INTRODUCTION
Sepsis
is a fatal syndrome resulting in abnormal functioning of body organs due to
host systemic inflammatory reaction to infection. This disorder is a serious,
global health concern leading to both morbidity and death (20%) in worldwide
(Singer et al. 2016). It is
the major cause of health expenses in United States that leads to the public
health problem (Rudd et al. 2020).
Therefore, to understand the cause of
dysregulation, research of sepsis condition has target point for
researchers on the host immune’ response (Rhee et al. 2017). The vital role of the gut microbiota in both the
progression as well as persistence of sepsis especially in predispose sepsis in
adults and post-operative sepsis (MacFie et al. 1999).
When an individual has sepsis, their microbial community generally
experiences a drop in variety, loss of helpful bacteria, and a rise in the
development of dangerous bacteria such as Enterococcus and Staphylococcus
(Dickson et al. 2016). The
host body's inflammatory reactions and increased intestinal microbiota
permeability that result from gut microbiota dysbiosis cause infections to
spread to organs like the liver. (Fox et al. 2012). As a result, changed microbiota compositions in the sepsis
state, the precise root cause for the beneficial function of gut microorganisms
in sepsis, and the lack of diagnostic procedures or treatments targeting the
gut microbiome in the treatment of sepsis are all unresolved issues (Knoop et al. 2016).
ROLE
OF GUT MICROBIOTA IN THE MANAGEMENT OF SEPSIS
In gastrointestinal
tract, microbiota refers to the diverse group of microorganisms that ultimately
inhabit the gastrointestinal tract. Microorganisms such as bacteria, viruses,
fungus, and archaea are all part of the microbiome. Numerous facets of host physiology,
metabolism, and immune response are significantly influenced by this intricate
ecosystem. The microbiome, a varied group of microorganisms that live in both
internal and external body parts, is found in the human body (Gilbert et al. 2018).
Metabolites produced by
commensal gut bacteria are considered important for the characteristics of
immune cells and contribute to the various systemic effects that intestinal
microbes have on host defense (Fox et al.
2017). Recent research has focused on the key immunological pathways influenced
by these metabolites. One example is the role of Kupffer cells, the macrophages
in the liver, which capture and eliminate circulating pathogens. Gut commensal
bacteria produce D-lactate, which is transported to the liver via the portal
vein and helps maintain the integrity of the intravascular barrier regulated by
Kupffer cells (Schlechte et al.
2022). Butyrate, a short-chain fatty acid (SCFA) produced through anaerobic
bacterial fermentation, plays a role in the differentiation of monocytes into
macrophages. Butyrate promotes the production of antimicrobial peptides and
enhances antimicrobial activity in both mice and in vitro (McDonald et al. 2020).
Oral administration of short-chain fatty
acids (SCFAs) has been shown to boost macrophage phagocytic activity against
Klebsiella pneumoniae. This effect is triggered by the activation of G
protein-coupled receptor 43. SCFAs also significantly enhance the
macrophage-driven removal of the bacteria during infection. The antimicrobial
effector LAMTOR2 is overexpressed, which leads to pneumonia infection. The
LAMTOR2 receptor activates extracellular signal-regulated kinase, facilitating
phagosome-lysosome fusion (Schulthess et
al. 2019). Metabolites produced by the gut
microbiota have a multifaceted effect on the host immune response. In addition
to influencing the host's immune system, commensal bacteria can alter their
metabolic activity in response to immune stimuli. For example, when mice
colonized with four anaerobic commensal bacteria were exposed to acute immune
stimulation via flagellin or anti-CD3 antibody, rapid transcriptional changes
were observed. Although the overall abundance of the bacteria remained
relatively unchanged, this reprogramming led to an increase in the expression
of strain-specific reaction mediators. Intestinal metabolite production was
observed to change within six hours of immune activation, with a marked
reduction in the levels of short-chain fatty acids (SCFAs) like acetate and
propionate (Wu et al. 2020)
SEPSIS AND ITS TREATMENT AFFECTS
THE GUT MICROBIOME
There are several factors that
affect sepsis (Miller et al. 2020; Fig. 1). The unclear underlying cause of the
beneficial role of gut microorganisms in sepsis, and the lack of diagnostic
approaches or therapies targeting the gut microbiota that are effective in
sepsis treatment, are still unresolved issues involve the changes in microbiota
composition during sepsis (Ubeda et al. 2010; Taur et al. 2012).
One finding is that stress by itself can change the makeup of the gut
microbiota. Artificial nutrition feeding is one of the many necessary
strategies to help septic patients. Given that food composition is one of the
most well researched elements that might alter the makeup and function of the
intestinal microbiota, careful study is warranted here (David et al.
2014). An instance of this phenomenon involves human participants who were
given a meal heavy in animal protein, fat, and low in fiber. Remarkable
alterations in the makeup of their gut microbiota were seen during a just
24-hour period. In contrast to those who consume a diet mostly based on plants
and rich in fiber, those who follow a different dietary pattern exhibit reduced
levels of short-chain fatty acids (SCFAs) and increased levels of secondary
bile acids. These secondary bile acids possess the ability to impede the
proliferation of beneficial bacteria such as Firmicutes and Bacteroidetes,
which are known to contribute to overall health. However, it is common for
sepsis patients who are hospitalized to receive casein-based, sterile,
chemically specified meals via an enteric tube, which are devoid of dietary
fiber (Reis et al. 2018).
Gut barrier integrity and bacterial
translocation
An initial line of defense in
case of infections and dietary antigens is the gut barrier (Paone et al. 2020). The intestinal barrier is
selectively permeable in a healthy organism, which implies that while it is
impenetrable to macromolecules, poisons, food allergies, and infections, it is
permeable to ions, water, and low-molecular compounds (Thoo et al. 2019). When these compounds leave
the colon, the immune system becomes hyperactive, leading to inflammation.
Prolonged inflammation can significantly impact health (Paone and Cani et al.
2020). The intestinal barrier is composed of the mucus layer, intestinal
microbiota, intestinal epithelial cells (IECs), and lamina propria (Takiishi et al. 2017). Intestinal epithelial
cells and bacteria are essential for maintaining the integrity of this barrier.
The IECs act as a physical barrier, preventing harmful substances from leaking
out of the intestinal lumen (Vancamelbeke and Vermeire 2017).
Role of gut microbiota in bacterial
translocation
Inflammatory illnesses that
can impact the gut and distant organs can be brought on by microorganisms,
bacterial 
chemicals, or toxins that are unable to pass through the epithelium due
to anomalies in the gut barrier (Sorini
et al., 2019). Mucins comprise the majority of
intestinal mucus and are complex clusters of glycoproteins with distinct
O-linked glycan’s that are produced by goblet cells (Sicard et al. 2017). There are several sources
of verification that show functional and structural changes to the intestinal
barrier are connected to dysbiosis and occur in both human and animal models
(Camara-Lemarroy et al. 2018).
Chronic exposures to molecules from microbial translocation and ongoing
dysbiosis, which are to responsible for the rise of
bacterial species that are harmful, are to fault. (Mirza et al. 2017). In mice, changes in the microbiota of the gut brought
on by antibiotic therapy can cause enteric bacteria to move across the
epithelium (Knoop et al. 2016). Due
to changes in the gut microbiota, this relationship may become pathogenic in
critical disease, resulting in bacterial translocation, gut-derived sepsis,
intestinal homeostasis disruption, and harmful clinical consequences
(Wischmeyer et al. 2016).
Alteration in gut barrier function in sepsis
Sepsis is a life
threatening medical emergency. As our body shows extreme response
towards a particular infection. Organ not performing their particular
function properly are linked with high risk of death and disease, as the
disease turns sever, several abnormalities begin to appear across multiple
organs. Sepsis and septic shock frequently result in damage to the digestive
system (Fig. 2).
The
very first signs are increased permeability, passage of viable bacteria from GI
tract to GI sites, and difficulty in absorption are the primary signs of shock
(Longhitano et al. 2020). Three main
lines of defense make up the gut barrier function. the typical intestinal flora
(gut microbiota), which makes up the intestinal barrier. Important metabolic,
immune, and gut-protective functions are carried out by the microbiota (Assimakopoulos
et al. 2007). Multiple organ
dysfunction syndrome in sepsis is hypothesized to be influenced by intestinal
barrier disruption. Although there are some commonalities in the clinical
course of sepsis, the host response varies significantly depending on the
initiating organism, disease time course, and pathways of gut injury in several
preclinical models of sepsis (Yoseph et
al. 2016). Critically sick individuals have leaked gut malabsorption which
leads to the emergence of multiple organ dysfunction syndrome (MODS) and
various health issues like systemic inflammatory response syndrome
(Assimakopoulos et al. 2018). Strange
assumptions of gut related sever issues and MODS awaited clinical validation.
In
1991, a researcher took 20 seriously injured individuals in
an effort to gather information about bacterial translocation in
critically ill patients. 60% added prevention of patient shock 30% of patients
develop MODS, 2% test positive, and no one develops systemic endotoxemia (Moore
et al. 1991). The investigation shows
fair doubts about the validity of the gut hypothesis of sepsis, but it was
challenging to conduct similar trials with badly damaged individuals
(Assimakopoulos et al. 2018). Group
randomized multicenter trial with surgical 2762 and non-surgical patients 3165
showed that the SDD patients had a fair chance of surviving. An extensive
clinical trial in which researchers and patients knows the given drug or
treatment, clustered group-randomized crossover study in 13 intensive care
units in the 
Netherlands with 5927 patients revealed comparable effects of the two
treatments in terms of infection rate, as well as low levels of colonization
with antibiotic-resistant pathogens. It is similar to
the comparison of SDD and SOD strategies (Oostdijk et al. 2013).
Sepsis's
systemic effects have been deeply studied, and proof of local changes and
effects in the intestinal mucosal compartment is increasingly defining changes
related to the gut during sepsis (Neish 2014). Six pertinent studies conducted
between 1998 and 2006 on 2125 patients found that 5% of patients had
post-operative infections, which escalated to 45% of infections overall,
whereas 19% of patients were in perfect health. A bigger randomized experiment
is being conducted to examine the impact of immune-nutrients, and 1223
critically ill adults with multiple organ failure who are hospitalized to 40
ICUs across different nations are included. To increase mortality, glutamine is
administered to them (Goodrich et al.
2014). The risk factor of sepsis is due to the disturbance of gut microbiome as
shown by circumstantial confirmations, according to two recent large
epidemiologic studies (Gergianaki et al.
2018).
A meta-analysis of all
randomized clinical trials was conducted in 2012 to upshot the effects of
micronutrients and antioxidants. Because selenium is highly effective and has
shown the survival by 28 days in these patients,
a high dose of selenium was given in this study (David et al. 2018). A test is
carried out in 2004 to determine the overall impact of beneficial bacteria on
gut health. After one week of therapy, occurrences of pathogen diminish
pathogenic bacteria 43% and multi-organism 39%, there is no discernible
difference among the 90 patients admitted to the ICU who received the RCT,
received a placebo effect, and experienced the symbiotic effect. Prebiotics and
probiotics are employed in two major clinical therapies for intestinal
bacterial over-growth, and 5393 individuals are treated using this approach. As
a result, there is a 50% reduction in incidence and an 11% reduction in
mortality. SDD in 28 days, SOD reduces mortality by 2.9% while reducing
motility by 3.5%. 10,000 beneficiaries in this cohort study were studied in
2015 (Sori et al. 1988)
GUT MICROBIOTA BASED THERAPEUTIC INTERVENTIONS IN SEPSIS
Gut microbiota, a set of microorganisms dwelling with
inside the GI tract that has been diagnosed as the critical factor for human
fitness. Recent studies have shed mild at the massive position of intestine
microbiota in sepsis, a life-threatening situation characterized through
systemic inflammatory reaction syndrome (SIRS) as a result of
excessive contamination. Therapeutic interventions concentrated on intestine
microbiota in the sepsis that have emerged as a promising location of
investigation, aiming to modulate the microbial composition and feature to
enhance affected person consequences (Wang et al. 2022). Fig. 3 explains some of the strategies used for the
treatment of sepsis.
Probiotics and prebiotics
Probiotics, stay microorganisms that confer fitness
advantages whilst administered in ok amounts, have received interest as an
ability healing choice for sepsis. Lactobacillus and Bifidobacterium species,
generally used as probiotics, have proven promise in restoring intestine
microbial variety, improving intestine barrier characteristic, and modulating
immune responses in animal fashions of sepsis (Shimazu et al. 2012). Clinical trials have proven that probiotic management
in septic sufferers improves intestine barrier characteristic, reduces
infection markers, and reduces mortality charges (Petrof et al. 2012). However, in addition studies is important to validate
the efficacy and protection of probiotics in sepsis. Prebiotics, indigestible compounds that
selectively stimulate the boom and pastime of useful intestine microorganisms,
have additionally emerged as capability interventions for sepsis.
Fructo-oligosaccharides and galacto-oligosaccharides, not unusual place
prebiotics, were proven to enhance intestine barrier feature, sell the boom of
useful bacteria, and decrease intestine-derived irritation in sepsis animal
fashions (Ciorba 2012). Although medical research investigating using
prebiotics in septic sufferers are limited, initial proof shows that prebiotic
management may also lessen contamination costs and enhance medical results
(Schulthess et al. 2019).
Fecal microbiota transplantation (FMT)
The FMT includes shifting wholesome donor fecal fabric
to a recipient’s gastrointestinal tract, aiming to repair a balanced 
microbial community.
Several research has explored the capacity of FMT in modulating intestine
microbiota in sepsis (Fig. 4). Animal fashions have proven that FMT restores
microbial variety, improves intestine barrier feature, and decreases infection
(Li et al. 2016). While medical proof
concerning FMT in septic sufferers is limited, early research has said high
quality results in phrases of decreased contamination costs and advanced
medical parameters (Zuo et al. 2018).
However, similarly studies and scientific trials are had to set up the
protection and efficacy of FMT in sepsis management.
The manipulation of the
blood-brain barrier and signaling via the enteric nervous system by microbial
metabolites has been shown to have an impact on several mental and neurological
illnesses. These disorders include autism spectrum disorders, depressive
disorder, hepatic encephalopathy, and Parkinson's disease. The modulation of
the metabolic disorder and obesity seems to be influenced by the presence of
short-chain fatty acids (SCFA) and secondary bile acids, which are generated by
bacterial activity. The introduction of lipopolysaccharides (LPS) together with
other structural molecules derived from bacteria into the portal circulation
has an impact on the overall health of the liver. The regulation of
cardiovascular health has been seen to be influenced by the production of
Trimethylamine-N-oxide (TMAO) by bacteria, as well as the induction of systemic
inflammation caused by the existence of circulatory bacteria and their
byproducts. Fecal microbiota transplantation (FMT), short chain fatty acids
(SCFA), lipopolysaccharide (LPS), and Trimethylamine-N-oxide (TMAO) are the
respective acronyms for the following terms (Baggs et al. 2018).
Postbiotics and synbiotics
Postbiotics are non-feasible microbial
mobileular additives or metabolites which have proven capacity blessings in
sepsis interventions. These additives, which includes mobileular wall
fragments, secreted proteins, and short-chain fatty acids, exert anti-inflammatory
and immunomodulatory effects, thereby mitigating sepsis-related complications.
In a current observe via way of means of, postbiotics derived from
Lactobacillus traces have been discovered to lessen organ dysfunction, decorate
microbial diversity, and enhance survival costs in sepsis models. Synbiotics,
the mixture of prebiotics and probiotics, have additionally proven promise in
sepsis intervention (Meszaros et
al. 2021). The state-of-the-art studies through proven that synbiotics
intervention stepped forward intestine barrier integrity, attenuated systemic
inflammation, and ameliorated sepsis-caused lung injury. These findings
underscore the capability of postbiotics and synbiotics as novel healing
procedures for sepsis management (Shimizu et
al. 2021).
Antibiotics and gut microbiota
Antibiotics play a critical position in
sepsis interventions through focused on and killing the infectious pathogens.
However, they also can disrupt the sensitive stability of the intestine
microbiota, main to dysbiosis and impaired immune response (Hutchings et al. 2019). Strategies together with
antibiotic stewardship and aggregate treatment options with probiotics or fecal
microbiota transplantation may also preserve promise in mitigating the negative
outcomes of antibiotics on sepsis results (Arora and Backhed
2016).
Dietary modifications
Dietary changes constitute any other
road to modulate intestine microbiota in sepsis. High-fiber diets, wealthy in
fruits, vegetables, and entire grains, were related to elevated microbial
variety and progressed intestine barrier characteristic, probably lowering the
danger of sepsis (Jandhyala et al.
2015). Conversely, diets excessive in saturated fat and occasional in fiber
content material had been related to dysbiosis and elevated susceptibility to
infections (Gutierrez et al. 2015).
However, in addition studies is needed to set up top-rated nutritional
techniques for sepsis prevention and management.
Visual
acuity for all participants was measured, and those with clinically significant
macular edema (CMO) or pre-proliferative/proliferative retinopathy were
excluded from the study. Color vision impairment was most pronounced along the
tritan axis, particularly in diabetic pseudophakes with background retinopathy.
A significant association was found between color vision defects and the
presence of background retinopathy (p = 0.05). The distribution of color vision
defects in the study population was as follows: 16.9% with normal color vision,
10.2% with red-green defects, and 61% with tritan defects. Tritan
discrimination sensitivity changes were determinant for figuring out patients
liable to excessive retinopathy. The poorer color changes following cataract
surgical operation in diabetic pseudophakes can be due to extended
short-wavelength transmission thru the intraocular lenses, that could lead to
retinal damage. This is mainly true inside the case of phacoemulsification, in
which there's a shorter period of exposure to radiation all through lens
removal, probably aggravating retinal harm.
FUTURE PERSPECTIVES AND CHALLENGE
·
Provision of proper approaches of treatment as well as
carefully selected probiotics to the identified patients well helpful for
selecting future therapies for gut microbiota for the treatment of sepsis. It
will be helpful in the upcoming years in targeting and curing sepsis disease.
·
Mostly in practice setting, clinical trials are needed
for benefiting septic patients and among them, fecal microbiota transplant
(FMT) is helpful in the treatment of sepsis but may be its only beneficial for
a fixed number of patients and there’s possibility of occurrence of different
factors that can cause alteration in the treatment of sepsis via using FMT
therapy. These factors included selection of patient, proper rout for
administration, timing etc. It is expected that by improving mechanistic insights
into the interaction between gut microbiome and sepsis will allow the
development of microbiome-based therapeutics for mitigation of sepsis morbidity
and mortality.
·
Probiotics are helpful in treating gastrointestinal
disorders through changes in the gut microbiota but there are still various
aspects remaining that will have to address better results such as safety
issues, evaluation models, stress resistance etc.
·
Hopefully in the future research, there must be some
mechanisms or ways to use gut microbiome composition as biomarkers for getting
better results of sepsis and this is all possible when all the aspects of the
gut microbiome are fully studied. This may be effective in changing the level
of mortality and morbidity of sepsis.
·
As the world is becoming more advanced day by day, still
a lot of things are hidden and need more research to find out the main reasons
behind the alterations of gut microbiota normal mechanism and will need more
research regarding the factors affecting the normal mechanism of gut bacteria
which play an important role in the growth and maintenance of gut
CONCLUSIONS
The gut microbiota plays a crucial role in
sepsis pathogenesis, affecting immune responses, gut barrier function, and
bacterial translocation. Modulating the gut microbiota through various
therapeutic interventions holds promise in sepsis management. However, further
research is required to fully understand the underlying mechanisms and optimize
treatment strategies for personalized care. Gut
microbiota healing interventions maintain enormous ability for enhancing sepsis
consequences. Probiotics, FMT, prebiotics, and nutritional changes have proven
promise in restoring intestine microbial balance, improving intestine barrier
feature, and modulating immune responses in septic sufferers. Nevertheless, the
efficacy, protection, and finest dosage of those interventions want to be in
addition elucidated thru large-scale scientific trials. Manipulating intestine
microbiota represents a promising approach to lessen mortality and enhance
affected person effects in sepsis.
AUTHOR CONTRIBUTIONS
Both the authors contributed equally to the write
up.
CONFLICTS OF INTEREST
The authors affirm that they possess no conflicts of
interest.
DATA AVAILABILITY
Not applicable
ETHICS APPROVAL
Not applicable
FUNDING SOURCE
No funding was acquired for this work.
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