Table 1.

Effects of dietary fatty acids on intestinal microbiome in human and animal studies.

Author	Model	Fat Intake and Type	Microbiome Changes	Metabolomics Changes
Human studies—Infants
Younge et al. [115] 2017	Randomized, controlled trial in preterm infants with enterostomy due NEC or SIP	Fish oil or safflower oil compared to standard of care -The fish oil supplements (EPA, DHA, and Vit E) -Safflower oil (enriched in n6 LA) for a goal n6 to n3 fatty acid ratio of 3.75 to 5.1	↓ Proteobacteria ↓ Enterobacteriaceae ↑ Actinobacteria ↑ Enterococcus	-
Human studies—Adults
Vijay et al. [116] 2021	6-week randomized dietary intervention	n3 fatty acid supplementation -Daily supplementation with 500 mg of n3 (165 mg of EPA and 110 mg DHA)	↑ Coprococcus spp. ↑ Bacteroides spp. ↓ Collinsella spp. ↓ Ruminococcus	↑ Butyrate, iso-butyrate, isovalerate ↑ Total plasma n3 fatty acids
Watson et al. [3] 2018	8-week randomized, open-label, cross-over trial with 12-week washout	n3 PUFA supplements 2000 mg EPA and 2000 mg DHA per day in two formulations Four soft-gel capsules Smartfish Remune drinks	↑ Bifidobacterium ↑ Roseburia ↑ Lactobacillus ↓ Faecalibacterium	-
Kjolbaek et al. [117] 2020	Cross-over design with two diet periods of 4 weeks with 4-week washout period	Arabinoxylan oligosaccharides and PUFA cross-over Daily PUFA intake of approximately 10% increasing the intake of PUFA including n3 fatty acids and lowering SFA intake. fish oil capsules containing 3.6 g/d n3 PUFA (DHA and EPA)	No change	-
Fava et al. [118] 2013	Randomized trial in adult volunteers with at least two features of metabolic syndrome	Participants followed a 4-week reference diet and then were randomly assigned to the intervention arms for 24 weeks. Reference diet: high SFA diet/high glycemic index Intervention arm: -High MUFA/high glycemic index -High MUFA/low glycemic index -High carbohydrate/high glycemic index -High carbohydrate/low glycemic index	↓ Total bacteria in high MUFA groups ↓ Total bacteria in high SFA compared to baseline ↑ Faecalibacterium prausnitzii in high SFA compared to baseline	↑ Acetate, propionate, and n-butyrate in high SFA compared to baseline
Wan et al. [119] 2019	6-month randomized controlled-feeding Trial in healthy young adults with normal BMI	The three isocaloric diets: -low-fat diet (fat 20% energy) -moderate-fat diet (fat 30% energy) -high-fat diet (fat 40% energy)	Low-fat diet: ↑ Shannon diversity ↑ Blautia ↑ Faecalibacterium Moderate-fat diet: ↑ Bacteroidetes High-fat diet: ↓ Firmicutes ↑ Bacteroidetes ↓ Faecalibacterium ↑ Bacteroides	-
Pig
Che et al. [120] 2019	Piglets with intrauterine growth retardation	Diet contained either flaxseed oil (enriched in n3 PUFAs) compared to soy oil (high in n6)	↑ Actinobacteria ↑ Melainabacteria ↑ Bifidobacterium ↑ Blautia ↓ Spirochaetes	↓ Diarrhea ↑ villus height ↑ Ileal Claudin-1 and ZO-1 ↓ Ileal MyD88, NF-κB, TNF-α and IL-10
Anderson et al. [121] 2011	Piglet	Piglets were grouped into these treatments: -Fish oil (n3 LC-PUFA, providing 34% EPA and DHA in a 1:1 ratio) -Sunflower oil (n6 PUFA, 67% linoleic acid)	Fish oil diet: ↑ Proteobacteria ↑ Actinobacteria Sunflower oil diet: ↑ Bacteroides spp.	-
Mouse
Liu et al. [122] 2012	Adult mice	Regular rodent chow for 14 days, and then mice received one of the three treatment groups for 10.5 weeks -High SFAs (soybean oil and fully hydrogenated soybean oil) -High n3 PUFAs (flaxseed oil, principally αLA, small amounts of EPA and DHA). -High n6 PUFAs (soybean oil principally LA)	↓ Bacteroidetes-to-Firmicutes in all groups ↓ Bacteroidetes in all groups (more in SFA-rich group) ↓ Porphyromonadaceae in n6 PUFA-rich group ↓ Lachnospiraceae in SFA-rich group	-
Ghosh et al. [123] 2013	Adult mice	Mice were weaned onto two high-fat diets fed for 5 weeks. -High n6 PUFA (corn oil) -High n6 and n3 PUFA (corn oil and fish oil containing 0.5–1.8 g of EPA and DHA	High n6 PUFA: ↑ Enterobacteriaceae ↑ Clostridia spp. High n3 PUFA: ↑ Bifidobacteria ↑ Lactobacillus ↑ Enterococcus faecium	-
de Wit et al. [124] 2012	Adult mice	Standard chow for 3 weeks followed by a low-fat diet based on palm oil for 3 weeks. Then either maintained on the low-fat diet or received high-fat diets for 8 weeks on Palm oil, Olive oil, or Safflower oil	↑ Firmicutes members bacilli and clostridia ↓ microbiome diversity	↑ Fecal fat overflow (more in Palm oil diet) ↓ Fat absorption ↑ Intestinal SFA transport
Saeedi Saravi et al. [125] 2020	Old mice	Standard chow until 8–12 weeks of age. One group remained on standard chow and the other mice received modified diets until >18 months of age. -High αLA (7.3%) -Low αLA (0.03%)	High αLA diet: ↓ decreased Faith’s phylogenetic richness ↓ Ruminococcaceae ↓ Clostridiaceae ↓ Lachnoclostridium ↑ Bilophila	↑ Acetate ↓ Trimethylamine N-oxide
Marques et al. [126] 2015	Adult mice	The animals were divided into two groups and received the intervention for 8 weeks. -Standard diet -Standard diet supplemented with 0.5% trans-10, cis-12 conjugated linoleic acid	↓ Firmicutes ↓ Bacteroidetes ↓ Desulfovibrionaceae ↓ Peptococcaceae ↑ Porphyromonadaceae	↑ Acetate ↑ Propionate ↑ Isobutyrate
Ghezzal et al. [127] 2020	Adult mice	Three-month-old male were fed standard chow diet. High fat mice received with palm oil rich in saturated palmitic acid (about 45%) and unsaturated oleic acid (about 35%)	↓ Clostridium leptum ↓ Akkermansia muciniphila ↑ Bacteroides	↑ Intestinal permeability
Huang et al. [128] 2013	Adult male mice	Intervention arms included isocaloric high-fat diets, where the dietary fat consisted of: -Milk fat -Lard -Safflower oil (rich in PUFA)	↓ Bacteroides in all groups compared to low fat control ↑ Proteobacteria in milk fat and PUFA groups	-

↑ increase; ↓ decrease; SIP, spontaneous intestinal perforation; NEC, necrotizing enterocolitis; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; Vit E, vitamin E; PUFA, polyunsaturated fatty acid; MUFA, monounsaturated fatty acid; SFA, saturated fatty acid; ZO-1, zona occludens-1; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa B; TNF-α, tumor necrosis factor alpha; IL-10, interleukin 10.