Influence of nutrition interventions and the microbiome on gastrointestinal side effects during cancer and its treatment

Alzoubi, Zainab

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https://hdl.handle.net/2142/125740 Copy

Description

Title

Influence of nutrition interventions and the microbiome on gastrointestinal side effects during cancer and its treatment

Author(s)

Alzoubi, Zainab

Issue Date

2024-07-19

Director of Research (if dissertation) or Advisor (if thesis)

Loman, Brett R

Committee Member(s)

• Swanson, Kelly S
• Anakk, Sayeepriyadarshini

Department of Study

Nutritional Sciences

Discipline

Nutritional Sciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

M.S.

Degree Level

Thesis

Keyword(s)

• Cancer
• Cancer Therapy
• Systematic Review
• Fiber

Abstract

Cancer and its treatment cause gastrointestinal (GI) side-effects that can lead to malnutrition, cachexia, and body wasting overall compromising patient quality of life. As physicians mainly focus on addressing malnutrition, medical nutrition therapy (MNT) focusing on calorically dense options is encouraged. However, these dietary recommendations are not targeted to relieve the underlying symptoms causing malnutrition, leading to a vicious cycle of exacerbated GI symptoms. Diarrhea is a main symptom both present during cancer and its treatment which is mainly caused by bile acid (BA) malabsorption which further influences nutrient malabsorption. The primary objective of this research is to comprehensively evaluate dietary recommendations to ameliorate cancer therapy-induced GI side-effects, to evaluate the role of the enteric microbiota on exacerbating chemotherapy-induced GI side-effects, and to evaluate dietary fiber on relieving cancer-induced GI side-effects. To understand the scope of MNT on cancer-treatment induced GI side-effects, a systematic review and meta-analysis were conducted to evaluate specific nutrient supplementation, oral nutrition supplementation (ONS), and nutrition counseling. The search was conducted in Scopus and PubMed. All articles were screened against specific PICOS selection criteria, and 143 were included. Meta-analyses were conducted on both incidence using the odds risk ratio (ORR) and severity using standardized mean differences (Hedge’s G) of symptoms. ONS was not effective at reducing either GI symptom incidence or severity; p > 0.05. Nutrition counseling was effective at reducing diarrhea and constipation incidence; p < 0.001. No studies assessed counseling for reducing symptom severity. Nutrient supplementation was effective at reducing almost all symptoms incidence and severity. The incidence of diarrhea, abdominal pain, constipation, anorexia, nausea, vomiting, mucositis, and ileus; all p < 0.001. Similarly, nutrient supplementation was effective at reducing severity of oral pain, anorexia, and diarrhea; all p < 0.001. Further sub-analyses were conducted on nutrient supplementation to identify the specific nutrients driving the reduction in symptoms incidence and severity. The main nutrients that contributed to GI symptom reduction were probiotics, amino acids (glutamine), fatty acids (omega 3), minerals (zinc sulfate), herbs (ginger), and prebiotics. Probiotics were the most studied and effective nutrients at reducing a variety of GI symptoms including nausea incidence (p = 0.01), abdominal pain incidence (p < 0.001), diarrhea incidence (p < 0.001), mucositis severity (p < 0.001), and vomiting incidence (p = 0.02). Amino acids reduced diarrhea incidence (p = 0.04), mucositis incidence (p < 0.001) and severity (p < 0.001). Fatty acids reduced anorexia severity (p < 0.001) and nausea incidence (p < 0.001). Minerals reduced mucositis severity (p = 0.01) and incidence (p = 0.03). Herbs reduced diarrhea incidence (p = 0.04) and vomiting incidence (p < 0.001). Prebiotics reduced mucositis incidence (p = 0.01) and severity (p < 0.001). To isolate the effects of chemotherapy-induced microbial alterations on exacerbating GI symptoms, a gut microbial transplant (GMT) of cecal and colonic contents from chemotherapy and vehicle treated mice (N = 18; n = 9/group) to germ free mice (Chemo-GMT and Veh-GMT) (N = 18; n = 9/group) was used. Chemotherapy or vehicle treatment was conducted for two weeks, and GMT was conducted for one week in which endpoint tissue samples were collected at sacrifice. Liver pathology was evaluated using Hal’s bile stain to assess for bile accumulation which can be indicative of disrupted bile flow and the Trichrome stain was used to assess for collagen formation which could be indicative of fibrosis. Furthermore, expression of BA metabolizing genes was assessed in the liver, ileum, and distal colon. Chemotherapy-induced changes in microbial composition increased collagen formation (p < 0.05). Similarly, BA synthesis (Cyp7a1 and Cyp7b1), transport (Abcb1b), and receptor (Nr1h2) were decreased in the liver for Chemo-GMT mice compared to Veh-GMT; all p < 0.05. In the ileum, BA transporter (Slc10a2) and signaling molecule (Fgf15) were decreased in the Chemo-GMT; p < 0.05. In the distal colon, only proliferation marker (Ki-67) was increased in the Chemo-GMT; p < 0.05. To understand the effects of fiber on cancer-induced GI symptoms, a pre-clinical model using 67nR cells, mammary tumor cell line, was implanted into BALB/c mice for three weeks to replicate breast cancer. To isolate the effects of fiber, all nutrient content was kept consistent between the groups except the fiber content using a pair feeding paradigm. There were 5 different diet groups: fiber free diet (FFD), 20% cellulose (CELL), 10% inulin and 10% cellulose (INU), 10% beta-glucan and 10% cellulose (BG), 5% inulin with 5% beta-glucan and 10% cellulose (INU+BG). On the day of implant, all mice were assigned to one of the five diet interventions (N = 40; n = 8/group). Longitudinal fecal and serum samples were collected one day prior to tumor implant and every other day until point of sacrifice. Tissues were collected at the point of sacrifice. Percent fecal wet mass was assessed using longitudinal data. Fecal moisture was decreased in the INU and INU+BG groups compared to the FFD; p < 0.05. Fecal microbial antigenicity was assessed using TLR4 and TLR5 stimulating cell culture assays. Independent of fiber type, all fiber groups reduced TLR4 and TLR5 activation compared to FFD; p < 0.05. Systemic circulation of citrulline, a biomarker of functional intestinal epithelial mass, and LBP, a biomarker of intestinal barrier disruption was not different between any of the groups; p > 0.05. Endpoint data showed an increase of colonic mass in the INU, BG, and INU+BG groups compared to FFD; p < 0.05. All other organ masses were not different between the groups; p > 0.05. Intestinal barrier function and nutrient absorption was assessed using Ussing chambers by measuring transliteral epithelial resistance (TEER) and absorption rate (A/min). INU and BG increased jejunal and colonic resistance compared to FFD; p 0.05. However, only INU increased ileal resistance; p 0.05. INU and BG increased jejunal glucose and amino acid absorption compared to FFD; p 0.05. All fiber groups increased ileal BA absorption compared to the FFD; p 0.05. Overall, this data highlights the importance of how cancer and its treatment influence GI symptom prevalence through intestinal barrier damage and microbial alterations. During cancer therapy, probiotics are mainly studied and prove to be effective in reducing GI symptom incidence and severity as demonstrated in chapter 2 of the systematic review and meta-analysis. Chemotherapy induces changes in microbial composition that further disrupt BA metabolism uncovering a potential target for alleviating cancer treatment-induced GI symptoms as shown in chapter 3. Inulin, a soluble, fermentable fiber, may be a likely intervention to help alleviate cancer-induced GI symptoms through reducing fecal moisture mass and increasing intestinal barrier function.

Graduation Semester

2024-08

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/125740

Copyright and License Information

© 2024 Zainab Alzoubi

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