Role of prebiotics, probiotics, and synbiotics in management of inflammatory bowel disease: Current perspectives

Table 1 Summary of preclinical studies of probiotics

Ref.	Model	Treatment	Dose and duration	Parameters analyzed	Conclusion
Yoo et al[26], 2022	DSS-induced colitis in male C57BL/6 mice	Lactobacillus plantarum, Bifidobacterium longum, and Bifidobacterium bifidum	1 × 109 CFU once daily for 5 d	Cytokines and corticosterone, colonic MPO activity, fecal LPS level	Suppressed colonic inflammation, and fatigue by the suppression of the IL-1β or IL-6 to IL-10 expression ratio and gut bacterial LPS production
Qin et al[27], 2022	DSS-induced colitis in mice	Lactobacillus (Pediococcus pentosaceus, Lactobacillus plantarum, and Weissella cibaria)	-	DAI, colon length, pathological score, cytokine secretion	Showed the potential to treat IBD
Khan et al[28], 2022	DSS-induced colitis in mice (C57BL/6)	Lactobacillus plantarum	-	Colitis indexes, IL-17A, IL-17F, IL-6, IL-22, and TNF-α and anti-inflammatory cytokines, i.e., TGF-β, IL-10	Restored gut microbiota balance and modulated the resident gut microbiota and immune response
Fei et al[29], 2022	DSS-induced colitis in mice (C57/BL6)	Ligilactobacillus salivarius Li01 and RSV	Li01 (109 CFU/d) and RSV (1.5 g/kg/d)	IL-1β and IL-6, TGF-β and IL-17A	An improved synergistic anti-inflammatory effect from the RSV and Li01 combination treatment
Liu et al[30], 2021	DSS-induced colitis in mice (C57/BL6)	Goji juice fermented by Lactobacillus plantarum, Lactobacillus reuteri and Streptococcus thermophilus	20 mL/kg/d for 30 d	Pro-inflammatory cytokines and total superoxide dismutase in serum and colon, MPO and glutathione peroxidase	Probiotics-fermentation enhanced the anti-ulcerative colitis function of goji berry juice and modulated gut microbiota
Kim et al[31], 2020	DSS-induced colitis in male C57BL/6 mice	Lactobacillus plantarum CBT LP3 (KCTC 10782BP)	1 × 108 bacteria in 0.1 mL PBS once daily for 16 d	DAI, analysis of macrophages and T cell subsets gene expression and cytokine profiles	Effective anti-inflammatory effects, with increased induction of Treg and restoration of goblet cells, suppression of proinflammatory cytokines
Chen et al[32], 2020	DSS-induced colitis in C57BL/6J mice	Bifidobacterium breve, CCFM683	0.2 mL (1010 CFU/d CCFM683, once daily for 2 wk	Weight loss, stool consistency and fecal blood	Improved intestinal epithelial barriers, restored gut microbiota
Chen et al[33], 2020	DSS-induced colitis in C57BL/6 mice	Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis with (quadruple probiotics, Pqua) or without (triple probiotics, P-tri) aerobic Bacillus cereus	B. infantis, L. acidophilus, and E. faecalis (1.5 × 109 CFU respectively) in 200 uL PBS and B. cereus (0.5 × 108 CFU) in 200 uL once daily for 45 d	Intestinal inflammation and functions of multiple barriers, including the mucus barrier, and epithelial barrier	Effective (Aerobe-contained Pqua was a powerful adjuvant therapy for chronic colitis, via restoring the intestinal microflora and recovering the multi-barriers in the inflamed gut)
Komaki et al[34], 2020	Mice	Lactococcus lactis subsp. lactic JCM5805	1 mg, 5 mg, 10 mg, 15 mg, or 20 mg, once daily for 1 wk	The survival rate, length, histopathological parameters of the colon, and concentrations of inflammatory cytokines in serum	Effective (high-dose administration deteriorates intestinal inflammation)
Silveira et al[35], 2020	C57BL/6 mice	Lactobacillus bulgaricus	1 × 109 CFU was diluted in 200 mL of PBS, 3 times per week for 12 wk	Intestinal inflammation, cytokines levels were determined from colon and/or tumor	Regulates the inflammatory response and prevents Colitis-associated cancer

DSS: Dextran sodium sulfate; CFU: Colony forming unit; LPS: Lipopolysaccharide; DAI: Disease activity Index; IBD: Inflammatory bowel disease; RSV: Resveratrol; MPO: Myeloperoxidase; IL: Interleukin; TNF-α: Tumor necrosis factor-α; TGF-β: Transforming growth factor-β; PBS: Phosphate buffer solution; Tregs: Regulatory T cells.

Table 2 Summary of clinical studies of using probiotics in inflammatory bowel disease patients

Ref.	Treatment	Dose and duration	Parameters analyzed	Conclusion
Agraib et al[43], 2022	Lactobacillus and Bifidobacterium species	3 × 1010 probiotic capsules	Partial mayo score, CRP, IgA, IL-10, hemoglobin, hematocrit, and RBC levels	Significantly induced remission in UC patients
Ojetti et al[44], 2022	Limosilactobacillus reuteri ATCC PTA 4659	Two times a day for 10 d	Inflammatory markers CRP and calprotectin	Significantly reduced both blood and fecal inflammatory marker
Wu et al[45], 2021	Live bacillus licheniformis capsules and live combined Bifidobacterium, lactobacillus, and enterococcus capsules followed by Chamomile capsules	Bacillus licheniformis capsules two capsules, three times a day and live combined Bifidobacterium, lactobacillus, and enterococcus capsules two capsules twice a day. Probiotics consumed at a level of 107 CFU/mL	Leiden Index of Depression Sensitivity, Beck Depression Inventory questionnaires	Probiotics tend to improve cognitive reactivity to the sad mood in CD patients
Bamola et al[46], 2021	Bacillus coagulans Unique IS-2	2 billion-CFU/capsule twice in day 4 wk	Presence of beneficial gut bacteria, serum cytokines, symptoms of the disease	Showed beneficial effect when administered along with standard medical treatment
Waal M van der et al[47], 2019	Nine bacterial strains (Bifidobacterium bifidum W23; Bifidobacterium lactis W51; Bifidobacterium lactis W52; Lactobacillus acidophilus W22; Lactobacillus casei W56; Lactobacillus paracasei W20; Lactobacillus plantarum W62; Lactobacillus salivarius W24; Lactobacillus lactis W19)	7.5 × 109 CFU per 3 g in powder form, once daily for 6 wk	Quality of life from a patient perspective (semi-structured interviews)	Effective
Kamarli Altun et al[48], 2022	Enterococcus faecium, Lactobacillus Plantarum, Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus, Bifidobacterium long, and FOS	Probiotic strains (3 × 109 CFU) and FOS (225 mg/ tablet), 1 tablet twice a day for 8 wk	Hemoglobin, leukocyte, neutrophil-to-lymphocyte ratio, sedimentation, and CRP, clinical and endoscopic activity indices	Effective
Sun et al[49], 2018	Clostridium butyricum	420 mg per capsule, 1.5 × 107 CFU/g, 3 capsules 3 times a day for 4 wk	Change from baseline in IBD symptoms, quality of life, stool consistency, and frequency	Effective
Matsuoka et al[50], 2018	Bifidobacterium breve strain Yakult and Lactobacillus acidophilus	10 billion bacteria of Bifidobacterium breve and 1 billion bacteria of Lactobacillus acidophilus, one pack per day for 48 wk	Clinical procedure (change in abdominal symptom score from baseline. Sutherland DAI subscore, change in abdominal symptom scores (passage of flatus and bloating), and intestinal microbiota	Less significant effect

CRP: C-reactive protein; UC: Ulcerative colitis; CD: Crohn’s disease; CFU: Colony forming unit; FOS: Fructooligosaccharides; DAI: Disease activity index; IBD: Inflammatory bowel disease; IgA: Immunoglobulin A; RBC: Red blood cell; IL: Interleukin.

Table 3 Summary of preclinical studies of prebiotics

Ref.	Model	Type of treatment	Composition	Dose	Parameters analyzed	Conclusion
Cui et al[57], 2021	DSS-induced colitis in C57BL/6J mice	Polysaccharide from Scutellaria baicalensis Georgi	Mannose, ribose, rhamnose, glucuronic acid, glucose, xylose, arabinose, fucose	50 and 200 mg/kg once daily for 10 d	Body weight, loose stools, morbidity, hematochezia, and the DAI	Effective (attenuated body weight loss, reduced DAI, ameliorated colonic pathological damage, and decreased MPO activity)
Tolonen et al[58], 2022	DSS-induced colitis in male C57Bl/6 mice	Synthetic glycans	FOS, GOS, XOS, pullulan, and lactulose	1% (v/v) glycans (days 7-14)	Weight loss, scores of diarrhea, endoscopy, and colonic histology	Synthetic glycans increase survival, reduce weight loss, and improve clinical scores in mouse models of colitis
Qian et al[59], 2022	DSS-induced colitis in male C57Bl/6 mice	GOS, FOS along with FMT	FMT alone or combined with various ratios of GOS, and FOS	-	DAI scores, histology, protein or mRNA expression levels of FFAR3 and ZO-1, a tight junction protein	Treatment with FMT plus a prebiotic blend restores thestructure of the intestinal flora and increased the levels of acetic acid, butyric acid, FFAR3, and ZO-1
Liu et al[60], 2016	DSS-induced colitis in male C57BL/6 mice	Alpha D-glucan from marine fungus Phoma herbarum YS4108	Glucopyranose	40 mg/kg/d once daily for 1 wk	DAI scores, histology immunohistochemistry analysis, evaluation of SOD and MDA activities, and determinations of inflammatory cytokines	Effective (significantly increased butyrate, isovaleric acid levels, and prominent alterations on specific microbiota)
He et al[61], 2020	DSS-induced colitis in male C57BL/6 mice	Stachyose	Stachyose	1.5 g/kg/d for 28 d	Inflammatory cytokines including IL-6, IL-10, IL-17a, and TNF-α	Increased beneficial microbiota and bacterial diversity to alleviate acute colitis in mice
Kanwal et al[62], 2019		Dictyophora indusiate polysaccharide	Glucose 59.84%, mannose 23.55%, and galactose 12.95%	Low dose 10 mg/kg and (high dose 33 mg/kg once daily for 2 wk	Assessment of DAI, histological, analysis of goblet cells and mucus layer thickness, cytokines	Effective
Li et al[63], 2020	Male C57BL/6 mice	FMG or dealcoholized muscadine wine	FMG: Fructose 34.7% glucose 31%, sucrose 9.9%. DMW: Fructose, sucrose, and glucose not detected	FMG (7%, w/w) or DMW (5.5%, v/ w) for 3 wk	Bodyweight, stool consistency and bleeding, DAI, short-chain fatty acids in feces, and Mucin 2 and IgA in feces	Effective (reduced dysbiosis in the colon)
K-da et al[64], 2020	Male C57BL/6 mice	GFO	Monosaccharide composition in the GFO was D-galactose	100, 500, or 1000 mg/kg once daily for 2 wk	GI transit time, ex vivo propulsive motility, in vitro colonic smooth muscle contractility, the composition of colonic microbiota, and production of SCFAs	Effective (prevented and attenuated colitis symptoms and GI dysmotility, reducing populations of harmful bacteria and increasing SCFAs)

DSS: Dextran sodium sulfate; DAI: Disease activity Index; MPO: Myeloperoxidase; FOS: Fructooligosaccharides; GOS: Galactooligosaccharides; XOS: Xylooligosaccharides; FMT: Fecal microbiota transplantation; ZO-1: Zona occludens; SOD: Superoxide dismutase; MDA: Malondialdehyde; SCFAs: Short-chain fatty acids; GI: Gastrointestinal; IL: Interleukin; TNF: Tumor necrosis factor; FMG: Freeze-dried muscadine grapes; DMW: Dealcoholized muscadine wine; FFAR3: Free fatty acid receptor 3; GFO: Gracilaria fisheri oligosaccharides.

Table 4 Summary of clinical studies of using prebiotics in inflammatory bowel disease patients

Ref.	Type of treatment	Dose	Parameters analyzed	Conclusion
Valcheva et al[68], 2022	β-fructans (oligofructose and inulin)	15 g/d for 6 mo	Mayo score. FCP, along with stool metabolites	Did not prevent symptomatic relapses in UC patients but reduced the severity of biochemical relapse and increased anti-inflammatory metabolites
Pietrzak et al[69], 2022	Sodium butyrate	150 mg sodium butyrate twice a day for 12-wk	DAI, FCP	As adjunctive therapy, it did not show efficacy in newly diagnosed children and adolescents with IBD
Vernero et al[70], 2020	Oral microencapsulated sodium butyrate (BLM)	Dose of two capsules/day for 12 mo (500 mg of BLM for each capsule)	DAI, FCP, CRP	BLM supplementation appears to be a valid add-on therapy to maintain remission in patients with UC
Valcheva et al[71], 2019	Oligofructose-enriched inulin	7.5 g (n = 12) or 15 g (n = 13) daily oral oligofructose-enriched inulin for 9 wk	Mayo score, endoscopic activity and FCP	15 g/d dose inulin-type fructans produced functional but not compositional shifts of the gut microbiota. Controlled studies for the use of β-fructans as an adjunct therapy in patients with active UC are required
Azpiroz et al[72], 2017	scFOS	5 g per sachet, twice daily for 4 wk	Rectal sensitivity, anxiety/depression, quality of life scores, and composition of fecal microbiota	Less significant (scFOS on rectal sensitivity may require higher doses and may depend on the subgroup)

FCP: Fecal calprotectin; DAI: Disease activity index; CRP: C-reactive protein; UC: Ulcerative colitis; scFOS: Short chain fructooligosaccharides.

Table 5 Summary of preclinical studies of synbiotics

Ref.	Model	Probiotics	Prebiotics	Dose	Parameters analyzed	Conclusion
Xue et al[80], 2023	DSS-induced colitis in mice	Lactobacillus plantarum LP90	Soluble dietary fiber obtained from Lentinula edodes by products	1 × 109 CFU/kg	DAI, histological studies, IL-10, IL-17, IgA levels, TNF-α	Alleviated colitis
Ivanovska et al[81], 2017	DSS-induced colitis in C57BL/6J mice	Bifidobacterium infantis and Bifodobacterium longum	Equal parts FOS, GOS and XOS	0.5 × 109 CFU Probiotics and 2.5 g of prebiotics for 1 mo	Gut microbiome, cecal and fecal SCFAs	Increased the diversity of the microbiome and be associated with more SCFAs, and less gut inflammation
Seong et al[82], 2020	Chronic restraint stress in male Wistar rats	L. paracasei	Opuntia humifusa extract (mucilage + pectin)	L. paracasei (1 × 1010 CFU/g) & (10.0/30.0 mg%, w/w) of Opuntia humifusa extract once daily for 4 wk	Fecal microbial analysis, serum corticosterone levels, TNF-α levels in the colon tissue	Effective (greater abundance of L. paracasei in fecal microbial analysis, lower serum corticosterone levels, lower TNF-α levels in the colon tissue
dos Santos Cruz et al[83], 2020	IL 10- knockout mice	VSL#3	Yacon (6% FOS + inulin)	VSL#3 (109 CFU/d) + PBY (6% FOS and inulin) for 13 wk	Manifestations of colitis, colon histology, expression of antioxidant enzymes, production of organic acids, and intestinal microbiota	Preservation of intestinal architecture, improve intestinal integrity, increased expression of antioxidant enzymes and concentration of organic acids
Wang et al[84], 2019	DSS-induced colitis in C57BL/6J mice	Lactobacillus acidophilus, L. Rhamnosus, and Bifidobacterium lactis	Inulin	Probiotics: 1.0 × 109 CFU per day per mice, and prebiotic 5 × 108 CFU/d	Pathologic scores, mucosal flora	Increased the proportion of helpful bacteria and regulated the balance of intestinal microbiota, reduced the degree of inflammation in acute colitis mice
Son et al[85], 2019	DSS-induced colitis in female BALB/c mice	LGG	Tagatose	109 CFU/mL of LGG and 25 mg of tagatose once in 2 d for 3 wk	Body weight, food intake, rectal bleeding, stool conditions, blood in stool, expression of proinflammatory cytokines	Effective (gut microbiota composition recovered from the dysbiosis caused by DSS treatment)
Ivanovska et al[81], 2017	TNBS-induced colitis in Wistar rats	L. Casey 01	Oligofructose-enriched inulin	1 mL containing non-encapsulated probiotic/prebiotics once daily for 2 wk	Assessment of colonic damage, inflammation scoring, MPO and microbiological studies	Effective

DAI: Disease activity index; IL: Interleukin; TNF: Tumor necrosis factor; FOS: Fructooligosaccharides; GOS: Galactooligosaccharides; XOS: Xylooligosaccharides; CFU: Colony forming unit; DSS: Dextran sodium sulfate; MPO: Myeloperoxidase; LGG: L. rhamnosus strain; SCFAs: Short-chain fatty acids.

Table 6 Summary of clinical studies of using synbiotics in inflammatory bowel disease patients

Ref.	Probiotics	Prebiotics	Dose	Parameters analyzed	Conclusion
Amiriani et al[86], 2020	Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Bifidobacterium breve, Bifidobacterium longum, Streptococcus thermophiles	FOS	Lactocare capsule twice daily for 8 wk	DAI	Mitigated symptoms in patients with UC and suggested to use pre-probiotics in the standard treatment, particularly in those with more than five years of the disease
Kamarlı Altun et al[87], 2019	Enterococcus faecium, Lactobacillus plantarum, Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus, Bifidobacterium longum	FOS	3 × 109 CFU probiotic and 225 mg/tablet prebiotic for 8 wk	Hemoglobin, leukocyte, neutrophil-to-lymphocyte ratio, sedimentation, and CRP and clinical and endoscopic activity indices	Improvement in clinical activity

DAI: Disease activity index; FOS: Fructooligosaccharides; UC: Ulcerative colitis; CRP: C-reactive protein; CFU: Colony forming unit.