The Lactobacillus Crispatus M247 oral administration: it really is an effective strategy in the management of papillomavirus-infected women?

doi:10.21203/rs.3.rs-1480641/v1

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The Lactobacillus Crispatus M247 oral administration: it really is an effective strategy in the management of papillomavirus-infected women?

https://doi.org/10.21203/rs.3.rs-1480641/v1

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-Background: Recent studies have shown the importance of the microbiota in women's health. In contrast, a dysbiosis condition can be a predisposing condition of viral infections by Human Papilloma Virus (HPV). The persistence of HPV-related lesions in patients with dysbiosis, could represent the antechamber of cervical cancer. The aim of this study is to evaluate whether long-term administration of oral lactobacilli may allow the restoration of eubiosis in women with HPV-infections with consequently viral clearance.

-Methods: A total of 160 women affected HPV-infections were enrolled at Department of Gynecological Obstetrics of “San Paolo” Hospital, Italy between February 2021 and February 2022.Women were randomized in two groups, in treatment with oral Lactobacillus Crispatus M247 (group 1, n = 80) versus controlled group, with only follow-up (Group 2 n= 80).

-Results: After a median follow up of 12 months (range 10-30 months) the chance to solve HPV-related cytological anomalies was higher in treatment with oral probiotic long-term users (group 1) versus group with placebo (group 2) (60.5% vs 41,3%, p = 0.05). Furthermore, a total HPV-clearance was shown in 9,3% in patients with only follow-up compared to a percentage of 15,3 % in group that assumed oral Lactobacilli long term users (p = 0.34). So, the percentual of patients assessed with HPV-DNA test documented at the end of the study period is not significatively different by the control group.

-Conclusions: Despite the limitations of our analysis, we find a higher percentage of clearance of PAP-smear abnormalities, in patients who have took oral Lactobacilli long term than the control group. These results represent a confirm that the eubiosis re-establishment could be the first step to eradicate efficiently HPV-infection. Larger studies are need yet but we believe that future researchs should act in this direction.

Trial registration: This word is retrospectively registered.

HPV infection

Lactobacillus Crispatus M247

Probiotics

Papillomaviridae

Microbiota

Uterine cervical neoplasms

The vaginal microbiota in healthy women (eubiosis) contains a diversity of anaerobic and aerobic microorganisms. Lactobacilli are the most common and principal subpopulation. In selected situations, this balance can be deteriorated (dysbiosis) and other pathogens may develop, decreasing the anti-bacterial defense [1]. The loss of this balance can lead, depending on several factors (hormonal levels, host defenses, sexual practices) to the onset of vaginosis making the subject more susceptible to sexually transmitted diseases. Indeed, the maintenance of a healthy vaginal environment could be protective against infections [2]. Indeed, the most common microbial species that populate the vagina (such as the Lactobacilli) are the most remarkable protagonists of this process. Indeed, Lactobacilli produce antimicrobial compounds (hydrogen peroxide, lactic acid, bacteriocin-like substances) and compete for adhesion sites in the vagina with other pathogens [3]. So, a relationship between long duration of dysbiosis and cancer progression have been observed [4]. Indeed, through the elevation of pH, vaginal dysbiosis could promote cervical Human Papilloma virus (HPV)-related alterations and thus precancerous lesions progress [5]. HPV infection is among the most diffuse sexually transmitted infections in the world, with the highest incidence among young women and has been known as the principal reason of cervical cancer insurgence[6].The synergistic effects of persistent high-risk HPV infection, changes in the cervical microenvironment, and other auxiliary carcinogenic factors (smoking, sexual propinquity) could favor the development of cervical precancerous lesions[7]. In particular, it appears that the composition of the microbiota may play a key role in conditioning individual susceptibility to infection and viral progression[8].To date, an increasing attention has been developed about the probiotics, since they could promote women’s well-being restoring the microbiota. [9].The aim of our analysis was to examine if Lactobacillus Crispatus M247 oral long administration in patients with HPV-infections, might be able to restore eubiosis and consequently has an useful effect on viral infection control [10–11].The oral use of Lactobacillus Crispatus M247 in order to modify the microbiota and increase HPV clearance, was recently evaluated[12]. Lactobacillus Crispatus M247 is a tested probiotic that shows fecal and vaginal colonizing properties after oral administration [13–14]. Therefore, we have administrated this strain in a preliminary, longitudinal, controlled, and open study enrolling HPV-positive women, to assess its possible impact both in terms of the microbiota and on HPV status. The aim of this study is to assess the possible impact of oral long-term administration of the Lactobacillus Crispatus M247 on cervical cytology and persistence of HPV infection. According to our albeit partial experience, the oral administration of the Lactobacillus Crispatus M247 strain, is a completely safe treatment and with a real potentiality on the regression of PAP-smear alterations.

Community state types of classification

The process to identify bacterial species in scientific studies is the 16S rRNA high-throughput sequencing (16S-HTS) [15]. On based of the 16S-HTS analysis, the cervicovaginal microbiota can be distingue in five groups that have been definite for the first time in 2011 “community state types “(CSTs) (Ravel in 2011) [16].CSTs were divided into in I to V: CSTs I, II, III, and V contain Lactobacillus Crispatus, Gasseri, Iners, and Jensenii as the dominant species, respectively [16].On the other hand, CST IV was constituted by anaerobic bacteria such as Gardnerella, Prevotella, Atopobium, Sneathia, and (scarce) Lactobacillus species but by Pseudomonas, Shigella, Peptostreptococcus, Enterococcus, Streptococcus, Propionibacterium, Bifidobacterium, and Brevibacterium species.(Fig. 1)

Why Lactobacillus Crispatus M247 was chosen for this study?

Lactobacillus Crispatus M247 is a well-documented probiotic that demonstrates fecal and vaginal colonizing properties after oral administration. Moreover, the rational of use Lactobacillus Crispatus M247 in HPV-infected women is represented by evidence on cross-sectional and longitudinal studies that revealed that the Lactobacillus Crispatus- dominated CST is detected more recurrently in patients without human papillomavirus (HPV) infection [10–13].

Why we prefer the orally the probiotic administration?

The administration of oral lactobacilli is based on the evidence that the intestinal microbiota is connected to vaginal one and that most dysbiosis may have an origin at the intestinal level [17]. Particularly two recently studies have investigated the relationship between the gut microbiome and cervical cancer. [17]. Wang et al connected the gut microbiome between eight women with cervical cancer and five healthy women [17]. Patients with cervical cancer shown a higher gut microbiota diversity, although this difference was not statistically significant[17].Actually, in a grander examination of the gut microbiome in cervical cancer patients versus women without cervical cancer, our group observed a statistically significant higher a-diversity in cervical cancer patients than in healthy controls [18].Moreover, literature reported significant differences in several taxa between cervical cancer patients and controls, predominantly that members of the phylum Proteobacteria were superior in cervical cancer women[19]Different studies reported a distinction in taxonomic abundance profiles between cervical cancer patients and the control group[18].The intestinal microbiome is deeply conditioned by diet, as well as by individual factors. Therefore, Sims et al concludes that since cervical HPV- lesion are associated with vaginal and gut microbiota [20]. Oral probiotic treatment could modulate both intestinal and vaginal microbioma reducing HPV lesions [20]. So, the use of Lactobacillus Crispatus orally allows to obtain a colonization in the intestine that in a few days allows the transfer of lactobacillus into the vagina. This allows you to have an intestinal reservoir of Lactobacillus crispatus that feeds the vaginal compartment even when you no longer use the probiotic for a few weeks / months, which would not happen if there was an application of the product topically. Thanks to adhesion properties of Lactobacillus Crispatus M 247 this probiotic allows a high permanence of intestinal and vaginal cells [21].

This is a pilot study, performed between February 2021 and February 2022 at Department of Gynecological Obstetrics “San Paolo “of Bari. The initial study group included 205 sexually active women, aged between 30 and 64 years old, with a Papanicolaou test reporting low-grade cervical cytology as atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (L-SIL) or with negative PAP-smear with positive HPV-DNA test. Exclusion criteria were pregnancy or breastfeeding, CIN2–3, immunological diseases or corticosteroid treatment, severe comorbidities. Consequently, these patients enrolled, during each routinary follow-up, after explaining the detailed of the aims of the study. On 205 patients selected according to inclusion criteria, 160 women agreed to take part in the study and provided informed consent to publish the results and completed all the necessary paperwork relating to privacy. All women data were completely anonymized, and the study was performed in accordance with the Declaration of Helsinki. Patients were randomized in two groups. The Group 1(n = 80) performed oral treatment with Crispatus for 90 day and repeated the treatment after for 3 moths. The second group (n = 80) represent control group and has been subjected to the routinary follow-up every six months without treatment. Bacteriological examination, PAP-smear and colposcopy were performed for every enrolled patient every 6 months whereas HPV-DNA test was repeated after 12 months. Bacterioscopic exam was executed by means of rehydrated vaginal sample was with normal saline solution and plotted under a phase contrast microscope with 400× magnification and an area of 0.016 mm2). The sign of bacteria, clue cells, number of vaginal leucocytes and other presence of potential microbial balance alteration were documented [11]. In case of presence of infection, standard antibiotic or antifungal therapy was administered and at the end of therapy the bacteriological examination was repeated and only after eradicating the infection was PAP performed-smeras. Moreover, assessment of pH was made with Litmus paper test. PAP-smears were assessed by expert pathologists by means of the three-tiered cervical intraepithelial neoplasia (CIN) classification and with Bethesda terminology [9]. An adequate smear was distinct as a sample of adequate number of squamous cells, with evidence of transformation zone noted. Colposcopy assessment was executed on the basis of the terminology presented by the Nomenclature Committee of International Federation for Cervical Pathology and Colposcopy in 2011 [12], identifying as Grade 1 (minor changes) the existence of a fine mosaic, fine punctation, a thin acetowhite epithelium, or an irregular, geographic border and as Grade 2 (major changes) the presence of a sharp border, an inner border sign, a ridge sign, a dense acetowhite epithelium, a coarse mosaic/punctation, or cuffed crypt openings. Atypical vessels or other suspicious signs of invasion (such as fragile vessels, irregular surface, exophytic lesion, necrosis, ulceration, tumor, or gross neoplasm) were involved under Grade 2. The squamo-columnar junction visibility was categorized as completely visible or non-completely visible. The transformation zone type was distincted in type 1 and 2 (completely visible) or type 3 (not fully visible). Lesion position was described: a) ectocervical (if lesion was only present on ectocervical biopsy), endocervical (if lesion was on endocervical curettage), or ectocervical and endocervical (if the lesion was present on both).

Pap test, HPV DNA test

The Pap test was executed by collecting eso- and endocervical cells by means of ayre’s spatula and a cytobrush. The cells were successively streaked on a glass slide and spray fixed. Smears were classified according to the 2001 Bethesda System [22].The test was carried out with a validated method for screening COBAS 4800 HPV-Test Real-Time PCR that detects strains: HPV-HR16,18,31,33,35,39,45,51,52,56,58,59,68 .In each report it was specific that the finding of a positive test is an indication of the presence of the virus in the sample examined but does not in itself make a diagnosis of disease [23].

Statistical analysis

160 women with low-grade cervical cytology as atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (L-SIL) or with negative PAP-smear with positive HPV-DNA test HPV-infection were selected for this study. For each patient, aged between 30 and 65 years, the following parameters were recorded:

Bacteriological examination every 6 months, PAP-smear and colposcopy every 6 months ,HPV-DNA-test every 12 months.

The collected data were were initially inserted into an Excel database (Microsoft, Redmond, Washing- ton, USA) and subjected a Least Significant Difference Test at p ≤ 0.05.

All statistical analyses were performed using the PlotIT program Ver. 3.2 (Scientific Programming Enterprises, Haslett, MI, USA).

Results Features of the enrolled patients

Out of the 160 HPV-positive enrolled patients, (median age: 45 years; minimum: 30; maximum: 64) 105 (65%) are tested positive for high-risk strains (29 women with HPV16; 17 with HPV18; 13 with HPV66; 15 with HPV68; 10 with HPV58; 18 with HPV45; 12 with HPV53; 18 with HPV51; 17 with HPV52; 18 with HPV35) and 55 (34%) tested positive for low-risk strains.

Adherence to therapy, tolerability, and unwanted- ed effects due to treatment

The patient referred an adherence to therapy greater than 98%. Moreover, women had referred that the treatment was well tolerated with no significant side effects. Only Nausea was reported by 2 patients that reported taking it in the morning, so we suggested taking it before meals and the disorder subsided.

Tested product

The probiotic product used in our clinical study corresponds Crispact® sachets. Each sachet contains no fewer than 20 billion colony form-ing units of L. Crispatus M247 (lMG-P-23257).21 The product is manufactured by Alfa Omega (Copparo, Ferrara, Italy) and traded by Pharmextracta SpA (Pontenure, Piacenza, Italy). The product was notified to the Italian Health Authorities in 2019 (March 1st) with the notification number 115450.

A total of 160 women were included in the study. Each patients performed fresh bacteriology before performing the PAP test and their infection sign in 25% of group 1 patients (13% bacterial 12% mycotic vaginosis) and 18.4% of Group 2 patients (bacterial 12% and 6,4% mycotic vaginosis). Moreover 95% of patients of vaginosis with group 1 and 98% of group 2 referred to suffer also of intestinal disturb (irritable colon, colitis).Vaginosis was identified following Amsel criteria [14] and by the presence of vaginal discharge in relationship with distinctive symptoms and signs of the disease (burning, dyspareunia ,itching).Therefore, patients with concomitant infections were in both groups treated in a standard way for infections and only after therapy and repetition of negative bacteriological examination was the Pap-test performed in order to reduce the potential interference of infections on the reading of the pap-test. Pap smear abnormalities were associated with HPV DNA positivity in 73,5 and 75.8% of cases in Group 1 and 2 respectively. Patients were sequentially randomized in two group as previously explained (Group 1, n = 80 and Group 2, n = 80). Of all participants 77% reported being in a monogamous heterosexual relationship and 23% women referred same-sex relationships. Compliance was very good, and all participants came back for all follow up visits. Median follow up time was 12 months (range 9–14 months) and they have a follow -up after six months. After six months, there were no statistically significant changes on cytological and HPV -test results between the two groups: remission rates of HPV lesion are (Group 1 = 20%, and Group 2 = 18% respectively). At the end of the study period, the chance to solve HPV-related cytological anomalies was statistically significant higher in Lactobacillus Crispate long-term oral users (61,5 vs 41,3%, p = 0.041) (Group 1 n = 80) versus controlled group. (Group 2 n = 80). On the other hand, HPV-DNA negative documented at the end of the study period, after median follow up of 12 months (range 9–14 months), was not significatively different (p = 0.034) in patients with only follow-up (9,3%) compared to patients who have taken oral Lactobacilli long term (15,3%).

Cervical cancer represents the most common neoplasia among patients in developing countries and the second most frequent female cancer worldwide [24]. Frequently, it developments through a sequence of premalignant lesions that was described as different grade of CIN 1, 2 and 3 [22]and just a few women with CIN lesions advance in invasive cancer. Moreover, although HPV is widespread, literature reports that only a small number of women have a recurrent HPV infection and subsequently develop precancerous lesions [25]. Indeed, several studies described that spontaneous HPV clearance was evaluated approximately in 20–30% of cases in three months, in almost 50% in six months, and in nearly 60–70% in one year[26].Consequently, several studies reports that, over 90% of HPV infections and infection-induced lesions are transitory and resolve spontaneously [27].The ability of each organism to eliminate the virus may depend on several factors, among which seem to be decisive concomitant vaginal infections, local microflora imbalance and immune response defect [28].The role chronic inflammation due to vaginal infections and consequently the development of pre-cancerous lesions it was recently profusely debated in literature as a risk factor for cervical dysplasia [29, 30].Indeed, it is described how the vaginal microbiome can play a crucial role in the maintenance of vaginal homeostasis with a protective role against fungal, protozoal bacterial and viral infections. Its defensive action has also been found against the human papillomavirus. Actually, a healthy vaginal ecosystem is characterized by Lactobacilli that could represent a local immune system and inflammation response modulation [31]with the capacity to control cell proliferation/apoptosis [32].Indeed, hydrogen peroxide, lactate and bacteriocins rreleased by Lactobacilli could inhibit pathogen overgrowth in the whole urogenital tract, being a vital support in achieving a good reproductive and general health in women[33–35].Therefore, the support of lactobacilli taken orally would allow to restore the endogenous balance and strengthen the defenses against HPV facilitating its clearance[35–37].Other study evaluated the role of oral probiotics in patients with HPV infection, but with an important bias that it was represents to enrolled only women with concomitant infection in progress. In fact, the execution of pap-smears in women with infection could be unreliable since the criteria for an optimal cytology valuation also include the absent of inflammation [37–39]. Moreover, interestingly, women who had vaginosis had an associated a chronic intestinal disease. This confirms the chosen the administration of oral lactobacilli, since intestinal and vaginal vaginal microbiota re connected each other. Therefore, it would be useful create a multidisciplinary equipe (made up of Gastroenterologists, Nutritionists and Gynecologists) to find a balance to these different aspects, restoring the vaginal and intestinal eubiosis. Moreover, the literature reports several evidence of the impact of diet on the microbiota [40–41]. On the other hand, to our knowledge, there is no study that correlates how a balanced diet can improve the microbiome and make the subject less predisposed to vaginocervical infections. It would be important to test this hypothesis through a personalized and multidisciplinary approach. Moreover, it is also necessary to deepen this field with proteomics studies that can sequence the intestinal and vaginal microbiome on a large scale effectively. Although the limit of these studies is the high cost. Moreover, even if the effectiveness of vaginal lactobacilli appears limited, the concomitant use of oral and vaginal lactobacilli could be considered to potentially obtained HPV negativization in less time [38]. Consequently, further studies could be carried out with comparison between several arms and with concomitant use of oral and vaginal probiotics.

Limitation of study

The results of our study appear to encourage the use of probiotics in patients with low-grade HPv lesions. Actually, this data must be carefully evaluated, since for the naturally HPV history the 60–70% of patients after 12 months undergo spontaneous regression. [23]. Consequently, it is difficult to assess whether pap smear negativizzation was link to oral probiotics treatment or the described high incidence for spontaneous viral clearance. On the other hand, there is not a significatively difference of the HPV -test result after 12 months between the two groups. Consequently, as result of this study we could described as the L. Crispatus M247 orally long-term administration could improve the microbiota and consequently the cytology, while the efficacy on definitive viral clearance, demonstrated with HPV-test, remains debated. Therefore, even if the data are encouraging, it would take more time and on a larger sample to verify the effectiveness of long therapy -term probiotic. In fact, one could evaluate in case of persistence, the viral strain by performing viral genotyping.

In this study, the oral Crispatus M247 long-term administration shown a potential effect by in solving cervical abnormalities, through the restoration of the physiological vaginal balance. Indeed, the high percentage of clearance of PAP-smear abnormalities obtained with oral L.Crispatus M247 long term administration, represented a fascinating and encouraging evidence. For a supplementary confirm, a metagenomics analysis on the vaginal, cervical, and intestinal microbiota in HPV infected women should be executed. Consequently, our experience could be a cornerstone for further discussion on this topic and, since in our opinion, will represent the right direction for the complete HPV infection-eradication.

-Ethics approval and consent to participate:

Written informed consent was collected from all patients enrolled. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 2013 Helsinki declaration and its later amendments or comparable ethical standards.

-Consent for publication:

We informed patient about the use of her personal data for scientific purposes, under the protection of the Privacy Act, and she accepted and signed a related informed consent.

-Availability of data and materials:

all the data in the manuscript have been archived and available through the corresponding author.

-Competing interests:

authors declare that have no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article

-Funding:

not applicable

-Authors' contributions:

Miriam Dellino and Antonella Daniele: Wrote the paper.

Giovanni Di Vagno and Antonio Malvasi: Conceived and designed the analysis.

Rosanna Zaccaro and Katia Maggipinto: Collected the data;

Gerardo Cazzato, Eliano Cascardi and Salvatore Scacco: Contributed data or analysis tools.

Raffaele Tinelli, Alessandro De Luca,Maria Elena Giacomino, Miriana De Nicolò and Marina

Vinciguerra: Performed the statistical analysis.

Vera Loizzi, Ettore Cicinelli Gennaro Cormio and Vincenzo Pinto: Conceived and designed the analysis.

-Acknowledgements:

Thank you to our supervisor, Dr Dellino Donato, for founding the II level HPV screening center on “San Paolo” Hospital of Bari and since he provides guidance throughout this manuscript and in our personal cultural and professional experience.

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No competing interests reported.

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Editorial decision: Major revision
06 May, 2022
Reviews received at journal
02 May, 2022
Reviewers agreed at journal
26 Apr, 2022
Reviewers invited by journal
19 Apr, 2022
Editor assigned by journal
19 Apr, 2022
Submission checks completed at journal
06 Apr, 2022
First submitted to journal
23 Mar, 2022

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The Lactobacillus Crispatus M247 oral administration: it really is an effective strategy in the management of papillomavirus-infected women?

Status:

Version 1

Abstract

Figures

Introduction

Community state types of classification

Why Lactobacillus Crispatus M247 was chosen for this study?

Why we prefer the orally the probiotic administration?

Materials And Methods

Pap test, HPV DNA test

Statistical analysis

Results Features of the enrolled patients

Adherence to therapy, tolerability, and unwanted- ed effects due to treatment

Tested product

Results

Discussion

Limitation of study

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1