Background　The　principal　therapeutic　agents　for　minimal　hepatic　encephalopathy　(MHE),　which　focus　on　the　modulation　of　the　gut　microbiota,　include　lactulose　and　rifaximin;　however,　the　precise　mechanisms　through　which　they　operate　remain　unclear.Aim　This　study　aimed　to　investigate　the　effects　of　rifaximin　and　lactulose　on　the　gut-liver-brain　axis　in　a　rat　model　of　MHE　and　to　clarify　the　underlying　mechanisms　involved.Methods　A　rat　model　of　MHE　was　established　by　subcutaneous　carbon　tetrachloride　(CCl4)　injection.　The　Morris　water　maze　(MWM)　test　was　used　to　assess　cognitive　function　in　MHE　rats　following　treatment　with　rifaximin　and　lactulose.　Serum　and　cerebrospinal　fluid　ammonia　levels　were　quantified,　along　with　measurements　of　portal　lipopolysaccharide　(LPS)　and　various　serum　inflammatory　markers.　Furthermore,　the　expression　of　Toll-like　receptor　4　(TLR4)　in　the　liver　was　examined　by　histopathological　evaluation.　Additional　analyses　included　the　detection　of　tight　junction　proteins　in　the　intestinal　mucosa　as　well　as　colon　fecal　16S　rRNA　sequencing　and　metabolic　pathway　assessments.Results　Both　rifaximin　and　lactulose　were　effective　in　reducing　ammonia　concentrations　in　MHE　rats　and　ameliorating　cognitive　deficits,　although　they　exhibited　a　minimal　impact　on　hepatic　function.　Post-treatment　assessments　revealed　significant　reductions　in　portal　LPS,　serum　interleukin-1　beta　(IL-1　beta),　and　tumor　necrosis　factor-alpha　(TNF-alpha).　The　expression　of　TLR4　in　the　liver　and　hepatic　inflammatory　infiltration　were　notably　diminished.　Rifaximin　administration　led　to　increased　occludin　expression　in　the　intestinal　tissues　of　MHE　rats.　Despite　no　significant　alterations　in　the　diversity　or　composition　of　the　gut　microbiota,　metabolic　pathway　analyses　indicated　a　downregulation　of　glycometabolism　pathways　following　treatment.Conclusion　Rifaximin　and　lactulose　may　enhance　cognitive　performance　in　MHE　rats　by　modulating　gut　microbiota　metabolism　and　preserving　the　intestinal　barrier　integrity.　This　modulation　is　associated　with　lowered　ammonia　levels,　decreased　translocation　of　LPS　to　the　liver,　and　reduced　inflammatory　response,　both　in　the　liver　and　systemically.