Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_151_библиотеки_им_акад_М_И_Перельмана
.pdf
The Interplay Between Immunity and Gut Microbiota in Colon Cancer 235
https://t.me/med1917
in the intestine, the gut microbiota is able to maintain epithelial homeostasis to
support gut-associated lymphoid tissue (GALT) and it enhances epithelial cytokine
production which regulates the action of T and B lymphocytes, macrophages, and
eosinophils.
Although the majority of host-microbiota interactions are symbiotic and beneficial, in specific conditions, the equilibrium of the microbiota-immunity axis breaks
being responsible for several pathologies. (Lee and Mazmanian 2010; Cheng et al.
2020).
Dysbiosis is defined as an alteration of the considered normal proportion of
different specimens composing the microbiota (Bartolini et al. 2020). It can be
caused by a variety of factors such as particular diseases (autoimmune and chronic
diseases) but also by metabolic conditions (overweight, obesity), drugs, activation of
inflammatory signaling, dietary intake changes, infection, and lack of nucleotidebinding oligomerization domain 2 (NOD2) (Ge et al. 2021; Song et al. 2020).
Alterations in the microbiome structure and function have been recently and
largely associated with host disease pathogenesis since they affect metabolic and
immune pathways, mediating CRC carcinogenesis (Song et al. 2020).
The growing body of evidence showing the association between dysbiosis,
immune system, and CRC development in a tripartite relationship (Sears and Pa rdoll
2011) brought to the formulation of three different dysbiosis-related oncogenic
models.
According to the “alfa-bugs” model, some specifical species (e.g., enterotoxigenic Bacteroides fragilis-ETBF, S. bovis, E. coli, superoxide-producing E. faecalis)
are able to grow out of protective microbial species remodeling the composition of
the microbiota and, at the same time, to act against the imm une system with both a
direct and indirect pro-oncogenic effect. Notably, true oncomicrobes in the inte stine
account for a very small proportion of all microbial population but still, alterations of
the balance between good and bad microbes seem to promote tumor development
(Sears and Pardoll 2011).
The “bacterial driver-passenger” model suggests that some “driver bacteria“ have
the ability to promote cancer development through genetic instability, producing
DNA-damaging compounds and inflammatory cytokines. In a second phase, they
would be outcompeted by “passenger bacteria”, such as Fusobacterium spp., bacteria which are usually poor colonizers of healthy intestines but have a competitive
advantage in tumoral microenvironment and exert cancer-promoting activities. All
these result in different compositions of the microbiota during CRC initiation and
development, so that pathogens responsible for tumor initiation may be absent in the
following stages (Tjalsma et al. 2012).
In the “keystone pathogen” model, some poorly represented pathogens have the
ability to remodel the microbiota either through direct or indirect effects on it,
respectively altering the transcriptional profile of the microbiome and affecting
host modulation (e.g., impaired immunosurveillance) or both, causing disruption
of host homeostasis.
Great effort was put into identifying a universal CRC-associated microbiota that is yet
to be determined. Fusobacterium nucleatum, Escherichia coli,andBacteroides fragilis
236 L. Malaspina et al.
https://t.me/med1917
seem to be involve d in CRC while the role of depleted strains is less well understood;
however, they are thought to play a key role in tumor-associated bacterial overgrowth
and subsequent CRC development (Cheng et al. 2020).
2.1 Microbiota-Associated Mechanisms of Carcinogenesis
It has been extensively shown that gut microbiota has a major role in cancer
initiation but also in its regulation, progressio n, and susceptibility to host immune
response and therapy (Ge et al. 2021).
Thus, gut microbiota and microbiome become targets in the search for biomarkers
for diagnosis and treatment purposes, opening new horizons in terms of screening
and therapeutic approaches.
An intact microbiota is necessary for optimal treatment response (Ge et al. 2021)
and the exact composition of the altered cancer-associated microbiota is hard to
encode, mainly because of major individual variation representing a challenge in
medical practice.
In this setting, understanding mechanisms underlying microbiota-mediated carcinogenesis is fundamental to identify novel approaches to the disease.
Microbiota-associated mechanisms in CRC carcinogenesis include:
• Inflammation;
Chronic inflammation is a well-established risk factor for CRC. It seems that
inflammation-associated mediators such as interleukin-6 (IL-6), tumor necrosis
factor-α (TNF- α), IL-23, and reactive oxygen species form a microenvironment
favoring carcinogenesis through DNA damage, thus altering the physiology of the
host, a mechanism that could explain colitis-associated CRC (Arthur et al. 2012).
In this setting, microbiota is both a target and a cause of inflammatory processes
promoting cancer and impacting on its progression.
Normally, the intestinal mucosal barrier segregates the intestinal microbiota from
immune cells but continuous bacterial stimulation can cause a perpetual state of low
inflammation (Cheng et al. 2020) with a double effect. Microbiota is targeted by
inflammatory cells and their mediators with the result of fostering the expansion of
bacteria with genotoxic potential and creating the opportunity for this microorganism to adhere to the colonic mucosa by decreasing protective mucins and antimicrobial peptide production (Arthur et al. 2012).
Conversely, inflammation cannot induce CRC without the microbiota or bacteriaderived compounds and toxins which allow barrier disruption and enable commensal
bacteria and their degradation products to invade the tumor stroma. Some examples
of these bacterial toxins strongly associated with carcinogenesis and tumor progression are those produced by Escherichia coli or Bacteroides fragilis (Cheng et al.
2020).
The Interplay Between Immunity and Gut Microbiota in Colon Cancer 237
https://t.me/med1917
Gut microbiome dysbiosis promotes inflammation via induction of the cytokine
CCL5 (C-C chemokine ligand 5) (Elinav et al. 2011), recruiting lymphocytes in the
intestine up to non-physiological levels (Ge et al. 2021). CCL-5-driven inflammation, in turn, prom otes epithelial cell proliferation through local activation of the IL-6
pathway, leading to cancer formation (Hu et al. 2013). F. nucleatum, enriched in
samples collected from colonic human adenomas and carcinoma, was studied in
ApcMin/+ mice models and it was found able to ingenerate a pro-inflammatory
environment suitable for neoplastic progression by activating the NF-kB pathway
and recruiting tumor-infiltrating immune cells (Kostic et al. 2013). Moreover,
F. nucleatum-associated inflammatory cytokines in colorectal cancer specimens
were assessed using immunoassays: expression of the cytokines IL17A and TNFα
was markedly increased (Ye et al. 2017).
A similar mechanism is exploited by P. anaerobius inducing a pro-inflammatory
immune microenvironment by recruiting a series of tumor-infiltrating immune cells,
especially immunosuppressive myeloid-derived suppressor cells, tumor-associated
macrophages, and granulocytic tumor-associated neutrophils, to promote tumor
progression (Cheng et al. 2020; Long et al. 2019).
• Immune dysregulation:
The gut microbiome can inhibit infection by intestinal pathogens by adjusting the
environment in the niche they occupied, competing for nutrients, and releasing
bacteriocins, in a highly dynamic dialogue with the host, THUS contributing to
protection against pathogens in and outside the gut (Schnupf et al. 2018). This
process starts during the constitution of the microbiome at birth, affecting the
maturation of the immune system, the development of tolerance, and the containment of the microbiome (Honda and Littman 2016; Ge et al. 2021).
In the intestinal mucosa, the microflora affects the phenotype and function of
T and B cells, playing a key role in maintaining immune homeostasis by inhibiting
the response to harmless antigens and preserving the integrity of the intestinal
mucosal barrier function (Honda and Littman 2016).
Indeed, the host intestinal mucosal surface barrier allows microbial symbiosis,
and resident bacteria profoundly shape mammalian immunity (Hooper et al. 2012).
Microbiota is subject to continuous modification to repair environmental damage
with the aim of maintaining homeostasis. Disruption of such a fragile balance results
in a confrontation between the microorganisms and the immune system, which may
result in proinflammatory or tumorigenic conditions (Ge et al. 2021).
Host recognition pathways of the microbiota exploit various pattern recognition
receptors (PRRs) such as Toll-like receptors (TLRs), modulating inflammatory
response to microorganism molecular patterns. TLRs engagement on tumorinfiltrating myeloid cells caused by invading bacterial components is mediated by
myeloid differentiation factor 88 (MyD88)-mediated production of inflammatory
cytokines, most notably interleukin (IL)-23. It subsequently determines a cytokine
activation cascade comprising IL -17A, IL-6, and IL-22, eventually promoting tumor
238 L. Malaspina et al.
https://t.me/med1917
cell proliferation by activating nuclear factor-kB (NF-kB) and STAT3 signaling
pathways. Moreover, the collateral upregulation of IL-17C can transform IEC
through TLR/MyD88-dependent signaling, and promote tumor cell survival and
tumorigenesis (Cheng et al. 2020).
• Pathogenic bacteria and their virulence factors
F. nucleatum, an oral commensal bacterium, acts at the early step of colorectal
carcinogenesis affecting the b-catenin signaling pathway thus inducing oncogenic
and inflammatory responses. To do so, F. nucleatum uses its unique FadA adhesin A
(FadA), which selectively binds to E-cadherin thus inducing oncogenic and inflammatory responses via activated b-catenin signal. FadA gene levels in patients with
adenomas and adenocarcinomas are >10–100 times higher compared to healthy
individuals (Rubinstein et al. 2013). Additionally, F. nucleatum inhibits T-cell
activation and natural killer cell cytotoxicity through another surface adhesin,
Fap2, which binds to the human immune inhibitory receptor T-cell immunoglobulin
and ITIM domain (Gur et al. 2015). Fap2-dependent invasion-induced secretion of
the proinflammatory cytokines, IL-8, and CXCL1, associated with CRC progression, increased metastatic potential and cell seeding, poor prognosis, and enhanced
recruitment of tumor-associated macrophages and fibroblasts (Casasanta et al. 2020).
F. nucleatum also modulates autophagy in IECs by activating regulatory
microRNAs (Yu et al. 2017).
P. anaerobius which normally resides in the oral cavity and gut, selectively
enriched in the fecal and mucosal microbiota from patients with CRC, promotes
cancer development via its surface protein, putative cell wall binding repeats
2 (PCWBR2). PCWBR2 directly interacts with intestinal epithelial cell receptor
integrin α2/β1, frequently overexpressed in human CRC tumors and cell lines to
initiate an oncogenic PI3K-Akt signaling pathway, promoting tumor cell proliferation (Long et al. 2019).
S. bovis, occasionally presents in the human gastrointestinal tract flora, was
remarkably associated with CRC development through inflammation-driven carcinogenesis via, but not limited to, IL-1, cyclooxygenase-2 (COX-2), and IL-8
(Abdulamir et al. 2010).
Finally, chronic Salmonella infection increases the risk of cancer since it
promotes colonic tumorigenesis by its protein AvrA, which can activate both the
Wnt/b-catenin and STAT3 signaling pathways in coloni c tumor cells (Wang et al.
2018; Lu et al. 2014).
• Genotoxins
Genotoxins are toxins capable of causing damage to the DNA leading to
mutations and eventually to cancer. Thus, bacteria producing this kind of substance
participate in colonic carcinogenesis.
Some strains of E. coli, usually commensal inhabitants of the mammalian colon,
harbor the genomic island, polyketide synthase (pks), coding for production of the
The Interplay Between Immunity and Gut Microbiota in Colon Cancer 239
https://t.me/med1917
polyketide-peptide genotoxin, colibactin. In different laboratory models, this toxin
was related to DNA damage and promotion of cell senescence and enhanced tumor
cell proliferation (Cuevas-Ramos et al. 2010; Cougnoux et al. 2014). Campylobacter
jejuni produces a cytolethal distending toxin, which causes double-stranded DNA
breaks and promotes colorectal tumorigenesis (Lasry et al. 2016). Salmonella
exploits the PI3K pathway in colonic epithelial cells to damag e the DNA using a
typhoid toxin (Martin et al. 2019).
• Oxidative stress
Oxidative stress originates from the breakdown of the balance between
pro-oxidative molecules [(e.g., reactive oxygen species (ROS) and reactive
nitrogen species (RNS)] and anti-oxidative defenses. Chronic inflammation induced
by microbial persistent stimulation induces inflammatory cells to increase the production of ROS and RNS, promoting DNA damage and CRC development through
oncogenes activation or tumor-suppressor gene inactivation (Cheng et al. 2020).
The gut microbiota can also directly produce ROS. E. faecalis infection contributes
to chromosomal instability and CRC risk because of superoxide production,
which damages DNA in epithelial cells via a bystander effect and hydroxyl radicals,
observed in laboratory models, powerful mutagens that cause DNA breaks,
point mutations, and protein-DNA crosslinking (Cheng et al. 2020;Wangetal.2014;
de Almeida et al. 2018). Similarly, the bacterium enterotoxigenic Bacteroides fragilis
(ETBF) is a significant source of chronic inflammation and ROS production and has
been implicated as a risk factor for colorectal cancer (Goodwin et al. 2011).
• Diet and bacteria metabolites
Diet is an important risk factor for cancer that is amenable to intervention.
More than a third of CRC cases are related to potentially modifiable factors such
as unbalanced diets low in whole grains and dairy products, and high in red and
processed meat (Zhang et al. 2019). At the same time, obesity is well known for
increasing CRC risk, directly proportionate to the increase of body mass index
(BMI) (Song et al. 2019).
Tilg et al. investigated microbiota as the “missing link” in the close interaction
between dietary factors and CRC. Diet can in fact rapidly alter the intestinal
microbiota potentially contributing to disease susceptibility (Tilg et al. 2018)by
modulating the intestinal microbiome composition and diversity (Cheng et al. 2020).
Unbalanced dietary patterns determine the production of pro-carcinogenic
chemicals such as N-nitroso compounds (NOCs), hydrogen sulfide (H2S), and
secondary bile acids.
Gut microbiota was found involved in the production of NOCs, highly mutagenic
carcinogens via DNA alkylation. In healthy individuals, NOC-producing bacteria
are a minority but excessive intake of nitrate and nitrite can make them the prevalent
population with resulting dysbiosis, inflammatory response, and enrichment in
240 L. Malaspina et al.
https://t.me/med1917
E. coli. Microbiota production represents the source of endogenous NOCs while the
major source of exogenous NOCS is highly processed meat whose intake has been
correlated with a higher risk of CRC. In addition, CRC risk was significantly
associated with exposure to heterocyclic amines (HCA) and polycyclic aromatic
hydrocarbon (PHA), derived from red meat cooked at high tem peratures. They are
able to alter microbial metabolism and disrupt homeostasis and at the same time,
microbiota can induce their bioactivation and transformation into toxic secondary
metabolites. Furthermore, red meat contains heme iron, which can cause dysbiosis in
mice models with a reduction of Firmicutes and Deferribacteres and an increase in
Proteobacteria and Bacteroides altering the digestive health with a mechanism
involving colonic levels of short-chain fatty acids (SCFAs) like butyrate (Tilg
et al. 2018). It has health-promoting effects, along with acetate and propionate,
and they are the predominant fermentation product in healthy adults consuming
balanced diets.
Butyrate, produced by Firmicutes via fermentation of dietary fiber and
resistant starches, regulates epithelial proliferation, downregulates proinflammatory
cytokines, and induces apoptosis in CRC cells. SCFAs reduce bacterial proliferation
and DNA damage lowering fecal pH and interacting with GALT T-cells differentiation. Enhanced apoptosis and prevent ed cancer cell proliferation result in a global
antitumoral effect and reduced SCFA levels were linked to a higher risk of carcinogenesis. Sulfate-reducing bacteria are abundant in the stools of CRC patients compared with those of healthy individuals. They use methionine and cysteine as
substrates to generate H2S that inhibits butyrate oxidation and generates
DNA-damaging ROS, altering the gut barri er and stimulating CRC progression.
Bile acids derive from a different type of microbial metabolism since intestinal
bacteria metabolize primary bile acids produced in the liver to secondary forms.
High-fat diets lead to impaired bile metabolism, demonstrated in animal models,
where populations fed in a western-style diet, high in fat components, developed
significantly more colonic tumors than those on a control diet, correlating with
higher cell proliferation in colonic crypts, impaired bile acid transport, and inactivation of the farnesoid X receptor (FXR), a nuclear bile acid receptor. Furthermore,
secondary bile acids have been shown to be genotoxic via oxidative stress from ROS
generation causing oxidative DNA damage (Cheng et al. 2020).
• Biofilm
Biofilm is an emerging concept about microbiota-related CRC carcinogenesis.
Biofilms are communities of different microorganisms (bacteria but also fungi,
Eukarya, and viruses) aggregated and encased in a polymeric matrix which makes
them extremely resilient.
They colonize different surfaces of the human body (Flemming and Wuertz 2019)
and when mucosal barrier disruption occurs they come into direct contact with
mucosal epithelial cells usually protected by mucus. Invasive polymicrobial biofilms
were detected in most right-sided tumors (89%) but in only 12% of left-sided tumors
and were accompanied by diminished E-cadherin, increased epithelial permeability,
The Interplay Between Immunity and Gut Microbiota in Colon Cancer 241
https://t.me/med1917
and enhanced IL-6 and STAT3 activation, subsequently increasing epithelial proliferation, diminishing apoptosis and promoting pro-carcinogenic tissue inflammation
mediated by bacterial antigen translocation (Dejea et al. 2014).
3 Clinical Value of the Microbiota
Recent insight into gut microbiota may help clinicians in selecting useful biomarkers
and developing effective strategies for CRC prevention and treatment with major
translational applications especially in age groups not covered by endoscopy screening, lowering CRC morbidity and mortality (Cheng et al. 2020).
3.1 Biomarkers for CRC Screening and Prognosis
Microbiota-related biomarkers may be used both for screening and as prognostic
tools for CRC treatment. It seems that alterations in the composition of the fecal
microbiome of patients with CRC overlap with those found in patients with colorectal adenoma. Screening the fecal metabolome and microbiome may serve to select
individuals at higher risk of developing CRC (Cheng et al. 2020).
As previously mentioned, a precise cancer-related ecosystem is yet to be defined
but many observations have been made.
For example, on healthy individuals’ stool samples, the prevalence of the phylum
Firmicutes, the genera Clostridium and the family Lachnospiraceae was observed
and proposed as a marker. On the contrary, the presence of Fusobacterium
nucleatum in CRC patients was prominent when compared with healthy volunteers,
suggesting its potential as a novel diagnostic biomarker (Bartolini et al. 2020).
A study conducted on the potential role of fecal-modified microbiota as a
screening tool confirmed that identifying enrichment and depletion panels of pathogenic bacterial populations is much more useful compared to the identification of a
single microbe, suggesting the polymicrobial pathogenesis of the disease. However,
further large-scale cross-sectional studies with diverse populations are still required
to confirm these findings and to obtain more information about bacterial species at
strain level. Nevertheless, the linkage between microbiota and other modifiable and
not modifiable characteristics of the patient (sex or age) have to be evaluated to
obtain a stronger correlation (Bartolini et al. 2020; Zackular et al. 2014).
3.2 Microbiota Modulation for CRC Prevention and Treatment
Considering the major role in CRC played by the microbiota via several
mechanisms, intestinal microbiota modulation may represent a way to reverse
established microbial dysbiosis, for CRC prevention and treatment. These strategies
242 L. Malaspina et al.
https://t.me/med1917
include dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation (FMT) (Cheng et al. 2020 ).
Dietary composition has been associated with marked intestinal microbial diversity and is therefore critical in CRC evolution. Dietary intervention, considered the
most reasonable and economical approach to CRC prevention, could encourage the
growth of specific bacterial strains that may convert indigest ible dietary components
into beneficial metabolites for the host (Cotillard et al. 2013).
As shown in Yusof et al. syst ematic review, the Western dietary pattern, mainly
consisting of red and processed meat and refined grains is associated with an
elevated risk of development of CRC. In contrast, a decreased risk is linked to the
adoption of a healthy dietary pattern (high intake of fruits and vegetables, whole
grain cereals, fish, poultry, and soy derivatives) (Yusof et al. 2012).
However, diet-induced remodeling is temporary-dependent since, once the longstanding dietary regime is resumed, the intestinal microbiome returns to its previous
composition too (Cheng et al. 2020).
Another ideal method for modulating the microbiota may be the direct consumption of probiotics and/or prebiotics or by recourse to fecal microbiota transplantation
(FMT).
Probiotics are defined by the Food and Agriculture Organization of the
United Nations and the WHO (FAO/WHO) as “live microorganisms that, when
administered in adequate amounts, confer a health benefit on the host” (Hill et al.
2014).
They may function in multiple ways: by inactivating carcinogens or mutagens,
modulating host immunity, inhibiting cell proliferation, and improving gu t barrier
function (Fong et al. 2020 ).
Liu et al. observed that treatment with a mixture of probiotics (Lactobacillus
plantarum, L. acidophilus, and Bifidobacterium longum) can improve the integrity
of the gut mucosal barrier, increasing the amount of cell junction proteins (Liu et al.
2011). Additionally, probiotic administration can ameliorate the adverse effects of
chemotherapy, immunotherapy, and radiation therapy suggesting that investigations
aimed at deciphering the microbiome-host interactions before and after intervention
may allow prediction of disease course (Packey and Ciorba 2010; Cheng et al. 2020 ).
Prebiotics are nondigestible food ingredients that feed beneficial intestinal bacteria and improve host health; clinical trials have reported the positive effects of
perioperative administration of symbiotic probiotics and prebiotics on patients
with CRC, including fewer postoperative infections and shorter hospital stay (Flesch
et al. 2017 ; Cheng et al. 2020).
Third, growing interest and deeper understanding of intestinal microbiota’s
effect on both inflammatory and neoplastic processes made FMT an emerging
biotherapeutic resource (Wang et al. 2014). It consists in transferring stool
transplants from healthy donors to patients believed to harbor a disease-inducing
dysbiosis to restore intestinal microbial homeostasis (Cheng et al. 2020).
The Interplay Between Immunity and Gut Microbiota in Colon Cancer 243
https://t.me/med1917
3.3 Gut Microbiota Interplay in Patients Undergoing
Chemotherapy After CRC Surgery
CRC can be treated with different chemotherapy (CT) regimens tailored to tumor stage,
patient’s general conditions, and mutational status, including 5-fluorouracil,
capecitabine, and/or platinum-based agents. Unequivocally, CT alters the composition
of intestinal microbiota and consequently, the so-called “pharmacomicrobiomics” is
increasingly attracting attention (Bartolini et al. 2020). Dysbiosis caused by chemotherapy administration is mainly due to colitis and diarrhea and it may interfere
with therapy through different ways: dysbiosis itself, immunomodulation, and
xenometabolism. Anaerobic strains are usually depleted and there is reduced production of butyrate, a short-chain fatty acid (SCFA) responsible for the trophism of the
intestinal mucosa and mucosal barrier efficacy through mucus secretion. It has
antitumoral action blocking cellular replication, promoting apoptosis, stimulating
IL-10 production, and inhibiting the NF-κB activation (Pouncey et al. 2018).
Moreover, microbiota appears also to have a direct causal role in chemotoxicity.
For example, irinotecan metabolism, in first-line chemotherapeutic treatment for
metastatic colorectal cancer, is linked to the compo sition of an individual’s gut
microbiota. Irinotecan-induced mucositis is the consequence of the reactivation of
its liver metabolite from intestinal bacterial β-glucuronidases and brings adverse
drug responses, including severe diarrhea (Guthrie et al. 2017).
On the contrary, an intact commensal microbiota is able to modulate the tumoral
micro-environment and is pivotal in an optimal response to chemotherapy, also
reducing side effects (Iida et al. 2013). For example, in animal models, the response
to cisplatin, oxaliplatin, or cyclophosphamide drug treatment was lower or inexistent
if preceded by antibiotics. However, combining cisplatin with probiotics, especially
Lactobacilli, improved response to therapy and, accordingly, the oral administration
of Lactobacillus johonsonii and Enterococcus hirae improve the efficacy of cyclophosphamide treatment in tumor-bearing mice, inducing a pro-inflammatory T
helper differentiation (Barbosa et al. 2021).
F. nucleatum is known to have a causal role in chemoresistance via the formation
and activation of autophagosome in the CRC cells with the production of their
related proteins. Detection of high levels of this species may represent a prognostic
biomarker leading to the need of modified schemes of administered chemotherapy.
Chemoresistance was also associated with high levels of IL-22 as well as a lower
efficacy of anti-blastic therapy was linked to high levels of regulatory T cells creating
an immunosuppressive environment (Yu et al. 2017).
Unraveling at least a part of the mechanisms of chemoresistance, may provide
new strategies for chemotherapy optimization allowing reduct ion in side effects and
better results in CRC management (Bartolini et al. 2020). Similarly, the discovery of
favorable or unfavorable microbiota for chemoresistance and side effects may help
in tailoring chemotherapy.
In perioperative settings, modulation of microbiota is involved in reduced recovery timing after surgery.
244 L. Malaspina et al.
https://t.me/med1917
Ambrosio et al. have recently demonstrated that immunonutrition modulates
tumor microenvironment by improving immune function and prolonging survival
in patients undergoing elective surgery for CRC (Ambrosio et al. 2023).
In this setting many precautions should be taken into consideration: supplementary food containing microbes able to ferment acid lactic may allow enhanced
healing of the surgical wound; in animal models, oral supplementation with
non-absorbable phosphate, usually lacking after surgery, reduced bacterial-related
anastomotic leak; antibiotic therapy should be carefully administered and, when
required, for the shortest needed period; analgesics should be preferred over opioids;
bowel preparation should be modified in order to try to eliminate only, or
mostly reduce, virulent strains while maintaining helpful biodiversity in the
microbiota (Bartolini et al. 2020).
3.4 Effects of Gut Microbiota on Immunotherapy
The immune system is not a simple bystander in cancerogenesis and its interplay
with cancer has been extensively studied in the last decade displaying its unquestionable key role during tumorigenesis.
It is crucial in controlling tumor growth; nonetheless, in some cases, the activity
of immune cells can also favor cancer progression. The improved understanding of
the interaction between the immune system and cancer, in the last years, brought a
revolution in cancer treatment that can either boost or damper immune pathways to
promote antitumor status.
Recent data demonstrated the role of the gut microbiota in the regulation
of antitumoral immune response and the efficacy of the recently developed
immunotherapies such as checkpoint blockade, making gut microbiota modulation
a novel adjunct approach to current therapies (Barbosa et al. 2021).
Microbiota’sinfluence on the efficacy of immunotherapy was demonstrated in
preclinical studies reporting a linkage between alterations in microbiota composition
and the efficiency of CTLA-4 and PD-1 blockade. Vétizou et al. highlighted the role
of microbiota since they reported that anti-CTLA-4 therapy did not inhibit tumor
growth in germ-free or antibiotic-treated mice; further experiments showed how
Bacteroidales and Burkholderiales were crucial for the therapeutic efficiency. As
counterevidence, oral or fecal transplantation of B. fragilis in combination with
B. thetaiotaomicron or B. cepacia restored the efficiency of anti-CTLA-4. The
underlying mechanism was found in the generation of antitumor antigen-specific
Th1 responses, promoted by the microbiota, which controlled tumor growth both in
animal models and humans, likely by producing cross-reactive antigens and enhancing antitumor T-cell responses (Vétizou et al. 2015).
Similarly, Sivan et al. investigated discrepancies in tumor growth and anti-PD-1
therapy when comparing genetically similar mice harboring distinct microbiota.
Interestingly, fecal transplants from responsive to unresponsive mice restored the
efficacy of PD-1 blockade, showing that microbiota composition plays a critical role
in anti-PD-1 therapy. By analyzing microbial composition in mice prone to response
Соседние файлы в папке Библиотека им академика М.И. Перельмана