LGG Supplementation in Patients With AUD and ALD

By lowering heavy drinking to meet the criteria on the responder definitions of abstinence, no heavy drinking days, WHO 1-level, and WHO 2-level reduction

Timeline Followback for past 180 days \[Unit: numerical frequency\], AUDIT \[Unit: numerical frequency\], monthly drinking questionnaire \[Unit: numerical frequency\]).

By reducing relapse episodes to minimal/absent incident level

(Unit: incident frequency).

By showing a significant positive effect on one or more of the underlying neurobehavioral domains.

Questionnaires: reward (reasons for heavy drinking questionnaire or RHDQ \[Unit: numerical frequency\]), craving (Penn Alcohol Craving Scale or PACS, \[Unit: numerical frequency\]; and obsessive compulsive drinking scale or OCDS \[Unit: numerical frequency\]), withdrawal (Clinical Institute Withdrawal Assessment Alcohol Scale Revised \[CIWA-AR\] or CIWA-AR \[Unit: numerical frequency\]), and reinforcement effects (Desires for Alcohol Questionnaire or DAQ \[Unit: numerical frequency\]).

By lowering a biochemical marker of alcohol intake

PeTH (Unit: μmol/L)

By significantly improving liver related and clinical markers

Liver markers: Aspartate transaminases or AST (Unit: IU/L), Alanine Transaminases or ALT (Unit: IU/L), Albumin (Unit: g/dL), Total bilirubin (Unit: mg/dL), Creatinine (Unit: mg/dL), and INR (Unit: numerical), AST:ALT ratio (numerical unit), Prothrombin Time or PT (Unit: seconds). Clinical marker: Model For End-Stage Liver Disease or MELD (\[=0.957 × ln(Cr) + 0.378 × ln(bilirubin) + 1.120 × ln(INR) + 0.643\]. Unit: numerical), Maddrey's Discriminant Function for Alcoholic Hepatitis or Maddrey DF (\[=4.6 \* (Pt's PT - Control PT) + TBili\]. Unit: numerical). Laboratory markers: K18M65 and K18M30 (Unit for both: IU/L).

By substantially improving the overall health as assessed by the patient reported outcomes

Quality of Life or QOL scale \[Unit: numerical frequency\], Drinker inventory of consequences or DrInC \[unit: numerical frequency\].

By lowering frequency and intensity of treatment/disease based adverse effects (AE).

Incident frequency of AE \[Unit: numerical\], Severity Scale (AE/SAE (Unit: 1-5).

To determine the therapeutic-mechanistic markers of gut-brain axis, pro-inflammatory activity in AUD

1. By identifying the blood biomarkers of gut-barrier dysfunction and endotoxemia as assessed by: LPS \[Unit: EU/ml\], LBP \[Unit: ng/ml\], sCD14 \[Unit: x 10\^6 pg/ml\]. Serum Inflammation markers: IL1β, IL33, IL18, IL17, IL22, TNFα \[Units for all: pg/ml\]. 2. By determining the therapeutic targets of LGG involved in the gut-brain axis of AUD using LC-MS metabolomic fecal assays (candidate markers of gut-dysfunction associated neurotransmitters): Gamma Aminobutyric Acid or GABA \[Unit: pmoles/ml\], hexyl-2-methyl butyrate or HMBA (Unit: mmol/L), serotonin (Unit: ng/mL), dopamine (Unit: ng/ml), acetylcholine (Unit: nmol/L), tryptophan (Unit: umol/L), and short-chain fatty acids (Unit: mmol/L). Units can be relative in intensity (as fold-change). 3. By validating the efficacy of LGG treatment vs. placebo to lower inflammation using an ex-vivo design: Candidate WBC type derived Inflammation markers: IL1β, IL33, IL18, IL17, IL22, TNFα \[Units for all: pg/ml\].