Gut microbiome and nutritional strategies in gastrointestinal cancers: Clinical implications and therapeutic perspectives

Table 1 Therapeutic approaches related to the gut microbiome in colorectal cancer

Therapeutic approach	Description	Key findings
Bacterial eradication	Targeting CRC-associated bacteria using antimicrobial agents	Colibactin-producing E. coli inhibited by ClbP inhibitors, reducing tumor growth in mice[169]
		F. nucleatum targeted with metronidazole, lowering bacterial load and tumor proliferation[140]
Probiotics	Using beneficial bacteria to modulate gut microbiome for CRC prevention and chemotherapy support[20,133,170]	Lactobacillus and Bifidobacterium species reduced preneoplastic lesions in animal models[171,172]
		VSL3 probiotic mix reduced adenoma formation and chemotherapy side effects[173]
		Human studies show mixed results on probiotics’ protective effects against CRC[174-176]
FMT	Transplanting healthy microbiome to modify gut composition and potentially prevent CRC[177]	FMT from wild mice improved CRC resistance and inflammation markers in recipient mice[177]
		Clinical evidence remains limited, requiring further studies[178]
Microbiome and chemotherapy resistance	Gut bacteria influence drug resistance and efficacy in CRC treatment[166]	F. nucleatum linked to resistance against 5-FU and oxaliplatin via immune signaling[166]
		Mycoplasma hyorhinis and Gammaproteobacteria impair gemcitabine by enzymatic deactivation[179]
		Ciprofloxacin restored gemcitabine sensitivity[179]
		Antibiotic use may reduce chemotherapy efficacy in some cases[180]
Microbiome and immunotherapy	Gut bacteria influence immune responses to CRC therapies[27]	Microbiome impact responses to immune checkpoint inhibitors (e.g., Ipilimumab)[181]
		Antibiotic-treated mice showed reduced immunotherapy effectiveness[181]
Microbiome and drug toxicity	Bacteria alter drug metabolism, affecting side effects and toxicity	E. coli β-glucuronidase reactivates irinotecan, increasing toxicity[182,183]
		Irinotecan alters microbiome, increasing inflammatory bacteria (Fusobacteria, Proteobacteria)[182]
		Antibiotic treatment reduced oxaliplatin-induced neuropathy in mice[184]

CRC: Colorectal cancer; ClbP: Colibactin precursor peptidase P; 5-FU: 5-fluorouracil; FMT: Fecal microbiome transplantation; E. coli: Escherichia coli; F. nucleatum: Fusobacterium nucleatum.

Table 2 Recent findings on microbiome-targeted therapies for pancreatic ductal adenocarcinoma

Therapeutic approach	Description	Key findings
Antibiotic therapy	Targeting tumor-associated bacteria to reduce tumor burden and enhance immunotherapy	Pushalkar et al[211] found a 50% tumor burden reduction in PDAC mouse models after oral antibiotic treatment
		Tumor microenvironment reprogrammed, reducing myeloid-derived suppressor cells and increasing M1 macrophages[211]
		Antibiotics improved PD-1 checkpoint inhibitor response, enhancing T-cell activation and reducing tumor size[211]
		A clinical trial is evaluating antibiotic-pembrolizumab combination in locally advanced PDAC[189]
Probiotics and PDAC prevention	Investigating probiotics’ role in mitigating PDAC risk factors (e.g., pancreatitis, obesity, diabetes)	Lactobacillus plantarum 299 reduced pancreatic sepsis and surgical need in acute pancreatitis patients[212]
		Probiotics reduced fibrosis, inflammation, necrosis, ductal damage, and atypical cellular regeneration, potentially lowering PDAC risk
Microbiome and chemotherapy resistance	Examining bacterial interference with chemotherapy efficacy	Gammaproteobacteria enriched in 76% of PDAC samples, degrading gemcitabine into an inactive form[179]
		Microbiome-targeted approaches could enhance chemotherapy effectiveness

PDAC: Pancreatic ductal adenocarcinoma; PD-1: Programmed death 1.

Table 3 Microbiome-targeted treatment strategies in gastroesophageal cancer

Topic	Findings	Key insights
Microbiomes in esophageal cancer treatment	Disrupting microbiome with antibiotics decreases xenograft tumor response to CpG oligonucleotide immunotherapy and platinum-based chemotherapy (e.g., oxaliplatin)[180]	A stable commensal microbiome may enhance cancer therapy effectiveness[180]
	Similar effects observed in germ-free mice[180,234]	Microbiome regulates myeloid-derived cell functions within the tumor microenvironment[234]
		Further clinical research is needed
H. pylori and GC risk	H. pylori eradication reduces GC risk but does not guarantee complete prevention[235,236]	Other factors contribute to GC beyond H. pylori infection[235]
	A Colombian clinical trial showed no significant GC incidence difference between treated and untreated individuals over six years, but treated individuals had higher precancerous lesion regression rates[235]	Eradication reduces GC risk by about 44% in asymptomatic, infected individuals[236]
Long-term impact of H. pylori eradication	A 15-year study showed a 39% reduction in precancerous lesions[237]	Protective effects are strongest in non-atrophic/atrophic gastritis patients[239,240]
	An 8-year study found that atrophic body gastritis reversed in 50% of treated patients[238]	Intestinal metaplasia and dysplasia patients do not experience the same benefit
	Meta-analyses confirmed a significant reduction in GC risk post-eradication[239]	Early eradication is crucial as intestinal metaplasia is irreversible
Epigenetic modifications in GC prevention	DNA demethylating agent (5-azadC) suppresses aberrant methylation and reduces GC incidence in animal models[241]	Developing safer DNA demethylating agents could benefit high-risk individuals[223]
	Clinical use is limited due to high toxicity
Probiotics and H. pylori eradication	Probiotics inhibit H. pylori in animal studies[242]	Probiotics may play a role in GC prevention[243,244]
	Clinical trials/meta-analyses show probiotics improve eradication rates, patient compliance, and reduce treatment side effects	Used alongside antibiotics, they enhance treatment efficacy

H. pylori: Helicobacter pylori; CpG: Cytosine-phosphate-guanine; GC: Gastric cancer.

Table 4 Microbiome-targeted treatment strategies in hepatobiliary cancers

Topic	Findings	Key insights
Antibiotics, probiotics, and GBC	Limited experimental and clinical evidence on their use for GBC prevention or treatment[255]	Salmonella infection may trigger lasting oncogenic changes
	A study by Scanu et al[255] found that Salmonella-infected mouse embryonic fibroblasts formed tumors even after bacterial eradication with ciprofloxacin
	Salmonella infection activates Akt/MAPK signaling pathways, potentially sustaining carcinogenesis post-eradication[255]	Further research is needed to explore microbiome-targeted GBC therapies
	Cholecystectomy remains the most effective preventive measure for chronic typhoid carriers at risk of GBC[251]
Probiotics and HCC prevention	Probiotic-fermented milk and chlorophyllin reduced tumor incidence in AFB1-induced HCC in rats[276]	Probiotics show potential in reducing HCC risk and progression in animal models
	VSL3 probiotic formula inhibited chemically induced HCC, reducing LPS levels, tumor size, and tumor count[267]
	Prohep (novel probiotic mix) decreased tumor growth by 40%, enhanced anti-inflammatory responses, promoted T-cell activation, and reduced pro-angiogenic factors in mice[277]	Clinical evidence remains limited, requiring large-scale human trials
Probiotics and aflatoxin exposure	Some studies suggest probiotics reduce aflatoxin exposure and toxic DNA adduct formation, potentially lowering HCC risk[278]	Needs further validation in human studies
FMT and liver disease	FMT has shown promise in treating[279]: (1) High-fat diet and alcohol-induced liver injury (animal models)[280]; (2) Severe alcoholic hepatitis (clinical studies)[281]; (3) Chronic hepatitis B[282]; and (4) Advanced liver cirrhosis and hepatic encephalopathy	FMT may help restore gut-liver axis balance[279]
		Its role in HCC prevention and therapy remains unclear, requiring further clinical trials

GBC: Gallbladder cancer; Akt: Protein kinase B; MAPK: Mitogen-activated protein kinase; HCC: Hepatocellular carcinoma; AFB1: Aflatoxin B1; LPS: Lipopolysaccharide; FMT: Fecal microbiome transplantation.