional study to investigate the relationship between
health indices and self-reported probiotic consumption in people with Type I diabetes. The
participants were drawn from 1039 people with Type I diabetes who did not have end-stage renal
disease as part of the Finnish Diabetic Nephropathy research. Participants had to have finished a
dietary questionnaire within two years of their research visit in order to meet the inclusion
criteria. Individuals who had received a kidney transplant or had end-stage renal illness were not
included. Standard health measures, such as blood pressure following a 10-minute rest, height,
weight, and obesity, were obtained during the research visits. Descriptive statistics and statistical
tests like Mann-Whitney U-tests and chi-squared t-tests were employed in the investigation. To
investigate the connection between probiotic consumption and different health outcomes, logistic
regression and generalised linear regression were used. According to the study's findings, people
with Type I diabetes who take probiotics have better health indicators, especially when it comes
to glycaemic control and a lower risk of developing metabolic syndrome. To validate these
results, the authors stressed the necessity of randomised controlled trials(Zhang et al., 2023).

From October 2015 to March 2017, three neonatal intensive care units' worth of
extremely low birth weight infants participated in prospective controlled triple-centre cohort
research. Centre K (Klagenfurt) employed Bifidobacterium infantis, Lactobacillus acidophilus,
and fluconazole to conduct the trial, whereas Centre G (Graz) used a mixture of Lactobacillus
rhamnosus, gentamycin, and nystatin. Gentamycin and nystatin were employed by Centre L
(Leoben), but no probiotics were used. For the first two weeks of this life span, stool samples
were taken every other day, and the samples were analysed using an amlicon-based microbiome.
Seventeen of these were treated as negative controls. The study discovered that hospital routines
had a major impact on the amount, variety, and composition of the microbiome from birth to the
more developed microbiome that developed starting at two or three weeks of age. It was shown
that probiotics caused an earlier rise in the bacterial load, which may help to avoid newborn
morbidities. However, some notable individual differences were also discovered(Kurath-Koller
et al., 2020).
22
2.3 PREVALENCE

2.3.1 GLOBAL PREVALENCE

The global market for probiotics, including both food products (like yogurt, kefir, and
fermented foods) and dietary supplements, was valued at approximately USD 49.4 billion in
2020 and is expected to continue growing(Reid et al., 2005).

2.3.2 PREVALENCE IN PAKISTAN

Pakistan, like many South Asian countries, has a culinary tradition that includes
fermented foods like yogurt (often consumed as "lassi"), which naturally contain probiotics.
These traditional foods may contribute to a level of probiotic intake among the population (Ali et
al., 2019).

Probiotics were utilised in 51,723 (2.6%) of hospitalisations that took place in 139 (96%)
of the 145 hospitals that discharged 1,976,167 patients in 2012. Probiotic-using patients were 21
times more likely to be diagnosed with a Clostridium difficile infection (P <.0001) and 9 times
more likely to get antimicrobials (P <.0001). Saccharomyces boulardii accounted for 32% of
probiotic-treated patients, followed by Lactobacillus acidophilus and Lactobacillus bulgaricus
(30%), Lactobacillus acidophilus (28%), and Lactobacillus rhamnosus (11%). Between 2006 and
2012, probiotic usage rose from 1.0% of 1,090,373 discharges to 2.9% of 1,006,051 discharges
(P<.0001)(Sarah et al., 2016).

23
CHAPTER NO.03

METHODOLOGY

This chapter is all about methods and techniques used in research.

3.1 STUDY DESIGN

“A Cross-Sectional Study to Evaluate the Prescribing Patterns of Probiotics in

various Public and Private Hospitals” was conducted among all age groups in public and
private hospitals by adopting and culturally modifying a questionnaire to collect the needed
data. The questionnaire used consists of a few questions related to demographic factors,
probiotics prescribing trends and their effectiveness. We referred an existing study(Kim et al.,
2019) to assess the prescribing patterns of probiotics, whereby we provided different options
regarding probiotics with answers “yes”, “No”. The data was collected through self-
administration via convenient sampling.

In medical research a Cross-sectional studies, often referred to as cross-sectional

analyses, transverse studies, or prevalence studies, are a kind of observational research that
examines data from the population or a representative sample at a particular moment in
time(Kumar et al., 2018).

A descriptive study is a type of research study that aims to methodically explain a

scenario, problem, phenomenon, service, or program; it also furnishes information on, for
example, the living circumstances of a community; or it depicts attitudes towards a problem.
For instance, it might try to explain the kinds of services that an organisation offers, the
living conditions of Aboriginal people in the outback, community needs, the experience of
going through a divorce, the feelings of a child living in a home where there is domestic
violence, or the attitudes of staff members towards management. These studies' primary goal
is to outline the prominent aspects of the topic or subject being studied(Kumar et al., 2018).

The only distinction between an interview schedule and a questionnaire is that the
former involves the interviewer asking the questions and recording the respondent's responses
on an interview schedule, while the latter involves the respondents recording their own
responses. This distinction is significant in light of the respective advantages and
disadvantages of the two approaches. A questionnaire is a written list of questions, to which
24
 respondents respond after reading the questions, interpreting what is expected, and then
writing down their responses(Kumar et al., 2018).

3.2 STUDY SETTING

The research project was conducted in following settings included all departments of
private and government hospitals:

 Mirpur AJK (Divisional head quarter)

 Kotli AJK (District headquarter)

 Bhimber AJK (District headquarter)

 Sialkot Pakistan (Alkhidmat children hospital)

3.3 STUDY POPULATION

The study included randomly selected patients of all age groups that were taking
probiotics to assess the prescribing patterns of probiotics from the wards of above-mentioned
hospitals.

3.3.1 INCLUSION CRITERIA

The research study included patients of all age groups using probiotics and admitted to
wards. Moreover, patients who can understand English and Urdu, and who were willing to
participate voluntarily were included.

3.3.2 EXCLUSION CRITERIA

Inpatients who refused to participate in research were not included. Patients with severe
illnesses and conditions were not asked to complete the survey. Patients who were unable to
understand Urdu or English were not included. Probiotic-naive patients were not included in the
study.

3.4 STUDY DURATION

From the literature research to the questionnaire's creation, translation, and validation, data

25
gathering, and thesis writing, the study conducted from May to November 2024. The information
was gathered between September and November.

3.4 SAMPLING TECHNIQUE

Convenient sampling was used to gather the data, and the questionnaires were self-
administered under supervision. Members of the targeted population who satisfy specific
practical requirements, such as ease of access, close proximity, availability at a specific time,
or willingness to participate, are included in the study using convenience sampling, a non-
probability or non-random sampling technique(Etikan et al., 2016).
Self- administered surveys are one of the most used methods for gathering data in
research projects when respondents are invited to fill out questionnaires on their own(Babbie
et al., 2008). There are two forms of self-administered questionnaires: supervised and
unsupervised; one requires respondents to fill out the questionnaire in the presence of the
surveyor, while in the other respondent’s fill the survey themselves(Bourque et al., 1995).

3.5 SAMPLE SIZE

There is a universal sample size. Rao Soft was used to determine the sample size, which
came out to be 385 based on the average monthly population of patients at a hospital of 8400, a
5% margin of error, a 95% confidence level, and a 50% response distribution. We factored in
20% for incomplete and missing questionnaire responses.
In order to gather data, we distributed 460 questionnaires to inpatients. However, due to
time constraints, ethical considerations, exclusion criteria, and data refinement, 390
respondents with a 93.6% response rate were chosen to participate in this research-based study.

3.6 DATA COLLECTION TOOL

It is possible that differently worded questions will provide widely disparate estimations if
evaluations of prescribing patterns of probiotics. For effective survey and evaluation of
prescribing patterns of probiotics, it is anticipated that nomenclature will be required(Chu et al.,
2021).

26
 A quantitative survey that includes demographic data (gender, age, city),clinical
information of patient(department, known allergies, use of any other conventional medicines,
reason of hospitalization and duration of hospital stay), a section regarding probiotic use( include
brand name of prescribed probiotic, strain of probiotic prescribed, duration and frequency of
prescribed probiotic), clinical outcomes and issues after taking probiotics and patient’s
satisfaction and feedback was culturally adopted. The questionnaire contained 23 items,
including 5 items regarding clinical information, 6 items regarding probiotics use and 2 items
regarding outcomes and complications and 7 items regarding patients’ satisfaction and feedback.

For better understanding It is crucial that our enquiries are understandable and
unambiguous. Additionally, the questionnaire should have an easy-to-follow style. An interactive
approach should be used while creating a questionnaire. Respondents should therefore have a
sense of conversation. An interactive statement outlining the question's significance should come
before any delicate or difficult questions in a questionnaire that respondents might be reluctant to
answer(Kumar et al., 2018).

3.6.1 TRANSLATION

After all writers agreed, the final version of the questionnaire was created using a typical
instrument back translation method. Initially, the pre-validated English version was translated
into Urdu. The Urdu version was then translated back into English, and the two original language
versions were compared to eliminate any obscurity from the final form.

Back translation is a technique that was developed to assist researchers in evaluating surveys
written in languages they couldn’t understand. The translated questionnaire is then re-translated
into the original questionnaire language, and a comparison is made between the two original
language versions. Conclusions on the quality of the translated versions are drawn based on
differences or similarities between the original questionnaire and back-translated version, which
is not reviewed(Harkness et al., 1998).

3.7 STATISTICAL ANALYSIS

Tests were conducted using SPSS® for Windows, version 20, and demographic data, such
as age, gender, and city, as well as clinical data, outcomes and problems, frequencies, and
descriptive statistics of each variable, were reported.
27
 A program called SPSS Statistics is used for interactive, or batch, statistical analysis. It
was purchased by IBM in 2009 after being manufactured for a long time by SPSS Inc.
Although the program is now widely used in other domains, including as marketing and the
health sciences, its original moniker, statistical package for the social sciences (SPSS), reflected
the product's initial market(Quintero et al., 2013). Descriptive analysis is part of the statistical
tools.

3.9 ETHICAL CONSIDERATION

This study was conducted by the permission of respective institute Akson College of
pharmacy joint venture with Mirpur University of science and technology, Mirpur AJK. The
permission from executive directors of relevant study settings will also be taken prior to the
conduction of the research. Prior to data collection, the participants gave their consent, which
included a statement that their information would be kept private and that they could choose
not to answer any questions. Their involvement in the study was entirely voluntary and self-
initiated.

28
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