Microbiome and Gynaecologic Cancer: Comparison
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 The term “human microbiota” is the set of symbiotic microorganisms that coexist with the human organism without damaging it. The term “microbiome” refers to the entire microbiota habitat, including microorganisms, their genomes, and the surrounding environment. The microbiome has been identified in the gut, oral cavity, vagina, respiratory tract, skin, and other mucosal surfaces. Despite significant advances in understanding the pathogenetic mechanisms underlying gynaecological cancers, these cancers still remain widespread. Recent research points to a possible link between microbiota and cancer, and the most recent attention is focusing on the relationship between the microbiome, the immune system, and cancer. The microbiome diversity can affect carcinogenesis and the patient’s immune response, modulating the inflammatory cascade and the severity of adverse events.

  • microbiome
  • cancer
  • immunity

1. Microbiome in Gynaecologic Cancer

1.1. Microbiota and Cervical Cancer (CC)

Recent evidence suggests that the vaginal microbiome is implicated in cervical carcinogenesis [1][2]. It is known that the high-risk HPV genotypes, such as HPV 16 or HPV 18, are oncogenic factors in CC.
Bacterial vaginosis (BV), anaerobic bacteria and non-Lactobacillus-dominant vaginal microbiome have been associated with an increased risk of HPV acquisition, persistence, and decreased clearance [3]. Different bacteria species, such as Gardnerella, Atopobium, Prevotella, Megasphaera, Parvimonas, Peptostreptococcus, Anaerococcus, Sneathia, Shuttleworthia, are associated with HPV-affected microenvironment, dysplasia or cancer in particular. Sneathia, a member of the phylum Fusobacteria, was the most important microorganism implicated in cervical carcinogenesis, and its presence can represent a meta-genomic marker for HPV persistence and progression of cervical neoplasm [1].
A recent review reported an association between non-Lactobacillus-dominant vaginal microbiome dysbiosis and carcinogenesis by predisposing women to HPV acquisition (overall RR 1.33; RR among young women 1.4), persistence, and consequent precancerous dysplasia (RR 1.14; RR 2.01; I2 0%) [4].
Norenhag et al. conducted a network meta-analysis that underlined that women with vaginal microbiome dominated by Lactobacillus iners and gasseri (OR, 3.3; 95% CI) had two to three times higher odds of high-risk HPV infection and cervical neoplasia than women with a vaginal microbiome dominated by Lactobacillus crispatus [5]. These results were confirmed by a subsequent meta-analysis, in which Lactobacillus crispatus, but not Lactobacillus iners, was related to lower detection of high-risk HPV (OR 0.49; 95% CI; I2 10%) and dysplasia (OR 0.50; 95% CI; I2 0%) [6].
After investigating the cervical metagenomes in the case of Cervical Intraepithelial Neoplasia (CIN) and CC, Kwon et al. showed that Lactobacillus, Staphylococcus, and Candidatus endolissoclinum were prevalent in CIN2/3, while Alkaliphilus and Wolbachia were the prevalent species in the case of CC [7]. Kang et al. presented a prevalence of Prevotella in faecal samples of women with early CC. Recent studies theorize that the gut microbiome can induce the growth of CC through an inflammatory response mediated by the activation of TLRs [8].
Laniewski et al. investigated the association of immune response with the microbiome in the progression to malignancy for cancer cells. Women with cervical cancers but not with dysplasia exhibited increased genital inflammatory scores and elevated specific immune mediators; for example, IL-36γ were significantly associated with cervical cancers [9].

1.2. Microbiota and Uterine Cancer

The uterus is not a germ-free organ but is colonized through an ascending mechanism from the vagina, and it is dominated by a greater variety of bacterial species and different strains of Lactobacillus [10].
In women undergoing total hysterectomy, after eliminating the vaginal contamination, Lactobacillus species were detected in the endometrium, similar to microorganisms of the vagina. In contrast, Winters et al. recently, through 16S rRNA gene qPCR and sequencing, reported that microbiota in the middle endometrium is not dominated by Lactobacillus as was previously concluded but is dominated by Acinetobacter, Pseudomonas, Cloacibacterium, Escherichia, and Comamonadaceae [11]. A strong correlation has been demonstrated between gut microbiota, estrogen metabolism, and obesity [12].
Estrogens may induce alterations of vaginal microbial communities and play an important role in modulating the inflammatory response with the production of pro-inflammatory molecules, for example, TNF alpha ad IL-6 [13]. Conjugated estrogens excreted in the bile can be modified by bacterial species in the intestine, such as estroboloma, which performs its function through the enzymatic action of beta glucuronidase. The estrogen modulatory effect can induce the development of hyperplasia and endometrial cancer (EC) by interfering with the gut–vaginal microbiome axis. Furthermore, EC is promoted by obesity, diabetes, and metabolic syndrome that may promote changes in the microbiome [14].
One of the first studies about the association between microbiome and EC was conducted by Walther-Antonio et al. [15]. Culture-independent models, through 16s rDNA, reported the presence of Atopobium vaginae, Porphyromonas sp. and a high vaginal pH in women with EC. The same group confirmed the presence of Porphyromas somerae as the most important biomarker for EC [16]. Schreurs et al. described an abundance of Actinobacteria, Firmicutes, Proteobacteria, and Bacteroides in obese women with EC compared to non-obese women [17].
A recent study conducted by Lu et al. suggested a link between inflammatory cytokines, bacterial flora, and EC. Micrococcus species were found to be associated with the alteration of endometrial microbiota and with the production of inflammatory cytokines. In particular, in the group of EC, IL-6, and IL-17 mRNA levels were elevated [18].
Walsh et al. described a correlation between EC, postmenopausal status, and increased microbial diversity of the lower genital tract. Furthermore, they identified that the presence of Porphyromas somerae was associated with type II EC risk and described that the dysbiosis was correlated with menopause, obesity, and high vaginal pH to uterine dysbiosis [16]. A recent work conducted by Gressel et al. described the microbiota of postmenopausal undergoing hysterectomy for endometrioid and uterine serous cancer and demonstrated the microbial diversity of anatomic niches in these women compared to controls [19].

1.3. Microbiota and Tubal and Ovarian Cancer

The fallopian tube is a precursor for ovarian carcinogenesis, and recent evidence analysed the microbiome of fallopian tubes as a starting point for ovarian cancers. Zhou et al. showed reduced biodiversity and microbiome richness in OC tissues compared to tissues from normal distal fallopian tubes and proposed that the microbiome may influence the tumour microenvironment in OC through the activation of Treg cells [20]. The change of microbial composition with the increase of Proteobacteria/Firmicutes might be associated with the initiation and progression of OC and could regulate the local immune environment. Banerjee et al. showed that the microbiome of ovarian tumours is different from ovarian tissue that has never been in the proximity of cancer. They detected an unexpected and robust microbiome, including members of the bacterial, viral, fungal, and parasitic family and suggested an association with the genesis or propagation of cancer. Banerjee et al. also hypothesised that the tumour microenvironment might provide a favourable milieu for these microorganisms to persist [21]. These works suggested an important link between inflammation and microbiome in the genesis of OC. The latest evidence also described changes in the microbiota at the site distant from the tumour tissue. A recent work conducted by Morikawa et al. analysed the cervicovaginal microbiota of OC women and observed a Lactobacillus-poor, highly-diversified microbiota in OC premenopausal women compared to healthy subjects. This study demonstrated that cervicovaginal microbiota could be considered a biomarker of OC in premenopausal women. In particular, a correlation between BRCA1/2 mutations, known to increase OC occurrence rate, and cervicovaginal microbiota could be, an intriguing issue [22].
Therapeutic approaches may alter microbiomes and induce OC progression. As for colon cancer, also for OC, there could be a correlation between surgery and changes in the gut microbiota. Ohigashi et al. described an alteration of microbiota after surgery with an increase of Enterobacteriaceae, Enterococcus, Staphylococcus, and Pseudomonas [23]. Tong et al. evaluated the effects of surgery and chemotherapy for OC on microbiomes and described a reduction of Bacteroidetes and Firmicutes in faecal samples collected after surgery for OC, while an abundance of the same species was detected before chemotherapy. Conversely, Proteobacteria species increased after surgery, but a decrease in the same group and an increase in anaerobic bacteria, such as Bacteroides, Collinsella, and Blautia, was discovered [24].
Platinum-based chemotherapy following primary debulking surgery is the standard treatment for OC. Platinum may damage the intestinal mucosa and dysbiosis, in particular, a decrease of Firmicutes species, which can be related to side effects of chemotherapy such as body weight loss and cardiac dysfunction [25]. Gram-positive bacteria may also contribute to an alteration of response to anti-cancer activities of cisplatin by the production of inflammatory cells producing reactive oxygen species (ROS). Some mechanisms may influence the efficacy of chemotherapy, in particular translocation, which is the process by which the commensal or pathogenic bacteria pass across the gut barrier into the systemic milieu [26]. Therefore, a microbiome reset may contribute to a better response to chemotherapy and a reduction of collateral effects. Hawkins et al. described that [27] an alteration of the intestinal microbiome, which occurs after the administration of broad-spectrum antibiotics, has an impact on the progression of the tumour and on the response to therapy. As a consequence, there is a worsening of survival linked not only to disease progression but also to platinum resistance. In addition, paclitaxel, used in the case of OC, could influence gut microbiota with a decrease in the number and function of beneficial bacteria and an increase in collateral effect. Wang et al. performed studies in mice and showed that in OC-bearing mice, faecal microbiota transplantation (FMT) of OC patients accelerated the progression of the disease. Faecal microbiota supplementation with Akkermansia significantly suppressed neoplastic progression in mice [28].

2. Microbiota, Immunity, and Impact on Cancer Treatment

The correlation between the gut microbiota and the immune system has been demonstrated in studies using germ-free (GF) mice that are devoid of detectable microbiota during their lives. Pattern-recognition receptors on innate immune cells recognize bacteria-derived molecules leading to modulation of systemic immunity with induction of T reg cells through stimulatory effects on myelopoiesis and function of dendritic cells (DCs) with the production of transforming growth factor beta, macrophages, and neutrophils. The loss of commensal bacteria can lead to a decrease in T-reg frequency and an increase in T-helper cells with the production of cytokines and chemokines [29]. Biomarkers may be predictive of treatment response in gynaecologic cancer such as tumour genomic and proteomic markers, immune response markers, and tumour microenvironment markers. Recent evidence suggests that gut microbiota can be considered a tumour marker that may impact cancer treatment response by affecting immune response during and after chemotherapy (CHT). El Alam et al. studied changes in the diversity and composition of the gut microbiome during and after pelvic chemo-radiotherapy (CRT) for gynaecological cancers; 58 women with cervical, vaginal, or vulvar cancer were analysed. The microbiome analysis was conducted using 16Sv4 rRNA gene sequencing before, during treatment and after 12 weeks [30]. Gut microbiome richness and diversity levels continually decreased throughout CRT, with increases in Proteobacteria and decreases in Clostridiales and increases in Bacteroides species after CRT. After 12 weeks of treatment, gut microbiome diversity returned to baseline, but the structure and composition presented alterations. In addition, it is noted that CRT may induce gastrointestinal toxicity that may be increased by microbiota alteration, and CRT-induced dysbiosis increases the susceptibility to CRT-related gastrointestinal toxic effects [31][32][33]. The interactions between the gut microbiota and the host immune system have been reported. Specific bacteria may promote or suppress the activity of immune checkpoint inhibitors (ICI). ICIs have been one of the most recent treatments to demonstrate clinical benefits in many cancers, including recent gynaecological cancers [34][35][36]. Whereas standard treatments such as palliative surgery, radiotherapy, and chemotherapy have failed to control the disease in the advanced stages, good results have been obtained with the use of immunotherapy [37][38][39][40]. However, as described above, many changes in the gut microbiota may induce alteration in the number and functions of gut immune cells, resulting in systemic inflammatory responses [41]. In line with this, it is reasonable to think that the effectiveness of immunotherapy can be affected by alterations in microbiota composition. Recent studies demonstrated the association between the gut microbiota and the anti-tumour effects of ICIs. Multiple possible mechanisms underlying the modulation of anti-tumour immunity by the gut microbiota were suggested, such as the activation of IFN-γ pathways, production of IL-12, induction of the Th1 immune response in the tumour-draining lymph nodes through the activation of dendritic cells (DCs), and the maintenance of regulatory T cells [42]. The first few studies about the correlation between microbiota and immunity were conducted on mice, and the tumour growth decreased in specific pathogen-free (SPF) mice compared to that of germ-free (GF) mice. Faecal microbiota transfer (FMT) from responder patients into GF mice resulted in a better response to ICI. In 2018, Matson et al. confirmed the role of microbiota on the efficacy of immunotherapy in metastatic melanoma; in particular, Bifidobacterium was involved in enhancing the anti-tumour efficacy of anti-PD-1 therapy. The gut microbiome can be considered an essential mediator for therapeutic activities in ICIs and other cytotoxic agents [43]. The abundance of specific operational taxonomic units (OTUs) and enhanced gut microbiota diversity induced the efficacy of anti-PD-L1 therapy. The non-responder group presented an abundance of Bacteroides thetaiotaomicron, Escherichia coli. Conversely, the responder group presented an abundance of faecali bacterium with prolonged progression-free survival (PFS) [44]. Wang et al. demonstrated a specific correlation between microbiota and immune activation. Faecal microbiota supplementation with Akkermansia significantly suppressed neoplastic progression in mice through the production of acetate and subsequent secretion of interferon γ (IFNγ), upregulation of CD8 + T cells, and antiproliferative action. The use of antibiotics may be considered the principal risk factor for reduced response to immunotherapy because it may induce change in the gut microbiome. Pinato et al. investigated the role of antibiotic (ATB) therapy administered before (p ATB) or during (c ATB) immunotherapy in patients with non to small cell lung cancer, melanoma, and other tumour types. In the p ATB therapy group, but not c ATB therapy, there was a worse Overall Survival (OS) (2 vs. 26 months for p ATB therapy vs no p ATB therapy, respectively) and a refractory response to ICI therapy (21 of 26 [81%] vs. 66 of 151 [44%], p < 0.001). Multivariate analyses confirmed that the p ATB therapy (HR, 3.4; 95% CI, 1.9–6.1; p < 0.001) and responses to ICI therapy (HR, 8.2; 95% CI, 4.0–16.9; p < 0.001) were associated with OS, independent of tumour site, disease burden, and performance status [45]. Routy et al. also described the influence of microbiomes on the efficacy of PD-1 immunotherapy in epithelial tumours and described how the antibiotic administration near the start of immunotherapy was associated with a worsening in OS and PFS [46]. Microbiome compromission may also alter responses to treatment with CTLA-4 blockade. To date, the impact of ATB on ICI response and clinical outcomes is unclear in women with gynaecologic cancer. Some studies conducted in patients with non-gynaecological cancers demonstrated that antibiotic treatment may be associated with decreased clinical response and worse oncologic outcomes in patients treated with ICIs [46][47]. Spakowicz et al. evaluated the impact of medication use, also antibiotics, in 609 patients treated with ICIs; patients who received treatment, in particular cephalosporin, up to 100 days prior to ICI initiation presented worse OS. The use of antibiotics was associated with the reduction of OS. In a recent meta-analysis of 2363 patients with non-gynaecologic malignancies from 15 studies, patients exposed to ATB before ICI treatment had significantly reduced PFS and OS [48]. Chambers et al. in a retrospective cohort study of women with advanced Epithelial Ovarian Cancer (EOC) undergoing platinum chemotherapy studied the effect of antibiotic treatment on responses to ICIs therapy. ATB treatment was associated with decreased PFS and OS. ATB decreased PFS (17.4 vs. 23.1 months, HR 1.50, 95% CI 1.20–1.88, p < 0.001) and OS (45.6 vs. 62.4 months, HR 1.63, 95% CI 1.27–2.08, p < 0.001) compared to no ATB. Similarly, in multivariable analysis, all ATB and anti-G + ATB significantly worsened PFS (HR 1.31, 95% CI 1.04–1.65, p = 0.02), (HR 1.50, 95% CI 1.07–2.10, p = 0.02) and OS (HR 1.52, 95% CI 1.18–1.96, p = 0.001), (HR 1.83, 95% CI 1.27–2.62, p = 0.001), respectively [49]. The same group recently investigated the role of antibiotic treatment in women with recurrent EC, CC, and OC treated with ICIs. They demonstrated that p ATB was associated with decreased ICI response rate (RR). Similarly, the PFS and OS were also decreased in women with EC and CC treated with p ATB compared with women who did not receive ATB [50].

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