CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a § 371 national phase of International Application No. PCT/IB2018/056956, filed on Sep. 12, 2018, which claims the benefit of Italian Application No. 102017000101704, filed on Sep. 12, 2017, which applications are incorporated by reference herein.

The present invention relates to the use of specific strains ofLactobacillus paracaseior of a composition comprising said strains for the prevention and/or treatment of a physiopathological condition related to/associated withClostridium difficileinfection, preferably intestinal infections, or so-called CD-associated disease (CDAD) or CD infection (CDI).

PRIOR ART

Clostridium difficileis a gram-positive, anaerobic, spore-forming, rod-shaped bacterium widely disseminated in nature, both in the subsoil and in the intestinal tract of pets.

Contamination by this microorganism also occurs through the fecal-oral route; in particular, the spores ingested survive the acid barrier of the stomach and germinate in the colon.

In humans,Clostridium difficilemay be found in about 3% of healthy adults as a constituent of intestinal saprophytic flora and, in more substantial percentages, in infants under one year of age (15-70%).

Clostridium difficilegenerally does not cause any disorder. However, under certain conditions, it may cause diarrhea of variable intensity and, in certain cases, it may be associated with fever as well as a major general impairment of a person's state of health from a physical, psychological and social standpoint. In fact, the diarrhea is often accompanied by other major symptoms, such as: nausea, vomiting, general malaise, pain, abdominal distension and dehydration.

In the clinical realm,Clostridium difficileis known as being mainly responsible for a severe form of colitis, defined as pseudomembranous colitis, characterized by more or less extensive necrosis, prevalently affecting the rectum and sigmoid colon, and accompanied by often profuse diarrhea.

A cause for concern in this regard are in particular several strains ofClostridium difficile, defined as enterotoxigenic as they are capable of producing enterotoxin A and/or cytotoxin B. These toxins are internalized by the intestinal mucosa, bringing about the cell death of enterocytes.

The spectrum of histological lesions varies from a type I form, characterized by sporadic epithelial necrosis associated with an inflammatory infiltrate inside the lumen of the colon, to a type III form, characterized by widespread epithelial necrosis and ulcerations covered by greyish pseudomembranes (hence the term pseudomembranous colitis), made up of mucin, neutrophils, fibrin and cellular debris.

The severity ofClostridium difficileintestinal infection is variable. The symptoms can in fact range from mild to profuse diarrhea (up to 10 liters of serous discharges per day), with toxic megacolon, intestinal perforation, hypokalemia, intestinal hemorrhaging, and sepsis. The diarrhea can be accompanied by fever, nausea, anorexia, general malaise, pain, abdominal distension and dehydration. The diarrhea can be associated with mucus, blood and fever. Infants are often asymptomatic carriers. In fact, though on the one hand colonization appears to be favored by the immaturity of intestinal bacterial flora, on the other hand the lack of pathological evolution is due to the incapacity of the toxin to bind to the receptors of enterocytes, which are also still immature.

The infection often manifests itself following aggressive antibiotic therapies and very commonly spreads in hospital environments. Diarrhea is a common side effect of antibiotic therapies, but once the drug is suspended at the end of treatment the disorder normally resolves. However, in the case ofClostridium, the diarrhea, accompanied by the other symptoms, shows no sign of decreasing or improving.

Among the risk factors forClostridium difficileinfection we may mention:Use of antibiotics, especially broad-spectrum ones (i.e. the ones that are capable of eliminating various types of bacteria), also for an extended period, or associations of different antibiotics to cure antibiotic-resistant infections;Need for hospitalization or stays in other treatment facilities;Digestive system surgery;Abdominal surgery involving the intestine;Stays in a kindergarten, nursery school or rest home;Colon problems, e.g. irritable bowel syndrome or colorectal cancer;Kidney problems;Weakened immune system (due to diabetes or drugs);Intake of proton pump inhibitors or other drugs capable of reducing gastric acidity, which normally serves as protection against infections;PreviousClostridium difficileinfections;Age above 65 years.

Treatment of the infection in any case requires the use of antibiotics, albeit ones that particularly target this specific bacterium.

As noted earlier, the majority ofClostridium difficileinfections occur in settings such as, for example, hospitals and nursing homes, in which many individuals take antibiotics and are in close contact with one another. The lethality of severeClostridium difficileinfection is considerable, so much so as to make the adoption of prophylactic measures indispensable in order to stem the spread of the disease in hospital environments.

In recent years, various cases have been successfully treated with the fecal transplantation method.

Recourse to probiotics has proven effective in the prevention/treatment of most types of diarrhea, comprising that induced precisely byClostridium difficile, through the competitive inhibition of the pathogens, stabilization of resident microbiota and attenuation of the increase in intestinal permeability associated, for example, with rotavirus infections.

In the light of the foregoing, there is a strongly felt need for new and/or alternative therapeutic solutions which may alleviate the symptoms associated therewith and/or cure the physiopathological conditions related to/associated withClostridium difficileinfections, preferably intestinal infections.

The Applicant has found the use of probiotics based on bacteria and/or yeast and/or other micro-organisms as a solution to the above-described needs. In particular, the present solution proposes the use of bacteria belonging to the genusLactobacillusand/orBifidobacterium, preferably the bacterial speciesLactobacillus paracasei.

In fact, as a result of the use of probiotics, as described in detail below, an inhibition ofClostridium difficileis observed, evident above all from in vitro displacement tests.

