From:  Towards personalized microbial therapies for metabolic alterations in celiac disease

 Microbial tools used for celiac disease treatment in human studies

StudyMicrobial toolMain outcomes
Gluten-degrading bacteria
Caminero et al. [118]Cultivable gut microbiotaThirty-five bacterial species were involved in gluten metabolism. The main genera were Lactobacillus, Streptococcus, Staphylococcus, Clostridium, and Bifidobacterium.
Francavilla et al. [119]Eighteen commercial strains of probiotic lactobacilliTen bacterial strains provided the peptidase repertory required to completely degrade the immunogenic gluten peptides involved in CeD.
Herrán et al. [62]Bacterial species isolated from duodenal biopsiesThirty-two bacterial species showed extracellular proteolytic activity against gluten protein. They were included within the genera Actinomyces, Bacillus, Bifidobacterium, Lactobacillus, Neisseria, Prevotella, Pseudomonas, Staphylococcus, Stenotrophomonas, Streptococcus, Veillonella, and Virgibacillus.
Moreno Amador et al. [120]A bacterial strain belonging to the species Chryseobacterium taeanense isolated from the rhizosphereThe strain showed the presence of prolyl endopeptidases and the hydrolytic capacity of the gluten immunogenic peptides. Glutenase activity was detected in the extracellular medium, where gel electrophoresis and gliadin zymography identified the presence of about 50 kDa gluten-degrading enzyme.
Probiotics
Francavilla et al. [121]N = 109 diagnosed patients with CeD with IBS
Treatment for 6 weeks
Probiotic cocktail: Lacticaseibacillus casei (L. casei), Lactiplantibacillus plantarum (L. plantarum), Bifidobacterium infantis (B. infantis) subsp. lactis, and Bifidobacterium breve (B. breve) (2 strains)		Gastrointestinal symptoms and the severity of IBS substantially decreased in the probiotic-treated group compared to the placebo. Lactic bacteria, Staphylococcus, and Bifidobacterium increased in patients receiving probiotic treatment.
Håkansson et al. [122]N = 78 children with CeD autoimmunity
Treatment for 24 weeks
Probiotics: L. plantarum strain HEAL9 and Lactocaseibacillus paracasei (L. paracasei) strain 8700:2		Daily oral administration of probiotics modulates the peripheral immune response in children with CeD autoimmunity. Over time, median levels of IgA-tTG decreased more markedly in the probiotic group compared to the placebo group, whereas an opposite trend was observed for IgG-tTG levels.
Harnett et al. [123]N = 45 diagnosed patients with CeD
Treatment for 12 weeks
Probiotic cocktail: VSL#3 consists of Streptococcus thermophilus, B. breve, Bifidobacterium longum (B. longum), B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, and Lactobacillus delbrueckii subsp. bulgaricus		The primary outcome indicated that the probiotic formulation did not result in significant alterations in the GM composition between baseline and week 12.
Jenickova et al. [124]N = 78 (40 genetically predisposed children having tTG autoantibodies and 38 healthy controls)
Treatment for 24 weeks
Probiotics: L. plantarum strain HEAL9 and L. paracasei strain 8700:2		The findings indicate a modest yet significant impact of probiotic supplementation on the fecal metabolome, primarily affecting proteolytic pathways within the gut. Over the six-month intervention period, stool concentrations of 4-hydroxyphenylacetate increased in the probiotic group compared to controls, whereas levels of amino acids such as threonine, valine, leucine, isoleucine, methionine, phenylalanine, aspartate, and the intermediate fumarate were reduced.
Klemenak et al. [125]N = 49 children diagnosed with CeD
Treatment for 12 weeks
Probiotics: B. breve strain BR03 and strain B632		Probiotic intervention using B. breve strains demonstrated a beneficial effect by reducing the production of the pro-inflammatory cytokine TNF-α in children with CeD adhering to a GFD.
Lionetti et al. [126]N = 96 children diagnosed with CeD
Treatment for 12 weeks
Probiotics: L. casei, L. plantarum, B. infantis subsp. lactis, and B. breve (2 strains) + GFD		Treatment with a multispecies probiotic resulted in a more rapid and pronounced increase in BMI among children newly diagnosed with CeD.
Olivares et al. [127]N = 36 children diagnosed with CeD
Treatment for 12 weeks
Probiotic: B. longum strain CECT 7347		Decreased peripheral CD3+ T lymphocytes and slightly reduced TNF-α concentration were obtained in the experimental group. Comparison between the groups revealed that the administration of probiotics reduced the numbers of the Bacteroides fragilis group and the content of sIgA in stools compared to the administration of a placebo.
Pinto-Sánchez et al. [128]N = 24 untreated CeD patients
Treatment for 6 weeks
Probiotic: B. infantis subsp. lactis strain NLS-SS		The patients treated with GFD for 1 year showed a decrease in duodenal macrophages, whereas probiotic treatment decreases Paneth cell counts and expression of α-defensin-5 in CeD patients.
Primec et al. [129]N = 40 children with CeD
Treatment for 12 weeks
Probiotics: B. breve strain BR03 and strain B632		Probiotic administration showed a negative relationship between Bacillota and pro-inflammatory TNF-α. In addition, probiotic effect exposed new phyla, particularly Synergistota, which negatively correlated to acetic acid and total SCFAs, indicating a potential role in microbiome restoration.
Quagliariello et al. [130]N = 40 children with CeD
Treatment for 12 weeks
Probiotics: B. breve strain BR03 and strain B632		The effects of the probiotics produce an increase in members of the phylum Actinomycetota and a re-establishment of the physiological Bacillota/Bacteroidota ratio.
Synbiotics
Tremblay et al. [131]Commercial Synbiotic: probiotics Lactocaseibacillus helveticus strain Rosell®-52, B. infantis subsp. lactis strain Rosell®-33, and Bifidobacterium. bifidum strain Rosell®-71 with the prebiotic fructooligosaccharidesA review of twelve studies demonstrated that synbiotic administration significantly enhances the efficacy of standard diarrhea treatments, independent of the underlying etiology. In eight of these studies, synbiotic use was associated with improved immune function, as evidenced by increased levels of various immune competence and mucosal immunity markers, alongside a reduced incidence of common infections. Furthermore, probiotic supplementation was found to improve the therapeutic outcomes of iron deficiency anemia.
Postbiotics
Freire et al. [132]Patient-derived organoids monolayers. Microbiota-derived bioproducts from Bacteroides fragilis, including butyrate, lactate, and polysaccharide AMonolayers derived from CeD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to non-celiac controls. Microbiota-derived bioproducts, butyrate, lactate, and polysaccharide A, improved barrier function and reduced gliadin-induced cytokine secretion. These bioproducts can be used to modulate the epithelial response to gluten.
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BMI: body mass index; CeD: celiac disease; GFD: gluten-free diet; GM: gut microbiome; IgA: immunoglobulin A; tTG: tissue transglutaminase; IBS: irritable bowel syndrome; SCFAs: short-chain fatty acids; sIgA: secretory IgA; TNF-α: tumor necrosis factor alpha