Table 2.

Therapeutic applications in the management of certain bacteria-implicated gut diseases.

Target Pathogen	Phage Therapy	Disease	Study Type, Model	Reports	References
Vibrio spp.	Cocktail of five (5) lytic Vibrio phages	Fighting V. cholerae infection	In vivo, rabbits	Oral administration of cocktails before infection resulted in prophylactic effects. The phage cocktail significantly reduced bacterial load 6 and 12 h after the challenge.	Jaiswal et al. [109]
	Oral phage cocktail therapy	V. cholerae infection	In vivo, mice	Phage cocktail (108 PFU/mL) given once daily significantly reduced bacterial load.	Jaiswal et al. [110]
	Bacteriophage pVp-1	Multiple antibiotic-resistant V. parahaemolyticus implicated in gastroenteritis	In vivo, mice	Protection from infection and death 1 h after inoculation with V. parahaemolyticus.	Jun et al. [111]
	Cocktail of three (3) lytic (virulent) phages—ICP1, ICP2, and ICP3	Cholera pathogenesis/cholera-like diarrhea	In vivo, infant mice and rabbits	Effective at preventing mouse small intestinal colonization. Prophylaxis against the onset of cholera-like diarrhea was achieved after oral administration of the phages up to 24 h before V. cholera infestation.	Yen et al. [112]
Escherichia coli	Cocktail of three (3) bacteriophages from Siphoviridae and Podoviridae	E. coli implicated in gastrointestinal diseases	In vitro	Phage cocktail exhibited broad spectrum and strong lytic activity against E. coli isolates.	Nasr-Eldin et al. [113]
	Cocktail of lytic phages specific against E. coli	Gut pathogenic E. coli	In vivo, mice	Suppression of E. coli was observed 5–10 d after phage therapy.	Abdulamir et al. [114]
	Lytic Myoviridae phage phPE42	Extensively drug-resistant (XDR) E. coli implicated in foodborne infections	In vivo, rats	Effective eradication of XDR E. coli was observed in animal feces.	Abdelaziz et al. [115]
	T4-like phages	Childhood diarrhea-associated E. coli isolates	In vitro, cultures	T4-like phages combined in a cocktail resulted in increased bacterial lysis.	Bourdin et al. [116]
	Phage-based probiotic dietary supplement consisting of 7 bacteriophage strains	Traveler’s diarrhea (TD) caused by E. coli, S. flexneri, S. sonnei, S. enterica, L. monocytogenes, S. aureus	Clinical study, in vivo, humans and mice	Prophylactic effect against TD.	Aleshkin et al. [117]
	Specific bacteriophage	Enteropathogenic E. coli (EPEC)	In vivo, mice	A single dose of the phage rendered a protective effect on the bacteria throughout the study.	Vahedi et al. [118]
	T4-like coliphages	Acute bacterial diarrhea	Clinical trial, humans	Failure to improve diarrhea condition, possibly due to insufficient phage concentration.	Sarker et al. [119]
	Virulent bacteriophages targeting prototype of the Adherent Invasive E. coli (AIEC) strain LF82	Crohn’s disease (CD)	Ex vivo, in vivo, murine and human intestinal samples	Three virulent bacteriophage cocktails were active against the AIEC strain LF82. A single dose of the cocktail reduced colitis symptoms in mice colonized with AIEC.	Galtier et al. [120]
	Bacteriophage cocktail Ec17B153DK1 vs. the broad-spectrumantibiotic ciprofloxacin	E. coli infecting the gut environment	In vitro, simulated small intestine system	The cocktail was effective in reducing E. coli in simulated gut conditions. No impact on commensal, non-targeted bacteria.	Cieplak et al. [121]
	Commercial cocktail of E. coli-targeting bacteriophages (PreforPro®) containing four phages (LH01-Myoviridae, LL5-Siphoviridae, T4D-Myoviridae, and LL12-Myoviridae)	Effect on gut microbiota during GI distress and markers of intestinal and systemic inflammation	Clinical trial, humans	The potential of bacteriophages to selectively reduce target organisms without causing dysbiosis	Gindin et al. [122]
	Supplemental bacteriophages (PreforPro®)	Enhance the effects of a common probiotic, B. animalis subsp. Lactis (B. lactis) on GI health	Clinical study, humans	Improvements in GI inflammation and colon pain in individuals consuming B. lactis with PreforPro®.	Grubb et al. [123]
	Suppository containing probiotic strains of Lactobacillus spp. and bacteriophages specific for pathogenic E. coli	Diarrhea	In vivo, calves	Probiotic-phage suppositories reduced the duration of diarrhea in calves. The complete stopping of diarrhea was observed 24–48 h after use.	Alomari et al. [124]
	Lytic phages (T4, F1, B40-8, and VD13 phages)	Effect on mice gut colonized with human commensal bacteria	In vivo, gnotobiotic mice	Targeted lysis of susceptible gut bacteria. Modulation of non-targeted bacteria through interbacterial interactions.	Hsu et al. [95]
	Genetically engineered temperate phages	Shiga-toxin (Stx)-producing E. coli colonizing the mammalian gut	In vivo, mice	Significant repression of fecal Stx concentrations. Suppression of virulence factors in gut bacteria.	Hsu et al. [125]
	Phage PDX, a member of the Myoviridae family	Diarrheagenic enteroaggregative E. coli (EAEC)	In vitro, in vivo, cultures and mice	Bacteriolytic activity of EAEC isolates (EN1E-0007) in vitro and in vivo. No dysbiosis was observed in the anaerobic culture.	Cepko et al. [126]
	Phage ES17, a Podoviridae phage	Extraintestinal pathogenic E. coli (ExPEC) in the intestine	In vivo, mice	Selective elimination of invasive pathobiont species from mucosal surfaces in the intestinal tract.	Green et al. [128]
Clostridium difficile	Six (6) myoviruses and one (1) siphovirus	C. difficile infection (CDI)	In vitro, in vivo, hamsters	Specific phage combinations resulted in total lysis of C. difficile in vitro. Prevention of resistance. In vivo, the evaluation revealed a reduction in C. difficile colonization 36 h post-infection.	Nale et al. [129]
	Recombinant bacteriophage	C. difficile infection	In vitro, in vivo, cultures and mice	Targeting and killing of C. difficile.	Selle et al. [130]
Salmonella spp.	Phage SE20 (Podoviridae)	S. enterica serotype Enteritidis	In vitro, in vivo, mice	Oral administration of a single dose of bacteriophage protected against salmonellosis and treatment of salmonellosis. Animals developed hepatomegaly and splenomegaly as side effects but had no gastrointestinal complications with the phage therapy.	Dallal et al. [131]
	Bacteriophage cocktail (foodborne outbreak pill (FOP) targeting E. coli O157:H7, L. monocytogenes, and Salmonella)	Salmonella infection	In vitro	Simulator of the Human Intestinal Microbial Ecosystem (SHIME).	Moye et al., 2019 [133]
	Phage cocktail	Salmonella colonization in experimentally challenged birds	In vivo, birds	Phage treatment effectively reduced Salmonella colonization and enhanced growth performance weight gains in challenged birds.	Thanki et al. [132]
	Myoviruses and a siphovirus	Salmonella infection gastrointestinal enteritis	In vitro, in vivo, swine, birds, cultures	Phage cocktail (STW-77 and SEW-109) had the most lysing efficacy on the swine and bird models. Some phages from the cocktail could lyse resistant strains of the organism.	Nale et al. [134]
	Salmonella phages (vB_SenS_KP001, vB_SenS_KP005, and vB_SenS_WP110)	Salmonella colonization in the gastrointestinal tract of broilers	In vivo, broilers	The phage cocktail reduced Salmonella colonization in broilers’ gastrointestinal tracts from over 70% to 0% 4 d post-treatment.	Pelyuntha et al. [135]
Fusobacterium nucleatum	Irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages.	Colorectal cancer (CRC)	In vivo, mice	Phage administration inhibited the growth of F. nucleatum. It significantly boosted the effectiveness of first-line chemotherapy treatments for CRC.	Zheng et al. [136]
	F. nucleatum (Fn)-binding M13-phage-loaded silver nanoparticles (AgNPs)	Symbiotic F. nucleatum in the gut selectively increases immunosuppressive myeloid-derived suppressor cells (MDSCs), thereby promoting colorectal cancer (CRC) progression.	In vitro, in vivo, mice	Treatment with M13-phage-loaded AgNPs could mop up F. nucleatum in the gut, resulting in non-amplification in MDSCs at the tumor sites.	Dong et al. [137]
Shigella spp.	Shigella-specific bacteriophages: vB_SflS-ISF001, vB_SsoS-ISF002, and a cocktail of both	S. sonnei and S. flexneri causing human acute gastrointestinal infections	In vitro, cultures	More than 85% of the ESBL-positive and -negative isolates of S. sonnei and S. flexneri were inhibited by the phage cocktail (vB_SflS-ISF001 and vB_SsoS-ISF002.)	Shahin et al. [138]
Klebsiella pneumoniae	Lytic five-phage combination	Inflammatory bowel disease (IBD)-associated K. pneumoniae (Kp) strains	In vivo, mice	Suppression of colitis in mice	Federic et al. [139]
	Commercial bacteriophage preparations	K. pneumoniae strains isolated from children with functional gastrointestinal disorders (FGIDs)	In vitro, spot test	Phages show negligible lytic activity, indicating the need for a more radical approach to eradicating K. pneumoniae in children with FGIDs.	Grigorova et al. [140]
Listeria monocytogenes	Bacteriophage cocktail (Foodborne Outbreak Pill (FOP))	L. monocytogenes	In vitro, simulated ilium and colon conditions	Protection against L. monocytogenes infecting the human gastrointestinal tract without causing dysbiosis.	Jakobsen et al. [142]
Ruminococcus gnavus	Six bacteriophages	Mucin-degrading bacterium R. gnavus from the human gut	In vivo, mice	Results show the coexistence of phages with R. gnavus in the human gut microbiome.	Buttimer et al. [144]
Campylobacter spp.	Double-stranded phages (Φ 16-izsam and Φ 7-izsam)	C. jejuni associated with broilers	In vivo, broilers	Phage administration showed a significant one to two log reduction in C. jejuni counts on the cecal content compared with the control group after sacrifice. The lowest colony count was, however, observed with an MOI of 0.1 of Φ 16-izsam.	D’Angelantonio et al. [146]
	Bacteriophages φ4, φ44, φ22, φCj1, φ198, and φ287	C. jejuni associated with broilers	In vitro, in vivo, broilers	Demonstrated the susceptibility of a significant number of the multi-resistant Campylobacter spp. to the phage isolates, which had a lytic spectrum of 6, 4, 4, 3, 8, and 7, respectively.	Nowaczek et al. [147]
General	Chitosan-encapsulated bacteriophage cocktail	S. enterica, S. flexneri, and E. coli gastrointestinal infections	In vivo, rats	Reduction in positive cultures from stools of the group receiving the chitosan-encapsulated bacteriophage cocktail was observed after two days.	Rahimzade et al. [148]