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 / @xirurgi_2025 / @xirurgi_2025 - 926 - файл
.pdf
306 N. R. Suss and B. D. Shogan
https://t.me/med1917
12.3 “Healthy” Microbiota Composition
The microbiota of the human gut is comprised of bacteria, viruses, eukarya,
parasites, and archaea. The gut microenvironment predominantly promotes the
proliferation of seven key subdivisions of bacteria: Firmicutes, Bacteroidetes,
Actinobacteria, Fusobacteria, Proteobacteria, Verrucomicrobia, and Cyanobacteria
(Fig. 12.1)[18].
Approximately 90% of the microbiota population is made up of Bacteroidetes
(Bacteroides, Prevotella) and Firmicutes (Clostridium, Eubacterium, Ruminococ-
cus)[1]. The GI tract is a complex organ system divided largely into three
functionally and anatomically different organs: the stomach, the small intestine,
and the colon, each of which consists of a unique microenvironment that promotes the growth of different microbial populations. The healthy stomach, which
was once thought to be inhospitable to bacterial growth secondary to its high
acidity is home to five main phyla: Firmicutes, Bacteroidetes, Actinobacteria,
Fusobacteria and Proteobacteria and the bacterial genera Prevotella, Streptococcus,
Veillonella, Rothia, and Haemophilus [19]. The microbiota of the small intestine
is quite diverse and varies whether one is examining the duodenum, jejunum, or
the ileum, as each of these parts of the small intestine vary in their physiologic
function as it pertains to digestion and absorption of nutrition. Compared to other
parts of the small intestine, the diversity and density of bacteria (10
is lowest in the duodenum due to its environment consisting largely of bile acids,
pancreatic secretions, and antimicrobial agents [1]. The predominant bacteria in
the duodenum are Firmicutes and Actinobacteria [20]. The jejunum is largely
comprised of Gram-positive aerobes and facultative anaerobes, including Lacto-
bacilli, Enterococci, and Streptococci at a density of approximately 10
ml [20]. The ileum represents the area of the small intestine most densely popu-
9
lated with bacteria at 10
CFU/ml, mainly consisting of aerobic species. Starting
near the ileocecal valve, the bacterial population largely transitions to anaerobes
and Gram-negative organisms, as is seen in the colon. The colon, the main site
for water absorption and fermentation of undigested food is largely inhabited
by anaerobic bacteria, with a bacterial density approaching nearly 10
ml, mostly consisting of Firmicutes and Bacteroidetes [33]. The colonic lumen
3–4
CFU/ml)
3–7
CFU/
12
CFU/
Fig.12.1 Seven Key
Subdivision of Bacteria
within the Gut Microbiome
12 Microbiome Manipulation in Coloproctology 307
https://t.me/med1917
is inhabited by Bacteroides, Bifidobacterium, Streptococcus, Enterobacteriaceae,
Enterococcus, Clostridium, Lactobacillus, and Ruminococcus. Clostridium, Lactobacillus, Enterococcus, and Akkermansia can be found within the colonic mucosa
[21].
12.4 Manipulation of the Intestinal Microbiome and Its
Role in the Pathogenesis of Gastrointestinal Disease
Perturbations of the intestinal gut microbiome have been associated with several
pathological disorders and processes of the gastrointestinal tract, including colorectal cancer (CRC) development and recurrence, inflammatory bowel disease,
anastomotic leaks following surgical intervention, and surgical site infections, to
name a few. By developing a better understanding of these pathological changes, it
stands to reason that there may exist points at which intervention to manipulate the
microbiota to a more physiologically favorable microenvironment could prevent or
help manage these diseases.
12.4.1 Inflammatory Bowel Disease
Inflammatory bowel disease represents a chronic immune-mediated disease that are
thought to result from a combination of environmental and microbial factors that
collectively induce immune dysregulation in genetically susceptible individuals. To
better understand the role of the microbiota in the development of IBD, research
has been conducted that assesses the intestinal microbial profile in individuals
with active underlying intestinal inflammation that characterizes IBD. Several initial studies found that the transfer of proinflammatory bacteria from diseased mice
into healthy mice is capable of inducing inflammation in the healthy mice. Further work found that inoculating mice with intestinal microbes from IBD-positive
mice exacerbates colitis in the recipient mice by modulating immune responses [7,
22]. More evidence that supports the involvement of microbes in IBD pathogen-
esis stems from research pertformed decades ago that noted that faecal diversion
in IBD patients frequently resulted in remission of diseased segments, whereas,
reversal of diversion was associated with disease relapse [23, 24]. This lends support to the argument that the faecal stream, and more importantly, its associated
microbial contents, play a significant role in promoting intestinal inflammation.
Further support for this theory comes from the observation that disease activity in
IBD tends to be most prevalent in regions of the bowel that contain the greatest
density and diversity of bacteria, such as the distal small bowel and colon [7].
Microbial samples in patients with IBD have found increased populations
of Proteobacteria (particularly adherent invasive E. coli), Pasteurellaceae, Veillonellaceae, Fusobacterium species, and Ruminococcus gnavus, and decreased
populations of Clostridium, Bacteroides, Suterella, Roseburia, Bifidobacterium,
and F prausnitzii [5, 6]. While it is difficult to ascertain whether these microbial
308 N. R. Suss and B. D. Shogan
https://t.me/med1917
changes are causative or secondary to inflammation and/or previous treatment,
a study by Gevers et al., conducted in treatment-naïve patients with Crohn’s,
found similarly increased populations of Pasturellaceae, Veillonellaceae, Neisseriaceae, Fusobacteriaceae species, and E coli, as well as decreased populations of
Bacteroides, Clostridiales, Faecalibacterium species, Roseburia species, Blautia
species, Ruminococcus species and Lachnospiraceae, suggesting that changes may
precede disease development, and are independent of medical intervention [25].
Patients with IBD have also been found to harbor decreased populations of SCFAproducing bacteria, which are essential anti-inflammatory bacterial metabolites that
provide an energy source for colonic epithelial cells and promote regulatory T cell
development in the colon [7]. Specifically, reduced butyrate production has been
associated with decreased populations of Bacteroidetes and Clostridium, including
F prausnitzii, as seen in IBD patients. Several studies have focused on the particularly low levels of F prausnitzii in patients with Crohn’s Disease and have linked
its decreased abundance to increased risk for postoperative ileal disease recurrence,
as well as increased risk of relapse [26, 27]. F prausnitzii produces metabolites that
inhibit nuclear factor kappa-light-chain-enhanment of activated B cells (NF-kappa
B) and IL-8 production by epithelial cells within the intestine, thereby dysregulating the immune response. This may be done through the bacteria’s production of
microbial anti-inflammatory molecule (MAM), which has been identified to inhibit
the NF-kappa B pathway in intestinal epithelial cell lines [7]. Peptostreptococci,
of the Firmicutes phylum, has been shown to colonize a healthy intestinal environment by utilizing mucin-associated monosaccharides for energy. These strains
are also capable of metabolizing tryptophan into indoleacrylic acid, which regulates intestinal inflammatory responses and strengthens the barrier function of
the intestinal epithelium. Metagenomic analyses of human faecal samples from
patients with IBD have demonstrated decreased populations of microbes capable
of metabolizing mucin-associated monosaccharides and tryptophan, positing that
this loss of tryptophan-metabolizing bacteria subsequently results in an increased
inflammatory risk [8].
Thus, while the pathogenesis of IBD is complex and likely multifactorial in
origin, the scientific evidence is compelling that the microbiota plays a significant
role in the pathogenesis and exacerbation of this disease state.
12.4.2 Development of Colorectal Cancer, Recurrence,
and Metastasis
Colorectal cancer (CRC) remains one of the most commonly diagnosed malignancies [28]. In stages I-III disease, surgical resection of the primary tumour is the
primary potentially curative treatment. However, nearly 30% of those undergoing
potentially curative resection will ultimately develop postoperative local recurrence
or distant metastases with a relatively short survival (Fig. 12.2)[29, 30].
A large amount of research has been conducted that demonstrates the influence
of dietary intake on the intestinal microbiome and the secondary impact that these
12 Microbiome Manipulation in Coloproctology 309
https://t.me/med1917
Fig.12.2 Up to 30% of patients undergoing surgical resection for CRC will experience local or
distant recurrence
interactions have on CRC development. Certain microbes that reside within the
intestinal microenvironment are capable of metabolizing dietary sulfur into hydrogen sulfide, a known carcinogen that disrupts the colonic mucosal layer impairing
its protective function, and promotes inflammation [31]. Work from three large
prospective cohort studies found that the consumption of a sulfur microbial diet,
consisting of high consumption of low-calorie drinks, red and processed meats, and
low intake of fruits, vegetables, and whole grains was positively associated with an
increased sulfur microbial diet score [9]. An increased sulfur microbial diet score
corresponded to an increased mean relative abundance of sulfur-metabolizing bacteria. Among 214,797 participants, 3,217 cases of CRC were identified; a greater
adherence to a sulfur microbial diet was significantly associated with an increased
risk of CRC development (HR 1.27, 95% CI 1.12–1.44) [9]. In particular, increased
consumption of a sulfur microbial diet was associated with an increased risk of
distal CRC (HR 1.25, 95% CI 1.05–1.50) but not proximal colon cancers (HR
1.13, 95% CI 0.93–1.39) [9]. Similar work by Nguyen et al. found a positive association between sulfur microbial diet scores and the presence of two particular
sulfur-metabolizing bacterial previously found to play important roles in the CRC
microbiome, Erysipelotrichaceae bacterium and Bilophila wadsworthia [32].
A clear inverse relationship between dietary fiber consumption and the incidence of CRC and colonic adenoma development has been established [31]. As
discussed in earlier sections, bacteria within the intestinal microbiome ferment
dietary fiber products into SCFAs, such as butyrate, propionate, and acetate, which
play significant roles in supporting colonic mucosal health and host immune regulation. Research from Chen et al. evaluated dietary fiber intake in healthy patients
as well as in those with advanced CRC and subsequently analyzed faecal samples for the presence of SCFA as well as SCFA-producing bacteria [33]. The
results of this study demonstrated that the abundance of faecal SCFAs was significantly lower in those with CRC compared to the healthy controls, suggesting
a potential protective effect of SCFAs [33]. Microbiota analysis of faecal samples found decreased populations of Clostridium, Roseburia, and Eubacterium,
bacterial genera associated with butyrate-production, in the participants with CRC
compared to their healthy counterparts. In further subgroup analyses, both butyrate
310 N. R. Suss and B. D. Shogan
https://t.me/med1917
and butyrate-producing bacteria were present in greater quantities in the highfiber group compared to lower fiber group. These differences persisted when fiber
intake was assessed within the CRC participants alone, patients with CRC who
had a high-fiber diet possessed greater butyrate and butyrate-producing bacteria
than those with CRC who consumed a lower fiber diet; however, levels of butyrate
and butyrate-producing bacteria were still higher in the healthy control participants
who consumed a high-fiber diet [33]. These findings suggest that even in patients
with CRC, consumption of a high-fiber diet may not completely repair the perturbations seen in the intestinal microbiota of one with cancer compared to their
healthy counterparts.
While many studies have highlighted a likely association between the consumption of dietary fiber, increased SCFA production, and decreased development of
CRC, scientists have yet to determine the specific mechanism by which fiber and
its interactions with the microbiome may reduce cancer incidence. In a study by
Chen et al., Clostridium butyricum, a butyrate-producing bacteria, was specifically
isolated and evaluated to better understand the role in intestinal tumour formation
and progression. In this study, C. butryicum inhibited the development of intesti-
min/+
nal tumours in Apc
mice induced by a high-fat diet [34]. The authors found
that the mechanisms by which C. butyricum protect against CRC development is
through suppression of proliferation and enhancement of tumour cell apoptosis, as
well as modulation of the gut microbiome by increasing the population of SCFAproducing bacteria (i.e. Ruminococcaceae and Eubacterium), and inhibition of the
Wnt/Beta-catenin signaling pathway, a key pathway involved in the pathogenesis
of CRC [31, 34]. These findings give reason to believe that microbiome manipu-
lation may be achievable through dietary modifications that help address not only
intestinal malignancy, but inflammation in general. The topic of targeted intestinal
microbiota manipulation is explored further later in this chapter.
The microbiome is also plays a pivotal role in maintaining mucosal lining
integrity that serves to protect the colonic epithelium against ingested toxins.
Loss of this protective mucosal lining can result in repeated exposure to toxins
and injury that can overtime result in the development of malignancy. Research
has shown that a high-fat diet is associated with increased production of bile
acids, including deoxycholic acid (DCA), which influences the composition of
the intestinal microbiota and can ultimately promote the development of CRC.
In particular, the bile acid DCA, whose production is stimulated by a high-fat
diet, is linked to the disruption of the colonic mucosal protective lining, resulting
in the acceleration of CRC development in APC
min/+
mice [35]. In their study,
Ma et al. measured bile acid levels in paired cancerous and noncancerous intestinal tissues in patients with CRC [36]. This identified altered mucosal microbiota
with increased populations of Bacteroides, Curtobacterium, and Campylobacter
that was associated with increased DCA production. These findings persisted in
ex vivo cocultures in which the mucosal microbiota within the cancerous tissues
produced DCA at higher quantities than in the noncancerous tissue, suggesting that
the colonic malignant tissue created a microenvironment that was more conducive
to the growth of DCA-producing microbes [36]. These findings are significant, as
12 Microbiome Manipulation in Coloproctology 311
https://t.me/med1917
research has found that DCA promotes the overgrowth of tumourous cells, promotes epithelial-mesenchymal transition, and activates VEGF-2 which can lead to
the development of colorectal malignancy [37].
In addition to its influence on CRC development, the intestinal microbiome
has also been implicated in CRC recurrence risk following surgical resection. One
study by Schmitt et al. sought to assess changes in one’s microbiome following surgical resection. Specifically, they evaluated the association of post-surgical changes
with postoperative complications by analyzing stool samples of patients with
newly diagnosed CRC both before and after surgical resection [38]. They found
that preoperatively, the participant’s baseline microbiomes were largely similar,
regardless of their postoperative complication status. However, in the postoperative setting, patients who experienced postoperative complications experienced
a shift in their microbiome that persisted until six-month follow up, suggesting
that surgical resection itself likely induces a change in the microenvironment of
the microbiota [38]. Similar work by Yu et al. found alterations in the faecal
microbial composition following endoscopic resection of colonic adenomas that
persisted for at least three months [39]. E. faecalis, P. aeruginosa, and Serratia
marcescens spp., all of which have been shown to be associated with cancer recurrence and anastomotic leak, have been found to flourish in the post-surgical colonic
microenvironment (Fig. 12.3)[11, 40].
The occurrence of an anastomotic leak following resection for a colorectal malignancy is associated with increased risk of local disease recurrence and
reduced disease-free survival [41]. While the majority of these local recurrences
occur at the anastomotic site, mostly extraluminally, the exact mechanism by which
the cancer recurs remains unknown although hypotheses exist. These include the
implantation of exfoliated tumour cells at the anastomotic site, metachronous carcinogenesis, and inflammation-induced carcinogenesis [11, 42]. While the exact
mechanism has yet to be elucidated, it is likely that tumour recurrence is driven
by a combination of the aforementioned hypotheses, each of which can be influenced by the composition of the post-resection microbial environment. Work from
Shogan et al. has demonstrated that certain highly virulent strains of E. faecalis,
Fig.12.3 Bacteria
populations shown to be
associated with anastomotic
leak and CRC recurrence are
increased in the post-surgical
colonic microenvironment
312 N. R. Suss and B. D. Shogan
https://t.me/med1917
found to be present at the anastomotic site in rats following colorectal resection, possess high collagenase activity that can activate matrix metalloprotease-9
(MMP-9), resulting in tissue breakdown and potentially driving the pathogenesis
of anastomotic leak [12]. Through their ability to degrade extracellular matrix,
MMPs represent a marker of invasion that when present in high levels, worsen
clinical outcomes for those with colorectal malignancies [43, 44]. Collagenaseproducing strains of E. faecalis are capable of interacting with native macrophages
within the intestinal microenvironment and subsequently induce colonic epithelial
cells to express a mesenchyme-like phenotype that promotes invasive behavior,
essentially initiating an epithelial mesenchymal transition that is important in promoting cancer metastasis [45]. Additionally, collagenase-producing abilities have
been identified with P. aeruginosa, which has also been found to thrive in abun-
dance in the postoperative intestinal microbiome [46]. Thus, these findings go on to
support the hypothesis that collagenase-producing bacteria, found within the postoperative intestinal microenvironment, activate both MMPs and local macrophages
that collectively degrade and inhibit the healing processes of the new anastomotic
site, potentially allowing shed tumour cells to implant and subsequently migrate
to extramucosal sites resulting in disease recurrence.
Given the association between diet and microbiome composition, it is reasonable to evaluate whether the Western diet (that is associated with CRC development) creates an intestinal microenvironment conducive for collagenase-producing
bacteria that promote the development of anastomotic leak and ultimately increase
the risk for tumour recurrence. In patients diagnosed with CRC, consumption of a
high-fat, Western diet is associated with a significant decrease in 5-year recurrencefree survival [47]. This increase in cancer recurrence in the setting of a high-fat
diet is hypothesized to relate to the high ratio of Firmicutes (i.e., Enterococcus)to
Bacteroidetes. Gaines et al. found then when CRC cells were introduced in mice
after undergoing colonic resection and anastomosis, the mice formed tumours in a
pattern that similarly mimicked local and distant recurrences in humans. However,
interestingly, tumour growth was only identified in the mice fed a high-fat diet in
the presence of collagenase-producing E. faecalis or Proteus mirabilis at the site of
the anastomosis [48]. Thus, evidence supports that a high-fat diet may promote the
survival of atypical, collagenase-producing bacteria (capable of activating MMPs,
growth factors and cytokines) found at the anastomotic site following surgery,
thus making it possible for shed tumour cells to not only colonize the anastomotic site, but also invade more distantly. The network that connects diet and
intestinal microbiome to cancer development and recurrence is complex and multidirectional. However, through this complexity exists multiple avenues in which
clinicians and scientists may be able to intervene to manipulate the microbiome.
In later sections of this chapter, the dietary changes that can be implemented to
manipulate one’s intestinal microbiome in a way that serves to protect against
anastomotic leak and cancer recurrence are explored further.
The evidence that dysbiosis of the host-microbiome network influences the
pathogenesis of CRC is believed to extend beyond just initial cancer development and recurrence. Several studies have assessed the role of the microbiome
12 Microbiome Manipulation in Coloproctology 313
https://t.me/med1917
in promoting CRC metastasis. These mechanisms will be further explored in this
section.
The ability for cancer to become metastatic relies on both the primary tumour
microenvironment being conducive for cancer cell migration, and also on the
development of a habitable microenvironment at the metastatic organ site. The
development of these distant microenvironments suitable for cancer cell invasion,
survival, and proliferation have been termed premetastatic niches (PMN) [40]. For
metastasis to occur successfully, the development of these PMNs must first occur.
Recent research efforts have focused on the impact that host-microbiome dysbiosis
may have on promoting the development of these PMNs. By better understanding
the processes that underlie PMN formation and the development of metastatic disease, clinicians and scientists hope to identify a point at which PMN development
can be targeted to prevent the metastatic spread of disease [40].
Research into PMNs has found that tumour-specific secreted factors, as well as
chemokines and cytokines are capable of initiating PMN formation by promoting
vascular permeability and recruiting fibroblasts, platelets, and innate immune cells
that secrete metabolites that further promote PMN adaptation. This process allows
for the degradation and remodeling of the extracellular matrix, thereby permitting
circulating tumour cells to invade, adhere, and proliferate [49, 50]. It seems likely
that the microbiome plays a significant role in the development of metastatic disease. In patients with good intestinal health, microbes are unable to traverse across
an intact gut-vascular barrier (GVB). However, injury to the GVB can render this
barrier non-functional, allowing for the translocation of inflammatory metabolites,
toxins, and microbes across this vascular-endothelial barrier and enter the portal circulation. Therefore, it is plausible that injury to the GVB may represent
a mechanism by which colorectal tumour cells migrate to the liver through the
enterohepatic circulation [51, 52].
Research has been conducted into the connection between diet, gut dysbiosis,
and GVB disruption. Work by Mouries et al. found that mice fed a high-fat diet
for one week experienced diet-related intestinal microbiota dysbiosis that resulted
in disruptions to the integrity of the GVB, promoting the translocation of microbes
into the liver [10]. Furthermore, germ-free mice that underwent a faecal microbiota
transplant (FMT) from mice fed a high-fat diet for one week were also found to
experience GVB disruption allowing for bacterial translocation into the portal circulation [10]. The GVB disruption in these germ-free mice after undergoing FMT
from mice fed a high-fat diet exemplifies the role that the gut microbiome likely
plays in driving GVB injury. Based on these findings, it would be reasonable to
suspect that a similar mechanism is at play for the translocation of pathogenic
bacteria to migrate across a disrupted GVB and travel to the liver, where favorable PMNs can be created to promote migration and survival of CRC cells to
metastasize to the liver. Bertocchi et al. showed that cells positive for PV-1, an
endothelial-specific integral membrane glycoprotein, are associated with increased
blood vessel permeability and subsequent development of distant recurrences [52].
Thus, expression of PV-1 could be used as a biomarker for GVB dysfunction.
Using FISH microscopy, they noted that CRC patients with high levels of PV-1
314 N. R. Suss and B. D. Shogan
https://t.me/med1917
had a significantly increased number of bacteria in their liver metastatic tissues
than in the paired healthy hepatic tissue, compared to those with low PV-1 levels.
This finding suggests that bacteria translocate to regions of high PV-1 expression
(i.e. where GVB dysfunction exists) [52]. To assess whether bacterial translocation
preceded metastatic formation, Bertocchi et al. utilized mouse models to identify increased levels of PV-1 in colon tumours, even in the absence of metastatic
disease, compared to healthy colonic tissue. They utilized Apc-mutant mice and
wild-type mice to perform a FITC dextran permeability assay with orally-gavaged
dextran. In doing so, they found higher levels of circulating dextran in the blood of
the Apc-mutant mice compared with the wild type-mice, suggesting that increased
levels of PV-1 similarly reflects GVB disruption in the presence of tumour [52].
Therefore, increased PV-1, demonstrative of increased vascular permeability, likely
allows tumour-associated bacteria and other cellular factors and metabolites to
reach the liver to prime the microenvironment for the development of a PMN. In
additional experiments, bacterial strains from the colon and liver tissues of the
Apc-mutant were isolated to identify bacteria associated with tumour growth. The
most frequent bacterial strains identified were those of E. coli [52]. The strain E.
coli C17 was isolated and then C57BL/6 mice were orally gavaged with this strain
every other day for one week. Oral gavage with E. coli C17 led to increased detection of PV-1, increased translocation of bacteria to the liver, as well as increased
infiltration of macrophages and inflammatory monocytes, two key factors involved
in PMN formation. Further experiments then sought to assess the presence of E.
coli C17 in human models of CRC. The group observed that E. coli C17 was
present in significantly greater abundance in PV-1 high, metastatic CRC patients
than in PV-1 low, non-metastatic CRC patients. Additionally, the strain was also
identified within metastatic liver tissue of CRC patients [52]. This work has defined
a plausible mechanism by which E. coli C17, a component of the intestinal microbiota, upregulates PV-1, thereby mediating the GVB disruption necessary to allow
for the translocation of specific tumour-associated pathogens and immune cells to
travel to the liver and create a PMN conducive for the distant spread and survival
of CRC cells.
Further work by Bullman et al. investigated the association of Fusobacterium
and its associated microbiome, including Bacteroides, Selenomonas, and Prevotella
species, with CRC and its metastasis. Their research has demonstrated that human
CRCs that harbor Fusobacterium in their primary tumours, similarly did in their
metastatic tumours, demonstrating microbiome stability throughout the metastasis
process [53]. Further analysis using in situ hybridization techniques identified that
Fusobacterium is predominantly associated with metastatic cancer cells and was
not found to be localized within the surrounding healthy liver parenchyma [40, 53].
In further studies, Bullman et al. tested the use of oral metronidazole in mice with
Fusobacterium-positive xenografts from human CRCs and found a statistically significant decrease in Fusobacterium tumour load, tumour growth, and tumour cell
proliferation [53]. The paired presence of Fusobacterium detected in both primary
and metastatic colorectal tumours, as well as impaired tumour cell proliferation
with the treatment of antibiotic treatment appears to suggest that Fusobacterium
12 Microbiome Manipulation in Coloproctology 315
https://t.me/med1917
and its associated microbiome play a pivotal role in CRC growth and metastasis.
Further studies are needed to better understand the direct mechanisms by which the
intestinal microbiome contributes to CRC growth and metastasis and ways these
mechanisms can be targeted to alter the microbiome and decrease disease.
The following sections of this chapter will explore methods in which the
intestinal microbiota can be manipulated with the goal to reduce colorectal
malignancy.
12.5 Clinical Manipulations of the Intestinal Microbiome
to Target Disease
Given the evidence that the microbiome plays a role in intestinal disease pathogenesis, it is appealing that clinical manipulation and targeted intervention directed at
the microbiome may represent a possible vehicle for disease management.
12.5.1 Restoring the Intestinal Microbiota Through Faecal
Microbiota Transplantation
The utilization of Faecal Microbiota Transplantation (FMT) dates back to the
1950s, when Dr. Ben Eiseman performed rectal instillation of healthy donor faeces
in four patients with pseudomembranous colitis, curing them of what years later
would be identified as a Clostridium difficile infection (CDI) [54]. To this day, FMT
remains a common and guideline-recommended treatment for recurrent, as well as
severe and fulminant CDI. Given that the pathogenesis of CDI typically stems
from antibiotic-induced dysbiosis of the gut microbiota, it is unsurprising that the
restoration of a symbiotic microbial microenvironment through FMT poses a successful method for cure, without the potentiating risks for recurrence that are seen
with antibiotic management. There are several mechanisms through which FMT
restores the microbial diversity of the gut, thereby suppressing the activity of C. dif-
ficile. The increase in microbial diversity allows healthy microbiota to re-establish
their dominance in the intestinal microenvironment, outcompeting C. difficile for
space and nutritional resources [55]. The restored, healthy microbiota is capable
of producing bacteriostatic and bacteriocidal peptides that impede the growth and
survival of C. difficile [56]. Additionally, FMT restores the population of healthy
microbiota that metabolize primary bile acids such as cholic acid into secondary
bile acids like chenodeoxycholic acid in quantities that inhibit spore germination
of C. difficile [57]. Given the great success of FMT to restore homeostasis of the
gut microbiota seen in CDI, researchers have begun to explore the utility of FMT
in other gastrointestinal pathologies, most notably being ulcerative colitis.
Соседние файлы в папке @xirurgi_2025