Introduction

Although the exact mechanism of metabolic dysfunction-associated steatotic liver disease (MASLD) development is unknown, new research indicates that the gut microbiota may significantly impact the disease's progression through one of its most vital functions—the synthesis of butyrate. Animal models have already demonstrated the positive effects of butyrate administration, but no studies have yet investigated the possible impact of oral butyrate supplementation in the population of MASLD patients.

Aims & Methods

We conducted an interventional study of 177 individuals diagnosed with MASLD. MASLD was defined by a baseline attenuation coefficient (ATT) obtained by point shear-wave elastometry (pSWE) of 0.63 dB/cm/MHz or higher and a baseline alanine-aminotransferase (ALT) of more than 40 IU/L. After diagnosis was made, a total of 121 patients were administered 1000 mg of calcium butyrate, whereas 56 patients were treated with 1000 mg of sodium butyrate. Patients were prescribed a Mediterranean diet regimen, which required an intake of 20–30 kilocalories per kilogram of body weight, split between 35–40% fat, 20% protein, and 40–45% carbs. At the start of the investigation, patients were requested to provide stool samples for stool short chain fatty acids (SCFA) analysis and blood samples for miRNA panel (miR-192, miR-885, miR-122) analysis. We also followed the elastometry parameter, ALT, lipidogram, high-sensitive C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α), interleukin-1, interleukin-6, and cytokeratin-18 dynamics during the 12-week treatment period.

Results

We did not observe a significant effect of butyrate supplementation on the level of liver steatosis (baseline vs. endpoint ATT- 0.78 vs 0.76 dB/cm/MHz, p=0.33) and ALT (baseline vs. endpoint ALT 72 vs 73 IU/L, p=0.58). No significant effects were observed in inflammatory markers or lipidogram dynamics. Neither calcium- nor sodium-butyrate showed superiority. However, the benefit of butyrate supplementation was observed in the population of patients with MASLD and body mass index below 25 kg/m2 (baseline vs. endpoint ATT 0.80 vs 0.77 dB/cm/MHz, p=0.043; baseline vs endpoint hsCRP 3.7 vs. 2.4 mg/L, p<0.001), baseline SCFAs below 20 μmol/g (baseline vs. endpoint ALT 78 vs. 74 IU/L, p=0.0142; baseline vs. Endpoint ATT 0.84 vs. 0.78 dB/cm/MHz, p=0.002), baseline hsCRP levels above 10 mg/L (baseline vs. endpoint hsCRP 14.6±3 vs. 6.4±1.4 mg/L, p<0.001) and patients with upregulated miR-192 (baseline vs endpoint TNFα 30.4 vs. 24.6 pg/ml; baseline vs. endpoint cytokeratin-18 229 vs. 211 U/L, p=0.025).

Conclusion

Oral butyrate supplementation could benefit selected groups of patients with MASLD, especially in lean, those with higher inflammatory status, or low stool SCFAs.

Introduction

The only effective treatment for celiac disease (CD) is lifelong compliance with a gluten-free diet. Lactobacilli and Bifidobacterium spp. may play a role in the breakdown of gluten. Ithas been demonstrated that Lactobacilli can detoxify gliadin peptides after partial digestion by human proteases. These findings could suggest the use of probiotics as complementary therapy for CD.

Aims & Methods

We designed a study to determine the potential effect of a combination of Lactobacillus (acidophilus HA-122, casei HA-108) and Bifidobacterium bifidum HA-132 on perception of symptoms and on the inflammatory-immunological markers in patients with active CD.
25 adult patients were randomized to receive bid of a probiotic combination of Lactobacilus and Biffidobacter for six weeks (13 pts) va a placebo group (12 pts) while being on gluten-free diet. Laboratory studies included routine blood tests, CD specific antibodies, determination of IL-1b, IL-6 and TNF-alpha. CD serology and duodenal histology were performed at baseline, at the end of treatment and at 30 days after therapy. Histological damage in intestinal biopsy samples was graded according to the Marsh modified classification. At baseline and follow-up visit, patients completed the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Histological damage in intestinal biopsy samples was graded according to the Marsh modified classification.

Results

25 pacients, 13 in the probiotic associated arm, 12 in the placebo arm, with median age of 40, BMI 21.2, 18 with symptomatic CD (equal distribuited) and 7 with sublinical CD (4 in the probiotic arm, 9 in the placebo arm). Baseline serology: IGA tTG 1986.6 (group A) vs 1507.1 (placebo group). Baseline hystology (Marsh classification)- Marsh 3a 1 pacient in probiotic group, 2 in the placebo arm. 5 pts Mars 3b3 in group A and 2 in the placebo arm and 17 pts Marsh 3c (9 pts probiotic, 8 pts placebo). IELs density (mean range) was 44.5 in the first group vs 42.5
After treatment: clinical aleviation of indigestion and diareea (p=0.002), constipation (p=0. 0396), gastro-esophageal reflux (p=0.0493) and abdominal pain (p=0.0378)-superior in the probiotic associated treatment.
Serologic parameters: IgA tTG 0,96 in the probiotic arm vs 1,16 in the placebo (p=0.048), IgA EMA 1,05 vs 0,97 (p=0.028), IgG DGP 0,91 vs 1,12 (p=0.21).
Improvement of the inflamatory status: decrease of IL-1b, IL 6 and TNF-a was superior in the probiotic associated group (p=0.071, p=0.083, p=0.078).
Regarding the histologic response: IELs 0,83 vs 1.07 in the placebo arm (p=0.049).

Conclusion

Tests and the lymphocyte infiltrates in the mucosal biopsy specimen in uur study suggests that prebiotic/probiotic treatment may improve symptoms and serology in celiac disease.

Disclosure

I don t have any conflict of interest to declare

Introduction

Small intestinal bacterial overgrowth (SIBO) is frequent in patients with past or active upper GI cancer. SIBO is associated with clinical symptoms including, bloating and diarrhea that may impact negatively on quality of life. Current treatment of SIBO is empirical and relies on the cyclical use of antibiotics.

Aims & Methods

The aim of the present study was to characterize the microbiome composition of patient with upper GI cancer with or with no SIBO.
From April 2021 to May 2022, consecutive patients with past or active GI cancer attending our oncology outpatient department were enrolled in a prospective case control study. Treatment naïve patients with a first diagnosis of upper GI cancer but no SIBO-related symptoms served as controls. All included patients completed a standardised questionnaire about SIBO-related symptoms (bloating, diarrhoea), concomitant medications, and quality of life. They were offered upper endoscopy with duodenal aspirate, provided a 30-day period with no antibiotic intake. SIBO was defined as a bacterial count greater than 10³ colony forming units per millilitre in the duodenal aspirate. Using optimized protocol, the DNA from duodenal aspirate was extracted and the V1-V2 region of the 16S rRNA gene was amplified by PCR and sequencing using the Illumina platform. Dedicated bioinformatical approach was used for the multifactorial sample analysis.

Results

The microbiome composition was analyzed in 7 controls, 17 patients with SIBO and 12 with no SIBO.
We detected 513 phylotypes from 71 genera belonging to 11 phyla in the duodenal aspirate. The most abundant genera were Streptococcus, Veillonella and Prevotella. All three groups differed significantly in terms of their microbiome at phylum level (PERMANOVA p < 0.05). Based on the analysis of the individual phyla, we were able to show that the abundance of Proteobacteria was significantly higher in the SIBO group (Kruskal-Wallis test p < 0.05). Correlation analyses revealed an association between bacterial abundance and clinical phenotype. For instance, Proteobacteria, correlated positively with diarrhea intensity (Spearman r=0.35, p= 0.0362), and that Bacteroidetes correlated negatively with the reduction in quality of life (Spearman r=-0.4525, p=0.0056). Within the overall cohort, we were able to identify two clusters characterized by different microbial composition, underlying malignant diseases and clinical symptoms.

Conclusion

Among patients with upper GI cancer, the microbiome composition of the duodenal aspirate of patients with SIBO was different compared to patients with no SIBO and controls. Microbiome composition profiling may offer the opportunity for a personalized treatment in patients with SIBO.

Introduction

Nowadays the use of a gluten-free diet (GFD) is erroneously considered a healthy life choice worldwide, despite evidence supports its beneficial effect only in the treatment of celiac disease and, possibly, gluten sensitivity. GFD can modify microbiota composition, decreasing specifically bacterial species involved in polysaccharides metabolism and short chain fatty acids (SCFAs) production. In fact, a GFD usually show a lower carbohydrate composition with an increase of dietary fats, and a fiber intake significantly below the recommended range. In this study, we investigated whether the amount of daily intake complex carbohydrates during GFD was associated with the reduction of microbial richness and species’ relative abundance.

Aims & Methods

We enrolled 36 healthy subjects and randomly assigned to a self-made GFD (SGFD) regimen (n=23, yrs=35±14) or to a GFD under nutritional supervision (NGFD) that ensured 60% of daily dietary carbohydrates intake (n=13; 29±12 yrs). A total of 144 fecal samples were collected at day 0, and 3, 7, 30 days during GFD, sequenced via shotgun metagenomic and profiled via bioBAkery 3. Data were analyzed on MetaPhlAn 4.0 and HUMAnN 3.0 for taxonomic and functional profiling. Alpha-diversity (Shannon index, SI) and relative abundances were computed. Only species detectable in least 5 subjects were considered (600 species). Statistical analysis was performed using a linear mixed model and Friedman’s ANOVA. P-values were combined and corrected for multiple hypothesis testing (q-value).

Results

Alpha-diversity did not significantly change during 30 days of GFD in both groups.
However, 14 and 10 species significantly changed in their relative abundance in the SGFD and NGFD groups,respectively. We observed a decrease of Bifidobacterium longum (SGB17248) and Candidatus Cibionibacter quicibialis (SGB15286) (q<0.05) with no intergroup differences. SGFD showed a decrease of butyrate producing species, i.e. Dorea longicatena and Anaerobutyricum hallii.

Conclusion

During GFD, microbial alpha-diversity preservation is independent from the daily carbohydrate intake.However, we identified consistent modifications in microbial relative abundances that partially differ in the two groups. The NGFD group showed a significant decrease in five Bifidobacterium species’ bacteria. Bifidobacteria are functionally linked to complex carbohydrate metabolism and associated with immunomodulatory properties. Despite we cannot point out specific role for gluten or carbohydrate intake in the microbiota’s richness variation, healthy subjects should not be encouraged to follow a GFD for its negative effects on gut health.

References

Melini, Valentina; Melini, Francesca (2019). Gluten-Free Diet: Gaps and Needs for a Healthier Diet. Nutrients, 11(1), 170–. doi:10.3390/nu11010170
Jones AL. The Gluten-Free Diet: Fad or Necessity? Diabetes Spectr. 2017 May;30(2):118-123. doi: 10.2337/ds16-0022. PMID: 28588378; PMCID: PMC5439366.
Gessaroli M, Frazzoni L, Sikandar U, Bronzetti G, Pession A, Zagari RM, Fuccio L, Forchielli ML. Nutrient intakes in adult and pediatric coeliac disease patients on gluten-free diet: a systematic review and meta-analysis. Eur J Clin Nutr. 2023 Aug;77(8):784-793. doi: 10.1038/s41430-023-01280-0. Epub 2023 Mar 1. PMID: 36859658.
Hansen, L.B.S., Roager, H.M., Søndertoft, N.B. et al. A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults. Nat Commun 9, 4630 (2018). https://doi.org/10.1038/s41467-018-07019-x

Introduction

Data on Intestinal Ultrasonography (IUS) in ulcerative colitis (UC) are growing especially in monitoring colonic lesions after therapies. Ultrasonographic parameters derived from studies in Crohn’s disease populations.

Aims & Methods

Aim of our multicenter study was to define IUS parameters of normality and activity in UC patients compared to a healthy control group (HC). Secondary aim was to evaluate severity of colonic lesions using endoscopy as reference standard.
From July 2022 to Oct. 2023, we conducted a multicenter study at 6 IBD centers. Patients (pts) with UC and indication to perform colonoscopy were longitudinally enrolled. HC [no gastrointestinal symptoms, no anemia and normal fecal calprotectin (FC)] were enrolled to establish normal values. The analysis was performed per patient and per segment evaluating colonic wall thickening (CWT), colonic wall flow, Milan Ultrasound Criteria (MUC), Mayo endoscopic score (MES) and partial/full Mayo score. The sample size for UC cohort and HC, the area under (a ROC) curve, Spearman’s correlation among clinical data, FC, IUS and endoscopy were calculated.

Results

180 UC patients and 80 HC were enrolled. In the UC cohort, 53% were male with a median age of 40 years (range 18-78), 64% had extensive colitis and 36% had left colitis. In the HC, 44% were male with a median age of 29 years (range 19-70). Median CWT in comparison to MES in UC patients and median CWT in HC were shown in Table 1. Rectum wall thickening showed higher values than other colonic segments. A CWT> 2.75 mm showed a sensitivity, specificity, NPV and PPV of 54%, 96%, 48% and 97%, respectively, in differentiating UC patients from HC [AUC=0.72]. A rectum wall thickening >4.55 mm showed a sensitivity, specificity, NPV and PPV of 67%, 84%, 56% and 89%, respectively, in differentiating UC patients from HC [AUC=0.82]. A CWT> 3.5 mm showed a sensitivity, specificity, NPV and PPV of 57.4%, 94.3%, 86% and 78%, respectively, in differentiating activity from remission in UC patients [AUC=0.84]. A rectum wall thickening >5 mm showed a sensitivity, specificity, NPV and PPV of 57.5%, 85.7%, 41% and 92%, respectively, in differentiating UC rectal activity from remission [AUC=0.81]. The correlation of the CWT or MUC vs MES was better than clinical data and FC.

Conclusion

Introduction

Iron deficiency (ID) and iron deficiency anaemia (IDA) are common complications of inflammatory bowel diseases (IBD). Ferric maltol is an oral iron therapy which increased haemoglobin within 12 weeks and sustainably improved the quality of life in patients with IBD and IDA. [1,2] While IDA is also frequently associated with pregnancy [3], there is no available data on the efficacy and safety of ferric maltol in pregnancy or in pregnant women with ID/IDA.

Aims & Methods

This study documented the first known clinical experience of ferric maltol in pregnant women with IBD and either ID or IDA. Retrospective clinical data from January 2017 to February 2023 in the MVZ Immunology database included pregnant patients with a confirmed diagnosis of IBD and treatment with ferric maltol during their pregnancy. The following patient data were collected: haematological parameters [haemoglobin (Hb), transferrin saturation level (TSAT), soluble transferrin receptor (stfR), ferritin], biomarkers for intestinal inflammation (calprotectin) and safety data. Descriptive results are reported here.

Results

A total of 27 female IBD patients with ID/IDA were included in this analysis, 11 with ulcerative colitis and 16 with Crohn's disease. The mean age was 35.9 years. A total of 29 pregnancies were treated with ferric maltol therapy (two patients had two pregnancies during this period). Prescriptions started after a mean of month 5 of pregnancy. In the course of most pregnancies, dosing was one capsule daily, as patients tended to have mild anemia. The number of prescribed boxes (56 capsules of ferric maltol: one capsule twice a day) per pregnancy was 1 in 82.8% [24/29], 2 in 13.8% [4/29], and 3 in 3.4% [1/29]. Nine cases with Hb < 11g/dl did take two capsules per day. After FM therapy, mean Hb levels increased from 11.3 to 12.36 g/dl (4-7 months), mean stfR levels increased from 1.2 to 1.5 mg/l, and mean ferritin levels increased from 27.2 to 30.0 ng/l, while mean TSAT decreased slightly from 17% to 15.4% (Table). Two patients developed side effects: One had new onset of abdominal pain shortly after starting, one had abdominal pain and increased meteorism. Both patients discontinued ferric maltol treatment and complaints then stopped. At the time of the current analysis, all 27 completed pregnancies proceeded without complications and ended with healthy neonatal infants without abnormalities. Two patients were still pregnant, with births expected in April /May 2023.

Conclusion

These first clinical data on the use of ferric maltol in pregnancy suggest that ferric maltol appears to have a favourable safety profile with few side effects for pregnant patients with IBD and ID/IDA.

References

1. Gasche C, et al. Inflamm Bowel Dis. 2015, 21(3):579-88
2. J.P. Gisbert1, et al. UEG Journal 2022, Vol 10 (S8), MP323, p359
3. Lopez A, et al. Lancet. 2016, 387(10021):907-16

Disclosure

Stefanie Howaldt has served as a speaker or has received research or education funding or advisory fees from MSD, AbbVie, Biogen, Celltrion, Hospira, Takeda, Pfizer, Pharmacosmos, Janssen, R-Biopharm, Norgine, Sandoz, and Shield Therapeutics. Angela Schüller has no conflicts of interest.